Methods of treating pemphigus by administering (r)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile

Abstract

To provide a method for treating pemphigus in a human patient in need thereof.SOLUTION: A method for treating pemphigus comprising administering to a human patient a dose of at least 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once a day (QD) or twice a day (BID).SELECTED DRAWING: Figure 11

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 62 / 913,029, filed October 9, 2019, and U.S. Provisional Application No. 62 / 942,877, filed December 3, 2019, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention provides a method for treating pemphigus, such as pemphigus vulgaris (PV) or pemphigus foliaceus (PF), in a human patient in need thereof by administering (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile to the human patient. Disclosed herein are methods of treating smallpox, for example, methods that include administering to a patient a once daily (QD) or twice daily (BID) dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. Also disclosed herein is a method of achieving a particular outcome in a population of human patients being treated for pemphigus, comprising administering to each member of the human patient population (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. [Background technology]

[0003] Bruton's agammaglobulinemia tyrosine kinase (BTK) is an essential signaling element downstream of the B cell receptor (BCR), Fc-gamma receptor (FcγR), and Fc-epsilon receptor (FcεR). BTK is a non-receptor tyrosine kinase and a member of the TEC family of kinases. BTK is essential for B cell lineage maturation, and inhibition of BTK activity in cells results in phenotypic changes consistent with BCR blockade. Illustratively, BTK inhibition results in downregulation of various B cell activities, including cell proliferation, differentiation, maturation, and survival, as well as upregulation of apoptosis.

[0004] Rather than acting in an "on / off switch" fashion, BTK can best be viewed as an immune function "modulator" (Non-Patent Document 1; Non-Patent Document 2). Important insights into BTK function have been gained from loss-of-function analyses in humans and mice. Individuals with loss-of-function mutations in the BTK gene develop X-linked agammaglobulinemia (XLA), a condition characterized by a complete absence of circulating B cells and plasma cells and very low levels of all classes of immunoglobulins (Non-Patent Document 3; Non-Patent Document 4). This suggests that BTK inhibition may suppress the production of autoantibodies that are thought to be important in the development of autoimmune diseases such as pemphigus vulgaris (PV).

[0005] Although BTK is not expressed in T cells, natural killer cells, and plasma cells and has no traceable direct function in T cells and plasma cells (Non-Patent Document 5; Non-Patent Document 6), this enzyme also regulates the activation of other hematopoietic cells, such as basophils, mast cells, macrophages, neutrophils, and platelets. For example, BTK plays a role in neutrophil activation. Neutrophils are important players in the inflammatory response that contributes to wound healing, but can also cause tissue damage (Non-Patent Document 7).

[0006] Therefore, selective BTK inhibitors have the potential to target multiple pathways involved in inflammation and autoimmunity, including modulating BCR-mediated B cell pathways and inhibiting FcγR-induced cytokine release from monocytes and macrophages, FcεR-induced mast cell degranulation, granulocyte migration, and mediator release. Based on these effects, selective BTK inhibitors could block the initiation and progression of various inflammatory diseases and reduce the tissue damage caused by these diseases. While individuals with loss-of-function mutations in the BTK gene have reduced humoral immunity and are susceptible to pyogenic and enteroviral infections that require treatment with intravenous immunoglobulin, inhibition of BTK in individuals with intact immune systems is not expected to result in similar susceptibility to infection.

[0007] Pemphigus is a rare B cell-mediated autoimmune disease that causes debilitating intraepithelial blisters and erosions on the skin and / or mucous membranes. The characteristic intraepithelial blisters observed in pemphigus patients are caused by IgG autoantibodies binding to specific keratinocyte desmosomal adhesion proteins, desmogleins 1 and 3 (Dsg1 and Dsg3), resulting in loss of cell adhesion (Non-Patent Document 8; Non-Patent Document 9). For example, PV is caused by autoantibodies against epidermal proteins.

[0008] Pemphigus affects approximately 0.1–0.5 / 100,000 people annually and typically has a 10% mortality rate due to infections arising from damaged tissue and side effects of treatment (Non-Patent Document 10; Non-Patent Document 11). Because pemphigus is a chronic disease with no cure, most pemphigus patients have pre-existing conditions. The current standard of care for first-episode pemphigus is high-dose corticosteroids (CS) (0.5–1.5 mg / kg / day) (Non-Patent Document 12), either alone or in combination with other immunosuppressants such as rituximab, mycophenolate mofetil, or azathioprine (Non-Patent Document 13). For example, PV responds acutely to the anti-inflammatory effects of corticosteroids and responds to B-cell depletion with anti-CD20 therapy within 5–35 weeks (Non-Patent Document 14).

[0009] Rituximab, a chimeric monoclonal antibody against the B-cell surface marker CD20, was recently approved by the FDA and European Medicines Agency (EMA) for the treatment of moderate to severe pemphigus vulgaris (PV) based on studies in newly diagnosed patients demonstrating improved steroid-free / treatment-free complete remission (CR) rates compared with CS alone (NPL 15; NPL 16; NPL 17). However, patients treated with rituximab still require moderate to high steroid doses (0.5–1.0 mg / kg / day) for 2–3 months before steroid tapering is initiated, and no randomized controlled studies have evaluated the efficacy of rituximab in relapsed patients or patients with pemphigus foliaceus (PF). Other pemphigus treatments, such as intravenous immunoglobulin (IVIG), plasma exchange, and extracorporeal photochemotherapy (NPL 18), have some benefit but have not yet been evaluated in randomized controlled trials or large patient populations (NPL 19; NPL 20). Therefore, there is a great need for fast-acting, steroid-sparing, easily administered immunomodulatory therapies with improved safety profiles.

[0010] B cells play a key role in the production of autoantibodies and cellular tolerance mechanisms involved in pemphigus pathology, and therefore represent an attractive target for the treatment of pemphigus. For example, BTK inhibition is an attractive therapeutic strategy for pemphigus.

[0011] Several orally administered BTK inhibitors (BTKi), including ibrutinib (PCI-32765) and spebrutinib (CC-292), are currently marketed or approved for various indications. Currently in clinical development for BTK-targeted diseases (Non-Patent Document 21). For example, ibrutinib provides further clinical validation of the BTK target and was recently approved by the U.S. Food and Drug Administration (FDA) for human use in mantle cell lymphoma, Waldenstrom's macroglobulinemia, and chronic lymphocytic leukemia, demonstrating activity in other hematological malignancies (Non-Patent Document 22, Non-Patent Document 23, Non-Patent Document 24). Additionally, CC-292 has been reported to be well tolerated in healthy volunteers at doses that result in 100% occupancy of the BTK enzyme (Non-Patent Document 25). Furthermore, evobrutinib recently demonstrated efficacy in multiple sclerosis in a phase 2 trial (Non-Patent Document 26). Other BTKi compounds are in clinical development for various immune-mediated disorders, such as immune thrombocytopenia (NCT03395210), rheumatoid arthritis (NCT03823378, NCT03682705, NCT03233230), and asthma (NCT03944707) (Non-Patent Document 26; Non-Patent Document 27; Non-Patent Document 28; Non-Patent Document 29; Non-Patent Document 30; Non-Patent Document 31; Non-Patent Document 32). [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Crofford LJ et al., 2016 [Non-patent document 2] Pal Singh S et al., 2018 [Non-patent document 3] Tsukada 1993 [Non-patent document 4] Vetrie 1993 [Non-Patent Document 5] Sideras and Smith 1995 [Non-patent document 6] Mohamed et al., 2009 [Non-Patent Document 7] Volmering S et al., 2016 [Non-patent document 8] Amagai M et al., 2012 [Non-Patent Document 9] Diaz LA et al., 2000 [Non-Patent Document 10] Scully et al., 2002 [Non-Patent Document 11] Scully et al., 1999 [Non-Patent Document 12] Murrell DF et al., 2018 [Non-Patent Document 13] Kasperkiewicz M et al., 2017 [Non-Patent Document 14] Horvath et al., 2012 [Non-Patent Document 15] Joly P et al., 2017 [Non-Patent Document 16] RITUXAN Prescribing Information [Non-Patent Document 17] Cianchini et al., 2007 [Non-Patent Document 18] Harman KE et al., 2017 [Non-Patent Document 19] Amagai M et al., 2009 [Non-Patent Document 20] Martin LK et al., 2009 [Non-Patent Document 21] Lee A et al., 2017 [Non-Patent Document 22] Wang 2013 [Non-Patent Document 23] Byrd 2013 [Non-Patent Document 24] Imbruvica Package Insert, 2015 [Non-Patent Document 25] Evans 2013 [Non-Patent Document 26] Montalban X et al., 2019 [Non-Patent Document 27] Norman P 2016 [Non-patent document 28] Tam CS et al., 2018 [Non-Patent Document 29] Crawford JJ et al., 2018 [Non-Patent Document 30] Min TK et al., 2019 [Non-Patent Document 31] Gillooly KM 2017 [Non-Patent Document 32] Nadeem A et al., 2019 Summary of the Invention [Problem to be solved by the invention]

[0013] Covalent BTKis such as ibrutinib and acalabrutinib have ameliorated the selectivity issues that plagued many first-generation kinase inhibitors, but these inhibitors are typically irreversible, causing permanent modification of both on- and off-target kinases and side effects such as thrombocytopenia, anemia, platelet aggregation, and hepatotoxicity (RITUXAN Prescribing Information, 2018; Drug Record Kinase Inhibitors, 2019; Khan Y et al., 2019; Paydas S, 2019; IMBRUVICA, 2013; Rigg RA et al., 2016; Tang CPS et al., 2018). Therefore, there is a need for BTKi-based treatments with reduced side effects for immune-mediated diseases such as pemphigus.

[0014] Compound (I) has the following structure: [ka] (wherein *C is a stereochemical center). See PCT Publication No. WO2014 / 039899, ​​e.g., Example 31, which is incorporated herein by reference.

[0015] The following structure: [ka] (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, also known as PRN1008 and rilzabrutinib. This compound has been disclosed in several patent publications, such as PCT Publication Nos. WO2014 / 039899, ​​WO2015 / 127310, WO2016 / 100914, WO2016 / 105531, and WO2018 / 005849, the contents of each of which are incorporated herein by reference.

[0016] PRN1008 inhibits the B cell receptor, FcγR, and / or FcεR pathways PRN1008 is a novel, highly selective, small-molecule inhibitor of non-T cell leukocyte signaling via signal transduction. PRN1008 functions as a reversible covalent BTK inhibitor, forming both non-covalent and covalent bonds with its target, allowing for enhanced selectivity and prolonged inhibition. Compared to first- and second-generation BTKis, PRN1008 exhibits minimal cross-reactivity with other molecules and a low risk of off-target effects (Smith PF et al., 2017). Importantly, PRN1008's reversible binding minimizes the likelihood of permanently modifying the peptide (Serafimova IM 2012).

[0017] PRN1008 has shown encouraging results for the treatment of immune-mediated diseases. PRN1008 is the most advanced BTKi in development for autoimmune diseases (Phase 3, NCT03762265) and the first BTKi evaluated for the treatment of pemphigus. In a Phase 1 study of PRN1008 in 114 healthy volunteers, target BTK occupancy levels were consistently exceeded without incident, suggesting that PRN1008 may be highly effective in human pemphigus and other autoimmune diseases. Furthermore, preclinical and clinical PK / PD data demonstrated that the treatment effect persists even after the compound has been cleared from the circulation, demonstrating prolonged target residence times (Hill R et al., 2015) and high occupancy rates (>90% within 4 hours) (Smith et al., 2016). This was consistent with PF et al., 2015).

[0018] PRN1008 also demonstrated a favorable safety profile. Based on preclinical reproductive toxicity studies, PRN1008 is not expected to harm fetal development or male fertility. In a Phase 1 study in healthy volunteers, the most commonly reported adverse events were gastrointestinal adverse events, including nausea / vomiting and diarrhea. No serious adverse events or deaths were reported, and no participants discontinued treatment due to adverse events (Smith PF, 2017).

[0019] As of January 18, 2018, PRN1008 had been administered to 21 patients with pemphigus (pemphigus vulgaris (PV) and pemphigus foliaceus (PF)), 18 of whom had received PRN1008 treatment for ≥4 weeks. PRN1008 was well tolerated in this study. Of the 18 patients with efficacy data, 11 (61%) met the primary endpoint of "control of disease activity" (CDA) at a corticosteroid (CS) dose of ≤0.5 mg / kg / day (low-dose CS) by the Week 5 visit. Three patients achieved CDA without CS. Two patients required temporary high-dose CS during PRN1008 treatment due to worsening disease activity. Four patients achieved complete remission (CR) with CS 1–20 mg / day, three of whom achieved CR at Week 13 (25%) and one of whom achieved CR at Week 21.

[0020] The efficacy of PRN1008 is mediated by three simultaneous mechanisms of action: anti-inflammatory effects, neutralization of pathogenic autoantibodies, and blocking autoantibody production. PRN1008 inhibits inflammatory cell activity in mast cells and neutrophils (Langrish C et al., 2019). It also neutralizes autoimmune responses by blocking signaling from the Fc region of antibodies and reduces autoantibody production by blocking B cell activation and maturation (Langrish C et al., 2019; Langrish CL et al., 2017). These effects occur without directly affecting T cells or causing B cell depletion. PRN1008 improved disease symptoms and outcomes in rats with collagen-induced arthritis (Hill R et al., 2015) and dogs with spontaneous PF (Murrell DF, 2019), suggesting that PRN1008 inhibits inflammation and reverses tissue damage (Langrish CL et al., 2017).

[0021] The results of a phase 2 study with PRN1008 for the treatment of PV and PF are discussed herein. [Means for solving the problem]

[0022] Disclosed herein is a method of treating pemphigus in a human patient in need thereof, comprising administering to the human patient a dose of at least 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for at least 14 days.

[0023] In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 14 to 168 days. In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 14 days. In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 28 days. In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 84 days. In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 168 days.

[0024] In some embodiments, the method comprises administering to a human patient a 400 mg dose of PRN1008 QD for at least 14 days.

[0025] In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 14 to 168 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 14 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 28 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 84 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 168 days.

[0026] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 once daily (QD) for 14 days; The human patient is administered a second dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days after the first dose. Includes:

[0027] In some embodiments, a human patient receives a second dose of 400 mg of PRN1008 BID for 14 to 154 days after administration of the first dose.

[0028] In some embodiments, PRN1008 is administered to a human patient for up to 168 days.

[0029] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 once daily (QD) for 14 days; administering to the human patient a second dose of 400 mg of PRN1008 twice daily (BID) for 14 days following administration of the first dose; The human patient receives a third dose of 600 mg of PRN1008 twice daily (BID) after the second dose. Includes:

[0030] In some embodiments, the human patient is administered a third dose of 600 mg of PRN1008 BID for up to 140 days after the second dose. In some embodiments, the human patient is administered a third dose of 600 mg of PRN1008 BID for up to 56 days after the second dose. It is administered for days.

[0031] In some embodiments, PRN1008 is administered to a human patient for up to 168 days.

[0032] In some embodiments, the methods comprise administering PRN1008 in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day).

[0033] In some embodiments, the first corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

[0034] In some embodiments, the human patient is characterized by naive or recurrent pemphigus prior to administration of PRN1008. In some embodiments, the human patient is characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the human patient is characterized by naive or recurrent pemphigus foliaceus prior to administration of PRN1008.

[0035] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points prior to administration of PRN1008.

[0036] In some embodiments, the human patient is characterized by a second corticosteroid maintenance dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day) prior to administration of PRN1008.

[0037] In some embodiments, the second corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

[0038] In some embodiments, the first corticosteroid is the same as the second corticosteroid. In some embodiments, the first corticosteroid is not the same as the second corticosteroid.

[0039] In some embodiments, PRN1008 comprises the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, PRN1008 comprises the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, PRN1008 comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

[0040] In some embodiments, the methods include treating pemphigus vulgaris.

[0041] In some embodiments, the methods include treating pemphigus foliaceus.

[0042] 1. A method of treating pemphigus in a human patient in need thereof, comprising administering to the human patient a dose of at least 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl] Also disclosed herein is a method of treating pemphigus, comprising administering [[[(2-methyl-2-yl)-pent-2-enenitrile](PRN1008) twice daily (BID) for at least 14 days.

[0043] In some embodiments, a human patient is administered a dose of at least 400 mg of PRN1008 BID for 14 to 84 days. In some embodiments, a human patient is administered a dose of at least 400 mg of PRN1008 BID for 14 days. In some embodiments, a human patient is administered a dose of at least 400 mg of PRN1008 BID for 28 days. In some embodiments, a human patient is administered a dose of at least 400 mg of PRN1008 BID for 84 days.

[0044] In some embodiments, the method comprises administering to a human patient a 400 mg dose of PRN1008 BID for at least 14 days.

[0045] In some embodiments, a human patient is administered a 400 mg dose of PRN1008 BID for 14 to 84 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 BID for 14 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 BID for 28 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 BID for 84 days.

[0046] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days; A human patient is administered a first dose followed by a second dose of 500 mg of PRN1008 twice daily (BID). Includes:

[0047] In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 14 to 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for more than 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 33 days.

[0048] In some embodiments, PRN1008 is administered to a human patient for up to 84 days.

[0049] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days; A human patient is administered a first dose followed by a second dose of 600 mg of PRN1008 twice daily (BID). Includes:

[0050] In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 14 to 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for more than 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 22 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 56 days.

[0051] In some embodiments, PRN1008 is administered to a human patient for up to 84 days.

[0052] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days; administering to the human patient a second dose of 500 mg of PRN1008 twice daily (BID) for at least 14 days following administration of the first dose; The human patient was administered a third dose of 600 mg of PRN1008 twice daily (BID) after the second dose. Includes:

[0053] In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 14 to 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for more than 28 days.

[0054] In some embodiments, a human patient receives a second dose of 500 mg of PRN1008 BID for 14 to 28 days after administration of the first dose.

[0055] In some embodiments, PRN1008 is administered to a human patient for up to 84 days.

[0056] In some embodiments, the methods comprise administering PRN1008 in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day).

[0057] In some embodiments, the first corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

[0058] In some embodiments, the human patient is characterized by naive or recurrent pemphigus prior to administration of PRN1008. In some embodiments, the human patient is characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the human patient is characterized by naive or recurrent pemphigus foliaceus prior to administration of PRN1008.

[0059] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points prior to administration of PRN1008. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points prior to administration of PRN1008.

[0060] In some embodiments, the human patient is characterized by a second corticosteroid maintenance dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day) prior to administration of PRN1008.

[0061] In some embodiments, the second corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

[0062] In some embodiments, the first corticosteroid is the same as the second corticosteroid. In some embodiments, the first corticosteroid is not the same as the second corticosteroid.

[0063] In some embodiments, PRN1008 comprises the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. ... In some embodiments, PRN1008 comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

[0064] In some embodiments, the methods include treating pemphigus vulgaris.

[0065] In some embodiments, the methods include treating pemphigus foliaceus.

[0066] Example embodiment 1: Without limitation, some embodiments of the present disclosure include: 1. A method of treating pemphigus in a human patient in need thereof, comprising administering to the human patient a dose of at least 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for at least 14 days. 2. The method of embodiment 1, comprising administering to the human patient a dose of at least 400 mg of PRN1008 QD for 14 to 168 days. 3. The method of embodiment 1 or 2, comprising administering to a human patient a dose of at least 400 mg of PRN1008 QD for 14 days. 4. The method of embodiment 1 or 2, comprising administering to the human patient a dose of at least 400 mg of PRN1008 QD for 28 days. 5. The method of embodiment 1 or 2, comprising administering to the human patient a dose of at least 400 mg of PRN1008 QD for 84 days. 6. The method of embodiment 1 or 2, comprising administering to the human patient a dose of at least 400 mg of PRN1008 QD for 168 days. 7. The method of embodiment 1, comprising administering to the human patient a dose of 400 mg of PRN1008 QD for at least 14 days. 8. The method of embodiment 1 or 7, comprising administering to a human patient a dose of 400 mg of PRN1008 QD for 14 to 168 days. 9. The method of any one of embodiments 1, 7, or 8, comprising administering to a human patient a dose of 400 mg of PRN1008 QD for 14 days. 10. The method of any one of embodiments 1, 7, or 8, comprising administering to a human patient a dose of 400 mg of PRN1008 QD for 28 days. 11. The method of any one of embodiments 1, 7, or 8, comprising administering to a human patient a dose of 400 mg of PRN1008 QD for 84 days. 12. The method of any one of embodiments 1, 7, or 8, comprising administering to a human patient a dose of 400 mg of PRN1008 QD for 168 days. 13. Administering to a human patient a first dose of 400 mg of PRN1008 QD for 14 days; The human patient is administered a second dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days after the first dose. 2. The method of embodiment 1, comprising: 14. The method of embodiment 13, comprising administering to the human patient a second dose of 400 mg of PRN1008 BID for 14 to 154 days following administration of the first dose. 15. Human patients will receive a first dose of 400 mg of PRN1008 QD for 14 days. Things and; administering to the human patient a second dose of 400 mg of PRN1008 twice daily (BID) for 14 days following administration of the first dose; Human patients were administered a third dose of 600 mg of PRN1008 BID after the second dose. 2. The method of embodiment 1, comprising: 16. The method of embodiment 15, comprising administering to the human patient a third dose of 600 mg of PRN1008 BID for up to 140 days following administration of the second dose. 17. The method of embodiment 15, comprising administering to the human patient a third dose of 600 mg of PRN1008 BID for 56 days after administration of the second dose. 18. A method of treating pemphigus in a human patient in need thereof, comprising administering to the human patient a dose of at least 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for at least 14 days. 19. The method of embodiment 18, comprising administering to the human patient a dose of at least 400 mg of PRN1008 BID for 14 to 84 days. 20. The method of embodiment 18 or 19, comprising administering to the human patient a dose of at least 400 mg of PRN1008 BID for 14 days. 21. The method of embodiment 18 or 19, comprising administering to a human patient a dose of at least 400 mg of PRN1008 BID for 28 days. 22. The method of embodiment 18 or 19, comprising administering to a human patient a dose of at least 400 mg of PRN1008 BID for 84 days. 23. The method of embodiment 18, comprising administering to the human patient a dose of 400 mg of PRN1008 BID for at least 14 days. 24. The method of embodiment 18 or 23, comprising administering to a human patient a 400 mg dose of PRN1008 BID for at least 14 to 84 days. 25. The method of any one of embodiments 18, 23, or 24, comprising administering to a human patient a dose of 400 mg of PRN1008 BID for 14 days. 26. The method of any one of embodiments 18, 23, or 24, comprising administering to a human patient a dose of 400 mg of PRN1008 BID for 28 days. 27. The method of any one of embodiments 18, 23, or 24, comprising administering to a human patient a dose of 400 mg of PRN1008 BID for 84 days. 28. Administering to a human patient a first dose of 400 mg of PRN1008 BID for at least 14 days; A human patient is administered a first dose followed by a second dose of 500 mg of PRN1008 BID. 19. The method of embodiment 18, comprising: 29. The method of embodiment 28, comprising administering to the human patient a first dose of 400 mg of PRN1008 BID for 14 to 28 days. 30. The method of embodiment 28, comprising administering to the human patient a first dose of 400 mg of PRN1008 BID for more than 28 days. 31. The method of embodiment 28, comprising administering to the human patient a first dose of 400 mg of PRN1008 BID for 33 days. 32. The method of any one of embodiments 28-31, wherein PRN1008 is administered to a human patient for up to 84 days. 33. Administering to a human patient a first dose of 400 mg of PRN1008 BID for at least 14 days; Human patients received a first dose followed by a second dose of 600 mg of PRN1008 BID. and 19. The method of embodiment 18, comprising: 34. The method of embodiment 33, comprising administering to the human patient a first dose of 400 mg of PRN1008 BID for 14 to 28 days. 35. The method of embodiment 33 or 34, comprising administering to the human patient a first dose of 400 mg of PRN1008 BID for 22 days. 36. The method of embodiment 33, comprising administering to the human patient a first dose of 400 mg of PRN1008 BID for more than 28 days. 37. The method of embodiment 33 or 36, comprising administering to the human patient a first dose of 400 mg of PRN1008 BID for 56 days. 38. The method of any one of embodiments 33-37, wherein PRN1008 is administered to a human patient for up to 84 days. 39. Administering to a human patient a first dose of 400 mg of PRN1008 BID for at least 14 days; administering to the human patient a second dose of 500 mg of PRN1008 BID for at least 14 days following administration of the first dose; Human patients were administered a third dose of 600 mg of PRN1008 BID after the second dose. 19. The method of embodiment 18, comprising: 40. The method of embodiment 39, comprising administering to the human patient a first dose of 400 mg of PRN1008 BID for 14 to 28 days. 41. The method of embodiment 39 or 40, comprising administering to the human patient a second dose of 500 mg of PRN1008 BID for 14 to 28 days after administration of the first dose. 42. The method of any one of embodiments 39-41, wherein PRN1008 is administered to a human patient for up to 84 days. 43. The method of any one of embodiments 1-42, comprising administering PRN1008 in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less. 44. The method of embodiment 43, wherein the first corticosteroid is selected from prednisone, prednisolone, and methylprednisolone. 45. The method of any one of embodiments 1-44, wherein the human patient is characterized by naive or recurrent pemphigus prior to administration of PRN1008. 46. ​​The method of any one of embodiments 1-45, wherein the human patient is characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008. 47. The method of any one of embodiments 1-46, wherein the human patient is characterized by naive or recurrent pemphigus foliaceus prior to administration of PRN1008. 48. The method of any one of embodiments 1 to 47, wherein the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points prior to administration of PRN1008. 49. The method of any one of embodiments 1-48, wherein the human patient is characterized by a second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less prior to administration of PRN1008. 50. The method of embodiment 49, wherein the second corticosteroid is selected from prednisone, prednisolone, and methylprednisolone. 51. The method of embodiment 49 or 50, wherein the first corticosteroid is the same as the second corticosteroid. 52. The method of embodiment 49 or 50, wherein the first corticosteroid is not the same as the second corticosteroid. 53.PRN1008 is (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1 53. The method of any one of embodiments 1-52, comprising the (E)-isomer of [4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 54. The method of any one of embodiments 1-52, wherein PRN1008 comprises the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 55. The method of any one of embodiments 1-52, wherein PRN1008 comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 56. The method of any one of embodiments 1-55, comprising treating pemphigus vulgaris. 57. The method of any one of embodiments 1-55, comprising treating pemphigus foliaceus. 58. The method of any one of embodiments 1-57, comprising reducing the average daily use of corticosteroids by a human patient. 59. The method of embodiment 58, comprising reducing the average daily corticosteroid use by a human patient by at least 20%. 60. The method of embodiment 58, comprising reducing the average daily corticosteroid use by a human patient by at least 50%. 61. The method of any one of embodiments 1-60, comprising healing confirmed pemphigus lesions. 62. The method of embodiment 61, comprising healing at least 50% of confirmed pemphigus lesions. 63. The method of any one of embodiments 1-62, comprising preventing new pemphigus lesion formation. 64. The method of any one of embodiments 1-63, comprising reducing the Pemphigus Disease Activity Index (PDAI) skin score. 65. The method of embodiment 64, comprising reducing the PDAI skin score by at least 20%. 66. The method of any one of embodiments 1 to 64, wherein the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 or 1 after administration of PRN1008. 67. The method of embodiment 66, wherein the human patient is characterized by a PDAI skin score of 0 after administration of PRN1008. 68. The method of embodiment 66, wherein the human patient is characterized by a PDAI skin score of 1 after administration of PRN1008. 69. The method of any one of embodiments 1-60, further comprising achieving control of pemphigus disease activity. 70. The method of any one of embodiments 1-60, further comprising achieving the end of the consolidation phase of pemphigus. 71. The method of embodiment 70, wherein more than 60% of confirmed pemphigus lesions are healed. 72. The method of any one of embodiments 1-60, comprising achieving a complete remission. 73. The method of any one of embodiments 1-72, wherein PRN1008 is administered orally to the human patient. 74. The method of any one of embodiments 1 to 73, wherein PRN1008 is administered to the human patient in the form of at least one tablet. 75. The method of embodiment 74, wherein PRN1008 is administered with a glass of water. . 76. The method of any one of embodiments 1-75, wherein PRN1008 is administered with food. 77. The method of any one of embodiments 1-75, wherein PRN1008 is administered without food.

[0067] Example embodiment 2: Without limitation, some embodiments of the present disclosure include: 1. A method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising: A method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for a minimum of 14 days to a maximum of 168 days. 2. The method of embodiment 1, further comprising administering to the patient a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day). 3. The method of embodiment 1 or 2, wherein the patient is administered PRN1008 for 14 days. 4. The method of embodiment 1 or 2, wherein the patient is administered PRN1008 for 28 days. 5. The method of embodiment 1 or 2, wherein the patient is administered PRN1008 for 84 days. 6. The method of embodiment 1 or 2, wherein the patient is administered PRN1008 for 168 days. 7. The method of embodiment 1 or 2, further comprising increasing the dose of PRN1008 after 14 days to 400 mg twice daily (BID) for a minimum of 14 days and a maximum of 154 days. 8. The method of embodiment 7, further comprising increasing the dose of PRN1008 to 600 mg BID after 14 days, for up to 140 days. The method of embodiment 8, wherein a 9.600 mg BID dose is administered for 56 days. 10. The method of any one of embodiments 1-9, wherein prior to the administration of 400 mg QD of PRN1008, the patient is maintained on low-dose corticosteroid (LDCS) therapy comprising administering a corticosteroid at a dose of ≦0.5 mg / kg / day. 11. The method of any one of embodiments 1-10, wherein prior to the administration of 400 mg QD of PRN1008, the patient has: (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points. 12. The method of embodiment 2 or 10, wherein the corticosteroid is prednisone, prednisolone, or methylprednisolone. 13. The method of any one of embodiments 1-12, wherein PRN1008 comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 14. A method of achieving a primary endpoint in 27% to 29% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days in combination with a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein prior to the 400 mg QD administration of PRN1008, the patient The population will be (a) naive or recurrent PV; and (b) have a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and are maintained on low-dose corticosteroid (LDCS) treatment, including administering corticosteroids at a dose of ≤0.5 mg / kg / day; and will achieve the primary endpoint, including control of disease activity (CDA), defined as a check-up visit at which new lesions from PV or PF have stopped forming and confirmed lesions from PV and PF have begun to heal. 15. A method of achieving a primary endpoint in 43% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 28 days, wherein throughout administration of PRN1008 to the patient population, the patient population also receives 0.5 mg / kg / day or less (≦0.5 mg / kg / day). Prior to the administration of 400 mg QD of PRN1008, the patient population was maintained on low-dose corticosteroid (LDCS) treatment, including (a) naive or recurrent PV; and (b) having a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and receiving corticosteroids at a dose of ≤0.5 mg / kg / day; the primary endpoint was to achieve the primary endpoint, including control of disease activity (CDA), defined as a check-up visit at which new lesions from PV or PF cease to form and confirmed lesions from PV and PF begin to heal. 16. A method of achieving a primary endpoint in 50% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 84 days, wherein throughout administration of PRN1008 to the patient population, the patient population also receives 0.5 mg / kg / day or less (≦0.5 mg / kg / day). Prior to the administration of 400 mg QD of PRN1008, the patient population was maintained on low-dose corticosteroid (LDCS) treatment, including (a) naive or recurrent PV; and (b) having a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and receiving corticosteroids at a dose of ≤0.5 mg / kg / day; the primary endpoint was to achieve the primary endpoint, including control of disease activity (CDA), defined as a check-up visit at which new lesions from PV or PF cease to form and confirmed lesions from PV and PF begin to heal. 17. A method of achieving a primary endpoint in 53% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, followed by increasing the dose of PRN1008 to 400 mg BID for 14 days; Throughout administration of PRN1008 to the patient population, the patient population also received corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to administration of 400 mg QD of PRN1008, the patient population was maintained on low-dose corticosteroid (LDCS) treatment, including (a) naive or recurrent PV; and (b) having a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and receiving corticosteroids at a dose of ≦0.5 mg / kg / day; the primary endpoint was cessation of new lesion formation from PV or PF and beginning of healing of confirmed lesions from PV and PF. How the study achieves its primary endpoints, including control of disease activity (CDA), defined as a screening visit that is completed within 24 hours. 18. A method of achieving a primary endpoint in 80% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, followed by increasing the dose of PRN1008 to 400 mg BID for 14 days, followed by increasing the dose of PRN1008 to 600 mg BID for 56 days; Throughout administration of PRN1008 to the patient population, the patient population also received corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to administration of 400 mg QD of PRN1008, the patient population was maintained on low-dose corticosteroid (LDCS) treatment, including (a) naive or recurrent PV; and (b) having a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and receiving corticosteroids at a dose of ≦0.5 mg / kg / day; and methods of achieving the primary endpoint, including control of disease activity (CDA), defined as a checkup visit where new lesions from PV or PF have stopped forming and confirmed lesions from PV and PF have begun to heal. 19. A method of achieving complete disease remission in 7% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily. The method involves administering 400 mg of PRN1008 QD for 84 days. Prior to administration of 400 mg of PRN1008 QD, the patient population is maintained on low-dose corticosteroid (LDCS) treatment, which involves administering corticosteroids at a dose of ≤0.5 mg / kg / day, and includes (a) naive or recurrent PV; and (b) having a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points. Complete remission means the absence of new, confirmed lesions from PV or PF. 20. A method of achieving complete disease remission in 13% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, followed by increasing the dose of PRN1008 to 400 mg BID for 14 days, followed by further increasing the dose to 600 mg BID. Throughout the administration of PRN1008 to the patient population, the patient population is also administered a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to the administration of 400 mg QD of PRN1008, the patient population is maintained on low-dose corticosteroid (LDCS) treatment, including (a) naive or recurrent PV; and (b) having a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points, and is administered a corticosteroid at a dose of ≦0.5 mg / kg / day; a method of achieving complete remission of the disease, where complete remission means the absence of new, confirmed lesions from PV or PF. 21. A method of achieving complete disease remission in 40% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl ]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) administered once daily (QD) for 14 days, followed by an increase in the dose of PRN1008 to 400 mg BID for 14 days, followed by a further increase in the dose to 600 mg BID for 140 days, after which the patient population is subject to a 28-day post-treatment follow-up, during which the patient population receives neither PRN1008 nor corticosteroids; throughout the administration of PRN1008 to the patient population, the patient population also receives 0.5 mg of PRN1008. Prior to the 400 mg QD administration of PRN1008, the patient population consisted of (a) naive or recurrent PV; and (b) patients with a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points who were maintained on low-dose corticosteroid (LDCS) treatment, including the administration of corticosteroids at a dose of ≤0.5 mg / kg / day; a complete remission means the absence of new, confirmed lesions from PV or PF, achieving complete remission of the disease. 22. A method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF) in a patient population, comprising administering to the population a dosing regimen as follows: (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) was administered at a starting dose of 400 mg QD (week 1), with allowed dose escalation to 400 mg BID in week 3 and 600 mg BID in week 5, completing the dosing period at 25 weeks; The conditions for dose escalation were either (a) patients who had not achieved control of disease activity (CDA) or (b) patients who had not reached the end of the consolidation phase (ECP); Control of disease activity was defined as the visit at which new lesions from PV or PF stopped forming and confirmed lesions from PV or PF began to heal; End of the consolidation phase was defined as a visit in which no new lesions from PV or PF had developed for at least 2 weeks and the majority of confirmed lesions from PV or PF had healed; A method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF), wherein, through administration of PRN1008 to the patient population, the patient population is also administered a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); and prior to the administration of 400 mg QD of PRN1008, the patient population has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and is maintained on low-dose corticosteroid (LDCS) treatment, comprising administering a corticosteroid at a dose of ≦0.5 mg / kg / day. 23. A method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising: The patient is administered a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 168 days, and throughout the administration of PRN1008, the patient is also receiving no more than 0.5 mg / kg / day (≤0.5 mg / kg / day). A method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF), wherein the patient has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points, and is maintained on low-dose corticosteroid (LDCS) treatment comprising administering a corticosteroid at a dose of ≦0.5 mg / kg / day; and (c) administering 400 mg BID of PRN1008 to a human patient having pemphigus vulgaris (PV) or pemphigus foliaceus (PF). 24. The method of any one of embodiments 14-23, wherein the corticosteroid is prednisone, prednisolone, or methylprednisolone. 25.PRN1008 is (R)-2-[3-[4-amino-3-(2-fluoro-4- 25. The method of any one of embodiments 14-24, comprising a mixture of the (E) and (Z) isomers of]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 26. The method of any one of embodiments 14-25, wherein the patient has a PDAI score of 1 (close to clear skin) after administration of PRN1008. 27. A method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising: A method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF) comprising administering a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for at least 14 days. 28. The method of embodiment 27, further comprising administering to the patient a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day). 29. The method of embodiment 27 or 28, wherein a 400 mg BID dose is administered for up to 84 days. The method of embodiment 27 or 28, wherein a 400 mg BID dose is administered for 14 days. 31. The method of embodiment 27 or 28, wherein a 400 mg BID dose is administered for 28 days. 32. The method of embodiment 27 or 28, further comprising increasing the 400 mg BID dose to 500 mg BID after a minimum of 14 to 28 days. 33. The method of embodiment 32, wherein after 33 days, the 400 mg BID dose is increased to 500 mg BID. 34. The method of embodiment 27 or 28, further comprising increasing the 400 mg BID dose to 600 mg BID after a minimum of 14 to 28 days. 35. The method of embodiment 34, wherein after 22 days, the 400 mg BID dose is increased to 600 mg BID. The method of embodiment 34, wherein after 36.56 days, the 400 mg BID dose is increased to 600 mg BID. 37. The method of embodiment 32, further comprising increasing the 500 mg BID dose to 600 mg BID after 14 to 28 days. 38. The method of any one of embodiments 27-37, wherein prior to administration of the 400 mg BID dose, the patient is maintained on low-dose corticosteroid (LDCS) therapy comprising administering a corticosteroid at a dose of ≦0.5 mg / kg / day. 39. The method of any one of embodiments 27-38, wherein prior to administration of the 400 mg BID dose, the patient has: (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points. 40. The method of embodiment 28 or 39, wherein the corticosteroid is prednisone, prednisolone, or methylprednisolone. 41. The method of any one of embodiments 27-40, wherein PRN1008 comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. 42. The method of any one of embodiments 27-41, wherein the patient has a PDAI score of 1 (close to clear skin) after administration of PRN1008. 43. Patients receiving treatment for pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF) 1. A method for achieving a primary endpoint in 27% of a human patient population comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 14 days in combination with a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), Prior to the 400 mg BID administration of N1008, the patient population consisted of (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points and maintained on low-dose corticosteroid (LDCS) treatment, including administering corticosteroids at a dose of ≤0.5 mg / kg / day; and methods to achieve the primary endpoint, including control of disease activity (CDA), defined as a check-up visit at which new lesions from PV or PF cease to form and confirmed lesions from PV and PF begin to heal. 44. A method of achieving a primary endpoint in 54% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 28 days, at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day) of corticosteroids. Prior to the administration of 400 mg of PRN1008 BID, the patient population is maintained on low-dose corticosteroid (LDCS) treatment, including (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points, and administering corticosteroids at a dose of ≤0.5 mg / kg / day; and the primary endpoint is control of disease activity (CDA), defined as a visit at which new lesions from PV or PF have stopped forming and confirmed lesions from PV and PF have begun to heal. 45. A method of achieving a primary endpoint in 54% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 28 days, in combination with a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day). Prior to the administration of 400 mg of PRN1008 BID, the patient population is maintained on low-dose corticosteroid (LDCS) treatment, including (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points, and administering corticosteroids at a dose of ≤0.5 mg / kg / day; and the primary endpoint is control of disease activity (CDA), defined as a visit at which new lesions from PV or PF have stopped forming and confirmed lesions from PV and PF have begun to heal. 46. ​​A method of achieving a primary endpoint in 73% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxeta) The study included administering [[[(3-phenyl-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 84 days in combination with corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), where prior to the administration of 400 mg BID of PRN1008, the patient population had: (a) naive or recurrent PV; and (b) Pemphigus Disease Activity Index (PDAI) Patients will have a skin score of 8 to 45 points and will be maintained on low-dose corticosteroid (LDCS) treatment, which involves administering corticosteroids at a dose of ≤0.5 mg / kg / day; and will achieve the primary endpoint, including control of disease activity (CDA), defined as a check-up visit at which new lesions from PV or PF have stopped forming and confirmed lesions from PV and PF have begun to heal. 47. A method of achieving complete disease remission in 17% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily. The method involves administering 400 mg of PRN1008 BID for 84 days, where prior to the administration of 400 mg BID, the patient population is (a) naive or recurrent PV; and (b) has a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points and is maintained on low-dose corticosteroid (LDCS) treatment, which involves administering corticosteroids at a dose of ≤0.5 mg / kg / day; and achieving complete remission of the disease, meaning the absence of new, confirmed lesions from PV or PF. 48. A method for achieving complete disease remission in 15% to 17% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once a day. The study involves administering 400 mg of PRN1008 twice daily for 84 days, with the patient population consisting of (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points, who are maintained on low-dose corticosteroid (LDCS) treatment, including administering corticosteroids at a dose of ≤0.5 mg / kg / day; and achieving complete remission of the disease, meaning the absence of new, confirmed lesions from PV or PF. 49. A method of achieving complete disease remission in 25% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 84 days, after which the patient population is subjected to 84 days of post-treatment follow-up, during which follow-up the patient population also receives PRN1008. Corticosteroids are not administered; throughout administration of PRN1008 to the patient population, the patient population also receives corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to administration of 400 mg QD of PRN1008, the patient population has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points and is maintained on low-dose corticosteroid (LDCS) treatment, including administering corticosteroids at a dose of ≦0.5 mg / kg / day; a method of achieving complete remission of the disease, where complete remission means the absence of new, confirmed lesions from PV or PF. 50. A method of achieving complete disease remission in 23% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 84 days. Thereafter, the patient population is subjected to 84 days of post-treatment follow-up, during which the patient population is not administered PRN1008 or corticosteroids; throughout the administration of PRN1008 to the patient population, the patient population is also administered corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to the administration of 400 mg QD of PRN1008, the patient population has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points and is maintained on low-dose corticosteroid (LDCS) treatment, including administering corticosteroids at a dose of ≦0.5 mg / kg / day; a method of achieving complete remission of the disease, where complete remission means the absence of new, confirmed lesions from PV or PF. 51. A method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF) in a patient population, comprising administering to the population a dosing regimen as follows: (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) was administered at a starting dose of 400 mg BID (week 1) with intrapatient dose titration allowed to 500 mg BID or 600 mg BID, completing the 13-week dosing period; The conditions for dose escalation were either (a) patients who had not achieved control of disease activity (CDA) or (b) patients who had not reached the end of the consolidation phase (ECP); Control of disease activity was defined as the visit at which new lesions from PV or PF stopped forming and confirmed lesions from PV or PF began to heal; End of the consolidation phase was defined as a visit in which no new lesions from PV or PF had developed for at least 2 weeks and the majority of confirmed lesions from PV or PF had healed; A method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF), wherein, through administration of PRN1008 to the patient population, the patient population is also administered a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); and prior to the administration of 400 mg QD of PRN1008, the patient population has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and is maintained on low-dose corticosteroid (LDCS) treatment, comprising administering a corticosteroid at a dose of ≦0.5 mg / kg / day. 52. The method of any one of embodiments 43-51, wherein the corticosteroid is prednisone, prednisolone, or methylprednisolone. 53. The method of any one of embodiments 43-52, wherein PRN1008 comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. [Brief explanation of the drawings]

[0068] [Figure 1] The percentages of patients (n=26) enrolled in the Phase 2 clinical trial (Part A) who achieved control of disease activity (CDA) at 2 weeks (27%), 4 weeks (54%), and 12 weeks (73%) are shown. In the Phase 2 clinical trial (Part A), patients received PRN1008 400 mg BID for the 12-week treatment period, with dose adjustments up to PRN1008 600 mg BID at the investigator's discretion. One patient enrolled in Part A who withdrew on Day 10 due to an unrelated adverse event (AE) was excluded from the analysis. [Figure 2]Response rates (%) for disease activity control at Study Day 15 (27%), Study Day 29 (54%), or Study Day 85 (73%) were shown for patients enrolled in the Phase 2 clinical trial (Part A). In the Phase 2 clinical trial (Part A), patients received PRN1008 400 mg BID for the 12-week treatment period, with dose adjustments up to PRN1008 600 mg BID at the investigator's discretion. Error bars represent 95% confidence intervals (CI). n=26 for Study Days 15 and 29. n=24 for Study Day 85. [Figure 3] The percentage of patients (n=24) enrolled in the Phase 2 clinical trial (Part A) who achieved complete remission (CR) at 12 weeks (17%) and 24 weeks (12 weeks on treatment, 12 weeks after treatment completion) (25%) is shown. In the Phase 2 clinical trial (Part A), patients received PRN1008 400 mg BID for the 12-week treatment period, with dose adjustments up to PRN1008 600 mg BID at the investigator's discretion. Three patients enrolled in Part A were excluded from the analysis due to unrelated adverse events at days 10, 43, and 44. [Figure 4] Figure 1 shows PDAI scores (median (interquartile range)) over time for patients enrolled in the Phase 2 clinical trial (Part A), in which patients received PRN1008 400 mg BID for a 12-week treatment period, with dose adjustments possible up to PRN1008 600 mg BID at the investigator's discretion. [Figure 5] Figure 1 shows PDAI scores (mean ± 95% CI) over time for patients enrolled in the Phase 2 clinical trial (Part A), in which patients received PRN1008 400 mg BID for a 12-week treatment period, with dose adjustments possible at the investigator's discretion up to PRN1008 600 mg BID. [Figure 6]Percentages of patients (n=14) enrolled in the Phase 2 clinical trial (Part B) who achieved control of disease activity (CDA) at 2 weeks (29%), 4 weeks (43%), and 12 weeks (50%) are shown. In the Phase 2 clinical trial (Part B), patients received PRN1008 400 mg QD for a 24-week treatment period. One patient who crossed over from Part A to Part B and started on PRN1008 400 mg BID was excluded from the analysis. [Figure 7] Percentages of patients (n=15) enrolled in the Phase 2 clinical trial (Part B) who achieved control of disease activity (CDA) at 2 weeks (27%), 4 weeks (53%), and 12 weeks (80%) are shown. In the Phase 2 clinical trial (Part B), patients received PRN1008 400 mg QD for the 24-week treatment period, with dose adjustments up to PRN1008 600 mg BID at the investigator's discretion. Patients who moved from Part A to Part B and started on PRN1008 400 mg BID were included in the analysis. [Figure 8A] Percentages of patients (n=15) enrolled in the Phase 2 clinical trial (Part B) who achieved control of disease activity (CDA) at 4 weeks (60%) and 12 weeks (87%) are shown. In the Phase 2 clinical trial (Part B), patients received PRN1008 400 mg QD for the 24-week treatment period, with dose adjustments up to PRN1008 600 mg BID possible at the investigator's discretion. Patients who transitioned from Part A to Part B and started on PRN1008 400 mg BID were included in the analysis. Error bars represent 80% CI calculated by the Clopper-Pearson method. [Figure 8B]Percentage of patients (n=14) enrolled in the Phase 2 clinical trial (Part B) who achieved control of disease activity (CDA) at 4 weeks (50%) and 12 weeks (50%) are shown. In this Phase 2 clinical trial (Part B), patients received PRN1008 400 mg QD for a 24-week treatment period. Patients who moved from Part A to Part B and started on PRN1008 400 mg BID were excluded from the analysis. Error bars represent 80% CI calculated by the Clopper-Pearson method. [Figure 9A] The percentages of patients (n=14) enrolled in the Phase 2 clinical trial (Part B) who achieved complete remission (CR) at 12 weeks (13%), 24 weeks (33%), and 28 weeks (24 weeks on treatment, 4 weeks after treatment completion) (40%) are shown. In the Phase 2 clinical trial (Part B), patients received PRN1008 400 mg QD for the 24-week treatment period, with dose adjustments up to PRN1008 600 mg BID at the investigator's discretion. Patients who moved from Part A to Part B and started on PRN1008 400 mg BID were included in the analysis. [Figure 9B] Percentages of patients (n=14) enrolled in the Phase 2 clinical trial (Part B) who achieved complete remission (CR) at 12 weeks (7%), 24 weeks (7%), and 28 weeks (24 weeks after treatment, 4 weeks after treatment end) (7%) are shown. In the Phase 2 clinical trial (Part B), patients received PRN1008 400 mg QD for the 24-week treatment period. Patients who moved from Part A to Part B and started on PRN1008 400 mg BID were excluded from the analysis. [Figure 10] Mean and median PDAI scores are shown for patients enrolled in the Phase 2 clinical trial (Part B) (n=16 for 8 weeks, n=15 thereafter), in which patients received PRN1008 400 mg QD for the 24-week treatment period, with dose adjustments possible at the investigator's discretion up to PRN1008 600 mg BID. One patient withdrew from the study after 8 weeks due to worsening pemphigus and was not included in the 8-week PDAI score calculation. [Figure 11]Mean and median PDAI scores and mean and median corticosteroid (CS) use are shown for patients enrolled in the Phase 2 clinical trial (Part B) (n=16 for 8 weeks, n=15 thereafter), in which patients received PRN1008 400 mg QD for the 24-week treatment period, with dose adjustments possible at the investigator's discretion up to PRN1008 600 mg BID. One patient withdrew from the study after 8 weeks due to worsening pemphigus and was not included in the PDAI score / CS use calculation after 8 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0069] Definition: Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings: All undefined technical and scientific terms used in this application have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0070] As used herein, "a" or "an" entity refers to one or more of that entity; for example, unless otherwise stated, a compound refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0071] As used herein, the term "about" means approximately, in the region of, roughly, or approximately. When used in conjunction with a numerical range, the term "about" modifies that range by extending the boundaries above and below the stated numerical values. Generally, the term "about" is used herein to modify a numerical value above and below the stated value by a 5% variance. With respect to specific values, it should be understood that the specific values ​​described herein for a subject population (e.g., subjects in a described clinical trial) represent median, average, or statistical numbers unless otherwise specified. Thus, aspects of the present disclosure requiring specific values ​​in subjects are supported herein by population data in which the relevant values ​​are determined to be meaningful limits for the subject population.

[0072] As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") refers to a biologically active compound.

[0073] As used herein, the terms "administer," "administering," or "administration" refer to providing, giving, dispensing, and / or prescribing by a health professional or authorized agent and / or to taking, taking, or consuming by a patient or individual himself or herself, e.g., "Administration" of an API to a patient refers to any route of introducing or delivering the API to a patient (e.g., oral delivery). Administration includes self-administration and administration by another person.

[0074] As used herein, the term "characterized by naive or recurrent pemphigus" with respect to a human patient refers to a human patient with newly diagnosed or recurrent pemphigus, such as newly diagnosed or recurrent pemphigus vulgaris or newly diagnosed or recurrent pemphigus foliaceus. As a non-limiting example, the term "characterized by naive or recurrent pemphigus prior to administration of PRN1008" with respect to a human patient refers to a human patient who is newly diagnosed with pemphigus or a human patient suffering from recurrent pemphigus prior to beginning a dosing regimen that includes administering PRN1008.

[0075] As used herein, the term "characterized by a maintenance dose of a corticosteroid of 0.5 mg / kg / day or less (≦0.5 mg / kg / day)" with respect to a human patient refers to a human patient receiving a maintenance dose of a corticosteroid of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), including patients who have not previously received a corticosteroid (0 mg / kg / day). As a non-limiting example, "characterized by a maintenance dose of a corticosteroid of 0.5 mg / kg / day or less (≦0.5 mg / kg / day) prior to administration of PRN1008" with respect to a human patient refers to a human patient who has not received a corticosteroid or who has received a maintenance dose of a corticosteroid of 0.5 mg / kg / day or less (≦0.5 mg / kg / day) prior to beginning a dosing regimen that includes administering PRN1008 and optionally administering a corticosteroid, which may be the same or different from the corticosteroid used as maintenance therapy prior to administration of PRN1008, and which is administered at the same or different dose or dosing schedule as used for maintenance therapy prior to administration of PRN1008.

[0076] As used herein, unless otherwise specified, the term "complete response" (CR) is defined as the absence of new, confirmed lesions and is intended to mean "absence of disease activity."

[0077] As used herein, unless otherwise specified, the term "control of disease activity" (CDA) (disease control) is defined as the visit at which new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal. This is also considered the beginning of the consolidation phase. The expected interval of time to reach control of disease activity is on the order of several weeks, but may be shorter.

[0078] As used herein, unless otherwise specified, the term "end of consolidation phase" (ECP) is defined as a visit where no new lesions have developed for a minimum of 2 weeks and the majority (e.g., at least 60%, at least 70%, at least 80%) of the identified lesions have healed. Thus, to achieve ECP, CDA must be confirmed at a visit ≥ 2 weeks later and 80% of the previously seen lesions must have healed.

[0079] As used herein, the term "after administration of [X]" when modifying a period of time refers to a period beginning after administration of [X] is completed. As a non-limiting example, "administering to a human patient a second dose of 400 mg of PRN1008 twice daily (BID) for 14 days after administration of a first dose" refers to starting administration of the second dose after administration of the first dose is completed and administering the second dose for 14 days, i.e., if the first dose is administered once daily on days 1-14, the second dose is administered twice daily on days 15-28, for a total treatment period of 28 days.

[0080] As used herein, two or more compounds, drugs, or additional active ingredients are combined. The term "in combination" when referring to pharmaceutical ingredients means that two or more compounds, drugs, or active pharmaceutical ingredients are administered to a patient before, simultaneously with, or after each other during a treatment period. Unless otherwise specified, two or more compounds, drugs, or active pharmaceutical ingredients may be administered on different schedules during a treatment period, for example, one or more compounds, drugs, or active pharmaceutical ingredients may be administered once daily and one or more other compounds, drugs, or active pharmaceutical ingredients may be administered twice daily.

[0081] As used herein, amounts expressed in terms of "[X] mg" refer to [X], i.e., the total amount in milligrams of the free base. In some embodiments, PRN1008 can be administered as a pharmaceutically acceptable salt of PRN1008, in which case an amount expressed in terms of "PRN1008 mg" refers to the total amount in milligrams of PRN1008, i.e., the free base plus one or more pharmaceutically acceptable salts of PRN1008 in an equivalent amount based on the weight of the free base therein. For example, "400 mg of at least one compound selected from PRN1008 and pharmaceutically acceptable salts thereof" includes 400 mg of PRN1008 and one or more pharmaceutically acceptable salts of PRN1008 in a concentration equivalent to 400 mg of PRN1008.

[0082] As used herein, the term "pemphigus lesion" refers to a lesion associated with or caused by pemphigus, such as, for example, a lesion associated with or caused by pemphigus vulgaris or a lesion associated with or caused by pemphigus foliaceus.

[0083] As used herein, the term " pharmaceutically acceptable salt " refers to the salt form of active pharmaceutical ingredients, and the salt is non-toxic.Pharmaceutically acceptable salts are well known in the art, and include those derived from suitable inorganic and organic acids.For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19.

[0084] As used herein, the term "PRN1008" refers to the structure: [ka] A dose of PRN1008 may contain less than about 1% by weight or less than about 5% by weight of the corresponding (S) enantiomer as an impurity. Similarly, a dose of the (E) isomer of PRN1008 may contain less than about 1% by weight of the corresponding (Z) isomer as an impurity; a dose of the (Z) isomer of PRN1008 may contain less than about 1% by weight of the corresponding (E) isomer as an impurity. PRN1008 is (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl) When expressed as a mixture of the (E) and (Z) isomers of [piperazin-1-yl]pent-2-enenitrile, it means that the amount of the (E) or (Z) isomer in the mixture is greater than about 1% by weight. In some embodiments, the molar ratio of the (E) to the (Z) isomer is 9:1. PRN1008 or a pharmaceutically acceptable salt thereof is also referred to herein as the "drug," "active agent," "therapeutically active agent," or "API."

[0085] As used herein, the term "recurrence" is defined by the appearance of three or more new lesions within one month that do not heal spontaneously within one week, or by the expansion of confirmed lesions, in patients who have achieved disease control.

[0086] As used herein, the terms "treat," "treating," or "treatment," when used in reference to a disorder or condition, include any effect that results in improvement of the disorder or condition, such as alleviating, reducing, modulating, ameliorating, or eliminating. An improvement or reduction in the severity of any symptom of a disorder or condition can be readily determined according to standard methods and techniques known in the art.

[0087] Some embodiments of the present disclosure relate to a method of treating pemphigus in a human patient in need thereof, comprising administering to the human patient a dose of at least 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for at least 14 days.

[0088] In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 14 to 168 days. In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 14 days. In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 28 days. In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 84 days. In some embodiments, a human patient is administered at least a 400 mg dose of PRN1008 QD for 168 days.

[0089] In some embodiments, the method comprises administering to a human patient a 400 mg dose of PRN1008 QD for at least 14 days.

[0090] In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 14 to 168 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 14 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 28 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 84 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 168 days.

[0091] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 once daily (QD) for 14 days; The human patient is administered a second dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days after the first dose. Includes:

[0092] In some embodiments, a human patient receives a second dose of 400 mg of PRN1008 BID for 14 to 154 days after administration of the first dose.

[0093] In some embodiments, PRN1008 is administered to a human patient for up to 168 days.

[0094] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 once daily (QD) for 14 days; administering to the human patient a second dose of 400 mg of PRN1008 twice daily (BID) for 14 days following administration of the first dose; The human patient receives a third dose of 600 mg of PRN1008 twice daily (BID) after the second dose. Includes:

[0095] In some embodiments, the human patient is administered a third dose of 600 mg of PRN1008 BID for up to 140 days after the second dose, hi some embodiments, the human patient is administered a third dose of 600 mg of PRN1008 BID for 56 days after the second dose.

[0096] In some embodiments, PRN1008 is administered to a human patient for up to 168 days.

[0097] In some embodiments, the methods comprise administering PRN1008 in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day).

[0098] In some embodiments, the first corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

[0099] In some embodiments, the human patient is characterized by asymptomatic or recurrent pemphigus prior to administration of PRN1008. In some embodiments, the human patient is characterized by asymptomatic pemphigus prior to administration of PRN1008. In some embodiments, the human patient is characterized by recurrent pemphigus prior to administration of PRN1008.

[0100] In some embodiments, the human patient is characterized by non-sensitized or recurrent pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the human patient is characterized by non-sensitized pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the human patient is characterized by recurrent pemphigus vulgaris prior to administration of PRN1008.

[0101] In some embodiments, the human patient is characterized by asymptomatic or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, the human patient is characterized by asymptomatic pemphigus foliaceus prior to administration of PRN1008. In some embodiments, the human patient is characterized by recurrent pemphigus foliaceus prior to administration of PRN1008.

[0102] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points prior to administration of PRN1008.

[0103] In some embodiments, the human patient is characterized by a second corticosteroid maintenance dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day) prior to administration of PRN1008.

[0104] In some embodiments, the second corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

[0105] In some embodiments, the first corticosteroid is the same as the second corticosteroid. In some embodiments, the first corticosteroid is not the same as the second corticosteroid.

[0106] In some embodiments, PRN1008 comprises the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, PRN1008 comprises the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, PRN1008 comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

[0107] In some embodiments, the methods include treating pemphigus vulgaris.

[0108] In some embodiments, the methods include treating pemphigus foliaceus.

[0109] In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 20%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 25%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 30%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 35%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 40%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 45%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 50%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 55%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 60%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 65%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 70%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 75%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 80%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 85%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 90%.

[0110] In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 14 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 28 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 56 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 84 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 112 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 140 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 168 days after administration of PRN1008.

[0111] In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 20% 14 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 20% 28 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 50% 56 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 50% 84 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 70% 168 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 75% after 168 days of PRN1008 administration.

[0112] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 or 1 after administration of PRN1008. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 after administration of PRN1008. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 1 after administration of PRN1008.

[0113] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 or 1 after 168 days of PRN1008 administration. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 after 168 days of PRN1008 administration. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 1 after 168 days of PRN1008 administration.

[0114] In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 20%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 25%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 30%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 35%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 40%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 45%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 50%. In some embodiments, the method comprises reducing the average daily corticosteroid usage by the human patient by at least 55%. In some embodiments, the method comprises reducing the average daily corticosteroid usage by the human patient by at least 60%. In some embodiments, the method comprises reducing the average daily corticosteroid usage by the human patient by at least 65%.

[0115] In some embodiments, the method comprises administering PRN1008 to a human patient 56 days after administration of PRN1008. In some embodiments, the method comprises reducing average daily corticosteroid usage by a human patient by at least 20% after 84 days of PRN1008 administration. In some embodiments, the method comprises reducing average daily corticosteroid usage by a human patient by at least 30% after 84 days of PRN1008 administration. In some embodiments, the method comprises reducing average daily corticosteroid usage by a human patient by at least 50% after 112 days of PRN1008 administration.

[0116] In some embodiments, the method comprises achieving a complete remission. In some embodiments, the method comprises achieving a complete remission 84 days after administration of PRN1008. In some embodiments, the method comprises achieving a complete remission 168 days after administration of PRN1008.

[0117] In some embodiments, the method includes achieving control of disease activity, defined as a checkup visit where new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal. In some embodiments, the method includes achieving control of disease activity after 84 days of PRN1008 administration. In some embodiments, the method includes achieving control of disease activity after 168 days of PRN1008 administration.

[0118] In some embodiments, the method comprises healing the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 50% of the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 60% of the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 70% of the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 80% of the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 90% of the confirmed pemphigus lesions.

[0119] In some embodiments, the method comprises healing at least 50% of confirmed pemphigus lesions 84 days after administration of PRN1008. In some embodiments, the method comprises healing at least 60% of confirmed pemphigus lesions 84 days after administration of PRN1008. In some embodiments, the method comprises healing at least 70% of confirmed pemphigus lesions 84 days after administration of PRN1008. In some embodiments, the method comprises healing at least 80% of confirmed pemphigus lesions 84 days after administration of PRN1008. In some embodiments, the method comprises healing at least 90% of confirmed pemphigus lesions 84 days after administration of PRN1008.

[0120] In some embodiments, the method comprises healing at least 50% of confirmed pemphigus lesions 168 days after administration of PRN1008. In some embodiments, the method comprises healing at least 60% of confirmed pemphigus lesions 168 days after administration of PRN1008. In some embodiments, the method comprises healing at least 70% of confirmed pemphigus lesions 168 days after administration of PRN1008. In some embodiments, the method comprises healing at least 80% of confirmed pemphigus lesions 168 days after administration of PRN1008. In some embodiments, the method comprises healing at least 90% of confirmed pemphigus lesions 168 days after administration of PRN1008.

[0121] In some embodiments, the method comprises preventing new pemphigus lesion formation. In some embodiments, the method comprises preventing new pemphigus lesion formation 84 days after administration of PRN1008. In some embodiments, the method comprises preventing new pemphigus lesion formation 168 days after administration of PRN1008.

[0122] In some embodiments, the method achieves an end of the consolidation phase, defined as a medical visit in which no new pemphigus lesions have developed for at least two weeks and the majority of confirmed pemphigus lesions have healed. In some embodiments, more than 50% of the confirmed pemphigus lesions are healed. In some embodiments, more than 60% of the confirmed pemphigus lesions are healed. In some embodiments, more than 70% of the confirmed pemphigus lesions are healed. In some embodiments, more than 80% of the confirmed pemphigus lesions are healed. In some embodiments, more than 90% of the confirmed pemphigus lesions are healed.

[0123] In some embodiments, the method includes achieving an end of the consolidation phase 168 days after administration of PRN1008, defined as a medical visit where no new pemphigus lesions have developed for at least two weeks and the majority of confirmed pemphigus lesions have healed. In some embodiments, more than 50% of the confirmed pemphigus lesions have healed. In some embodiments, more than 60% of the confirmed pemphigus lesions have healed. In some embodiments, more than 70% of the confirmed pemphigus lesions have healed. In some embodiments, more than 80% of the confirmed pemphigus lesions have healed. In some embodiments, more than 90% of the confirmed pemphigus lesions have healed.

[0124] Also disclosed herein is a method of treating a human patient suffering from pemphigus vulgaris or pemphigus foliaceus, comprising administering to the human patient a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for at least 14 days.

[0125] In some embodiments, human patients are administered a 400 mg dose of PRN1008 QD for 14 to 168 days.

[0126] In some embodiments, human patients are administered a 400 mg dose of PRN1008 QD for up to 168 days.

[0127] In some embodiments, a human patient is administered a 400 mg dose of PRN1008 QD for 14 days. In some embodiments, a patient is administered a 400 mg dose of PRN1008 QD for 28 days. In some embodiments, a patient is administered a 400 mg dose of PRN1008 QD for 84 days. In some embodiments, a patient is administered a 400 mg dose of PRN1008 QD for 168 days.

[0128] Some embodiments of the present disclosure relate to a method of treating pemphigus in a human patient in need thereof, comprising administering to the human patient a dose of at least 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for at least 14 days.

[0129] In some embodiments, a human patient is administered a dose of at least 400 mg of PRN1008 BID for 14 to 84 days. In some embodiments, a human patient is administered a dose of at least 400 mg of PRN1008 BID for 14 days. In some embodiments, a human patient is administered a dose of at least 400 mg of PRN1008 BID for 28 days. In some embodiments, a human patient is administered a dose of at least 400 mg of PRN1008 BID for 84 days.

[0130] In some embodiments, the method comprises administering to a human patient a 400 mg dose of PRN1008: This includes dosing BID for at least 14 days.

[0131] In some embodiments, a human patient is administered a 400 mg dose of PRN1008 BID for 14 to 84 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 BID for 14 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 BID for 28 days. In some embodiments, a human patient is administered a 400 mg dose of PRN1008 BID for 84 days.

[0132] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days; A human patient is administered a first dose followed by a second dose of 500 mg of PRN1008 twice daily (BID). Includes:

[0133] In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 14 to 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for more than 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 33 days.

[0134] In some embodiments, PRN1008 is administered to a human patient for up to 84 days.

[0135] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days; A human patient is administered a first dose followed by a second dose of 600 mg of PRN1008 twice daily (BID). Includes:

[0136] In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 14 to 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for more than 28 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 22 days. In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 56 days.

[0137] In some embodiments, PRN1008 is administered to a human patient for up to 84 days.

[0138] In some embodiments, the method comprises: administering to a human patient a first dose of 400 mg of PRN1008 twice daily (BID) for at least 14 days; administering to the human patient a second dose of 500 mg of PRN1008 twice daily (BID) for at least 14 days following administration of the first dose; The human patient was administered a third dose of 600 mg of PRN1008 twice daily (BID) after the second dose. Includes:

[0139] In some embodiments, a human patient is administered a first dose of 400 mg of PRN1008 BID for 14 to 28 days. Doses of PRN1008 will be administered BID for more than 28 days.

[0140] In some embodiments, a human patient receives a second dose of 500 mg of PRN1008 BID for 14 to 28 days after administration of the first dose.

[0141] In some embodiments, PRN1008 is administered to a human patient for up to 84 days.

[0142] In some embodiments, the methods comprise administering PRN1008 in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day).

[0143] In some embodiments, the first corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

[0144] In some embodiments, the human patient is characterized by asymptomatic or recurrent pemphigus prior to administration of PRN1008. In some embodiments, the human patient is characterized by asymptomatic pemphigus prior to administration of PRN1008. In some embodiments, the human patient is characterized by recurrent pemphigus prior to administration of PRN1008.

[0145] In some embodiments, the human patient is characterized by non-sensitized or recurrent pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the human patient is characterized by non-sensitized pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the human patient is characterized by recurrent pemphigus vulgaris prior to administration of PRN1008.

[0146] In some embodiments, the human patient is characterized by asymptomatic or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, the human patient is characterized by asymptomatic pemphigus foliaceus prior to administration of PRN1008. In some embodiments, the human patient is characterized by recurrent pemphigus foliaceus prior to administration of PRN1008.

[0147] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points prior to administration of PRN1008. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points prior to administration of PRN1008.

[0148] In some embodiments, the human patient is characterized by a second corticosteroid maintenance dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day) prior to administration of PRN1008.

[0149] In some embodiments, the second corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

[0150] In some embodiments, the first corticosteroid is the same as the second corticosteroid. In some embodiments, the first corticosteroid is not the same as the second corticosteroid.

[0151] In some embodiments, PRN1008 comprises the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, PRN1008 comprises the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile. In some embodiments, PRN1008 comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

[0152] In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 20%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 25%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 30%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 35%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 40%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 45%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 50%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 55%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 60%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 65%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 70%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 75%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 80%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 85%. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 90%.

[0153] In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 14 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 28 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 56 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 84 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 112 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 140 days after administration of PRN1008. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score 168 days after administration of PRN1008.

[0154] In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 20% after 14 days of PRN1008 administration. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 20% after 28 days of PRN1008 administration. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 50% after 56 days of PRN1008 administration. In some embodiments, the method comprises reducing the Pemphigus Disease Activity Index (PDAI) skin score by at least 50% after 84 days of PRN1008 administration. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 70% after 168 days of PRN1008 administration. In some embodiments, the method comprises reducing a Pemphigus Disease Activity Index (PDAI) skin score by at least 75% after 168 days of PRN1008 administration.

[0155] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 or 1 after administration of PRN1008. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 after administration of PRN1008. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 1 after administration of PRN1008.

[0156] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 or 1 after 168 days of PRN1008 administration. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 0 after 168 days of PRN1008 administration. In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 1 after 168 days of PRN1008 administration.

[0157] In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 20%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 25%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 30%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 35%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 40%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 45%. In some embodiments, the method comprises reducing the average daily corticosteroid use by the human patient by at least 50%. In some embodiments, the method comprises reducing the average daily corticosteroid usage by the human patient by at least 55%. In some embodiments, the method comprises reducing the average daily corticosteroid usage by the human patient by at least 60%. In some embodiments, the method comprises reducing the average daily corticosteroid usage by the human patient by at least 65%.

[0158] In some embodiments, the method comprises reducing average daily corticosteroid use by a human patient by at least 20% after 56 days of PRN1008 administration. In some embodiments, the method comprises reducing average daily corticosteroid use by a human patient by at least 30% after 84 days of PRN1008 administration. In some embodiments, the method comprises reducing average daily corticosteroid use by a human patient by at least 50% after 112 days of PRN1008 administration.

[0159] In some embodiments, the method comprises achieving a complete remission. In some embodiments, the method comprises achieving a complete remission 84 days after administration of PRN1008. In some embodiments, the method comprises achieving a complete remission 168 days after administration of PRN1008.

[0160] In some embodiments, the method includes achieving control of disease activity, defined as a check-up visit where new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal. In some embodiments, the method includes achieving control of disease activity 84 days after administration of PRN1008. In some embodiments, the method comprises achieving control of disease activity after 168 days of administration of PRN1008.

[0161] In some embodiments, the method comprises healing the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 50% of the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 60% of the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 70% of the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 80% of the confirmed pemphigus lesions. In some embodiments, the method comprises healing at least 90% of the confirmed pemphigus lesions.

[0162] In some embodiments, the method comprises healing at least 50% of confirmed pemphigus lesions 84 days after administration of PRN1008. In some embodiments, the method comprises healing at least 60% of confirmed pemphigus lesions 84 days after administration of PRN1008. In some embodiments, the method comprises healing at least 70% of confirmed pemphigus lesions 84 days after administration of PRN1008. In some embodiments, the method comprises healing at least 80% of confirmed pemphigus lesions 84 days after administration of PRN1008. In some embodiments, the method comprises healing at least 90% of confirmed pemphigus lesions 84 days after administration of PRN1008.

[0163] In some embodiments, the method comprises healing at least 50% of confirmed pemphigus lesions after 168 days of PRN1008 administration. In some embodiments, the method comprises healing at least 60% of confirmed pemphigus lesions after 168 days of PRN1008 administration. In some embodiments, the method comprises healing at least 70% of confirmed pemphigus lesions after 168 days of PRN1008 administration. In some embodiments, the method comprises healing at least 80% of confirmed pemphigus lesions after 168 days of PRN1008 administration. In some embodiments, the method comprises healing at least 90% of confirmed pemphigus lesions after 168 days of PRN1008 administration.

[0164] In some embodiments, the method comprises preventing new pemphigus lesion formation. In some embodiments, the method comprises preventing new pemphigus lesion formation after 84 days of PRN1008 administration. In some embodiments, the method comprises preventing new pemphigus lesion formation after 168 days of PRN1008 administration.

[0165] In some embodiments, the method includes achieving an end of the consolidation phase, defined as a visit where no new pemphigus lesions have developed for at least two weeks and the majority of confirmed pemphigus lesions have healed. In some embodiments, more than 50% of the confirmed pemphigus lesions have healed. In some embodiments, more than 60% of the confirmed pemphigus lesions have healed. In some embodiments, more than 70% of the confirmed pemphigus lesions have healed. In some embodiments, more than 80% of the confirmed pemphigus lesions have healed. In some embodiments, more than 90% of the confirmed pemphigus lesions have healed.

[0166] In some embodiments, the method includes achieving an end of the consolidation phase after 168 days of PRN1008 administration, defined as a visit where no new pemphigus lesions have developed for at least two weeks and the majority of confirmed pemphigus lesions have healed. In some embodiments, more than 50% of the confirmed pemphigus lesions have healed. In some embodiments, more than 60% of the confirmed pemphigus lesions have healed. In some embodiments, more than 70% of the confirmed pemphigus lesions have healed. In some embodiments, more than 80% of the confirmed pemphigus lesions have healed. In some embodiments, more than 90% of the confirmed pemphigus lesions have healed.

[0167] Some embodiments of the present disclosure provide a method of achieving a primary endpoint in 17% to 39% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitized or recurrent pemphigus; and Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by The primary endpoint is about achieving the primary endpoint, which includes control of disease activity (CDA), defined as a check-up visit at which new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal.

[0168] In some embodiments, the method comprises achieving the primary endpoint in 22% to 34% of the human patient population.

[0169] In some embodiments, the method comprises achieving the primary endpoint in 27% to 29% of the human patient population.

[0170] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0171] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008.

[0172] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0173] 1. A method of achieving a primary endpoint in 27% to 29% of a human patient population being treated for pemphigus vulgaris (PV), pemphigus, or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days in combination with a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein the 400 mg of PRN1008 Before QD administration, the patient population consisted of (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (P) of 8 to 60 points. Also provided are methods of achieving primary endpoints, including control of disease activity (CDA), defined as a check-up visit at which new lesions from PV or PF stop forming and confirmed lesions from PV and PF begin to heal.

[0174] Some embodiments of the present disclosure provide a method of achieving a primary endpoint in 33% to 53% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 28 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by The primary endpoint is about achieving the primary endpoint, which includes control of disease activity (CDA), defined as a check-up visit at which new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal.

[0175] In some embodiments, the method comprises achieving the primary endpoint in 38% to 48% of the human patient population.

[0176] In some embodiments, the method comprises achieving the primary endpoint in 43% of the human patient population.

[0177] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0178] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008.

[0179] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone. In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population. In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0180] A method of achieving a primary endpoint in 43% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-propyl]-2-methyl-2-propanol]-2,3-diol, 2,4-diol, 2,5-trimethyl- ... and administering to the patient population] [4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 28 days, wherein during the administration of PRN1008 to the patient population, the patient population also receives a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); Also provided herein are methods of achieving a primary endpoint, including controlled disease activity (CDA), defined as a check-up visit where new lesions from PV or PF have ceased to form and confirmed lesions from PV and PF have begun to heal. The primary endpoint is controlled disease activity (CDA), defined as a check-up visit where new lesions from PV or PF have ceased to form and confirmed lesions from PV and PF have begun to heal.

[0181] Some embodiments of the present disclosure provide a method of achieving a primary endpoint in 40% to 60% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 84 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by The primary endpoint is about achieving the primary endpoint, which includes control of disease activity (CDA), defined as a check-up visit at which new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal.

[0182] In some embodiments, the method comprises achieving the primary endpoint in 45% to 55% of the human patient population.

[0183] In some embodiments, the method comprises achieving the primary endpoint in 50% of the human patient population.

[0184] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0185] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008.

[0186] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone. In some embodiments, the first corticosteroid administered to the member of the human patient population is selected from the group consisting of prednisone, prednisolone, and methylprednisolone. In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0187] 1. A method of achieving a primary endpoint in 50% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 84 days, wherein during the administration of PRN1008 to the patient population, the patient population also receives a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); Also provided herein are methods of achieving a primary endpoint, including controlled disease activity (CDA), defined as a check-up visit where new lesions from PV or PF have ceased to form and confirmed lesions from PV and PF have begun to heal. The primary endpoint is controlled disease activity (CDA), defined as a check-up visit where new lesions from PV or PF have ceased to form and confirmed lesions from PV and PF have begun to heal.

[0188] Some embodiments of the present disclosure provide a method of achieving a primary endpoint in 43% to 63% of a human patient population being treated for pemphigus, comprising: administering to each member of a patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), followed by administering a 400 mg dose of PRN1008 twice daily (BID) for 14 days, optionally in combination with the first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by The primary endpoint is about achieving the primary endpoint, which includes control of disease activity (CDA), defined as a check-up visit at which new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal.

[0189] In some embodiments, the method comprises achieving the primary endpoint in 48% to 58% of the human patient population.

[0190] In some embodiments, the method comprises achieving the primary endpoint in 53% of the human patient population.

[0191] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0192] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008.

[0193] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0194] A method of achieving a primary endpoint in 53% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, followed by a 400 mg dose of PRN1008. and increasing the PRN1008 dosing regimen to BID for 14 days, during which the patient population also receives corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to the administration of 400 mg QD of PRN1008, the patient population has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and is maintained on low-dose corticosteroid (LDCS) therapy, including administering corticosteroids at a dose of ≦0.5 mg / kg / day; methods of achieving primary endpoints are also included, including controlled disease activity (CDA), defined as a checkup visit at which new lesions from PV or PF have stopped forming and confirmed lesions from PV and PF have begun to heal.

[0195] Some embodiments of the present disclosure provide a method of achieving a primary endpoint in 70% to 90% of a human patient population being treated for pemphigus, comprising: Each member of a human patient population will receive a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, optionally followed by a first corticosteroid at a dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day). and administering a 400 mg dose of PRN1008 twice daily (BID) for 14 days in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), followed by administering a 600 mg dose of PRN1008 twice daily (BID) for 56 days in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by The primary endpoint was control of disease activity (CDA), defined as a follow-up visit at which new pemphigus lesions stopped forming and confirmed pemphigus lesions began to heal. The method for achieving this endpoint is as follows:

[0196] In some embodiments, the method comprises achieving the primary endpoint in 75% to 85% of the human patient population.

[0197] In some embodiments, the method comprises achieving the primary endpoint in 80% of the human patient population.

[0198] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0199] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008.

[0200] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0201] A method of achieving a primary endpoint in 80% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, followed by increasing the dose of PRN1008 to 400 mg BID for 14 days, followed by increasing the dose of PRN1008 to 600 mg BID for 14 days. and increasing the PRN1008 dose to BID for 56 days, during which the patient population also receives corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to administration of 400 mg QD of PRN1008, the patient population has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and is maintained on low-dose corticosteroid (LDCS) therapy, including administering corticosteroids at a dose of ≦0.5 mg / kg / day; methods of achieving primary endpoints are also included, including controlled disease activity (CDA), defined as a checkup visit at which new lesions from PV or PF have stopped forming and confirmed lesions from PV and PF have begun to heal.

[0202] Some embodiments of the present disclosure provide a method of achieving complete disease remission in 4.5% to 9.5% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 84 days, wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and First corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by Complete remission refers to a method of achieving complete remission of the disease, defined as the absence of new, confirmed pemphigus lesions.

[0203] In some embodiments, the method comprises achieving complete remission of the disease in 6% to 8% of the human patient population.

[0204] In some embodiments, the method comprises achieving complete remission of the disease in 7% of the human patient population.

[0205] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0206] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008.

[0207] In some embodiments, the method comprises administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 84 days in combination with a second corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day).

[0208] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0209] A method of achieving complete disease remission in 7% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 84 days, wherein the 400 mg of PRN1008 Prior to QD administration, the patient population had (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8-60 points and was maintained on low-dose corticosteroid (LDCS) therapy, including administering corticosteroids at a dose of ≤0.5 mg / kg / day; complete remission means the absence of new, confirmed lesions from PV or PF. Methods for achieving complete remission of the disease are also provided.

[0210] In some embodiments, PRN1008 is administered at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day). It is administered in combination with corticosteroids at a dose of 100 mg / kg / day.

[0211] Some embodiments of the present disclosure provide a method of achieving complete disease remission in 3% to 23% of a human patient population being treated for pemphigus, comprising: Each member of a human patient population will receive a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, optionally followed by a first corticosteroid at a dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day). and administering a 400 mg dose of PRN1008 twice daily (BID) for 14 days in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), followed by administering a 600 mg dose of PRN1008 twice daily (BID) for 56 days in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by Complete remission refers to a method of achieving complete remission of the disease, defined as the absence of new, confirmed pemphigus lesions.

[0212] In some embodiments, the method comprises achieving complete remission of the disease in 8% to 18% of the human patient population.

[0213] In some embodiments, the method comprises achieving complete remission of the disease in 13% of a human patient population.

[0214] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0215] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008.

[0216] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0217] A method for achieving complete disease remission in 13% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4 -methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) administered once daily (QD) for 14 days, followed by increasing the dose of PRN1008 to 400 mg BID for 14 days, followed by further increasing the dose to 600 mg BID for 56 days, wherein during the administration of PRN1008 to the patient population, the patient population also receives a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); Prior to QD administration, the patient population had (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8-60 points and was maintained on low-dose corticosteroid (LDCS) therapy, which included administering corticosteroids at a dose of ≤0.5 mg / kg / day; methods of achieving complete remission of the disease, where complete remission means the absence of new, confirmed lesions from PV or PF, are also provided.

[0218] Some embodiments of the present disclosure provide a method of achieving complete disease remission in 30% to 50% of a human patient population being treated for pemphigus, comprising: Each member of a human patient population will receive a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, optionally at a dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) in the first period. in combination with a corticosteroid, followed by a 400 mg dose of PRN1008 administered twice daily (BID) for 14 days in combination with the first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), followed by a 600 mg dose of PRN1008 administered twice daily (BID) for 140 days in combination with the first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); and subjecting each member of the human patient population to a 28-day post-treatment period following administration of PRN1008 in which neither PRN1008 nor a corticosteroid is administered, wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by Complete remission refers to a method of achieving complete remission of the disease, defined as the absence of new, confirmed pemphigus lesions.

[0219] In some embodiments, the method comprises achieving complete remission of the disease in 35% to 45% of the human patient population.

[0220] In some embodiments, the method comprises achieving complete remission of the disease in 40% of a human patient population.

[0221] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0222] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone. In some embodiments, the first corticosteroid administered to the member of the human patient population is selected from the group consisting of prednisone, prednisolone, and methylprednisolone. In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0223] A method of achieving complete disease remission in 40% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily (QD) for 14 days, followed by increasing the dose of PRN1008 to 400 mg BID for 14 days, followed by increasing the dose to 600 mg BID for 14 days. and further escalating the treatment to BID for 140 days, and thereafter subjecting the patient population to 28 days of post-treatment follow-up, during which follow-up the patient population is not administered any PRN1008 or corticosteroids; during the administration of PRN1008 to the patient population, the patient population is also administered corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to the administration of 400 mg QD of PRN1008, the patient population has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and is maintained on low-dose corticosteroid (LDCS) therapy, including administering corticosteroids at a dose of ≦0.5 mg / kg / day; also provided is a method of achieving complete remission of the disease, where complete remission means the absence of new, confirmed lesions from PV or PF.

[0224] Some embodiments of the present disclosure provide a method of treating pemphigus in a human patient, comprising: administering to a human patient a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) once daily, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); determining whether the human patient achieves control of disease activity during week 3 and / or reaches the end of the consolidation period, and if the human patient does not achieve control of disease activity during week 3 and / or reaches the end of the consolidation period, increasing the dose of PRN1008 to 400 mg BID; determining whether the human patient has achieved control of disease activity within week 5 and / or reached the end of the consolidation period, and if the human patient has not achieved control of disease activity within week 5 and / or reached the end of the consolidation period, increasing the dose of PRN1008 to 600 mg BID; Control of disease activity (CDA) was defined as a check-up visit at which new pemphigus lesions stopped forming and confirmed pemphigus lesions began to heal; For methods of treating pemphigus, the end of the consolidation phase is defined as a visit in which no new pemphigus lesions have developed for a minimum of two weeks and the majority of confirmed pemphigus lesions have healed.

[0225] In some embodiments, the human patient is characterized by naive or recurrent pemphigus prior to administration of PRN1008. In some embodiments, the human patient is characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the human patient is characterized by naive or recurrent pemphigus foliaceus prior to administration of PRN1008.

[0226] In some embodiments, the human patient is characterized by a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points prior to administration of PRN1008.

[0227] In some embodiments, the human patient is characterized by a second corticosteroid maintenance dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day) prior to administration of PRN1008.

[0228] In some embodiments, the human patient is: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by:

[0229] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0230] In some embodiments, PRN1008 is administered to a patient for 25 weeks.

[0231] In some embodiments, the end of the intensification phase is defined as a visit where no new pemphigus lesions have developed for at least two weeks and at least 50% of the confirmed pemphigus lesions have healed. In some embodiments, the end of the intensification phase is defined as a visit where no new pemphigus lesions have developed for at least two weeks and at least 60% of the confirmed pemphigus lesions have healed. In some embodiments, the end of the intensification phase is defined as a visit where no new pemphigus lesions have developed for at least two weeks and at least 70% of the confirmed pemphigus lesions have healed. In some embodiments, the end of the intensification phase is defined as a visit where no new pemphigus lesions have developed for at least two weeks and at least 80% of the confirmed pemphigus lesions have healed. In some embodiments, the end of the intensification phase is defined as a visit where no new pemphigus lesions have developed for at least two weeks and at least 90% of the confirmed pemphigus lesions have healed.

[0232] 1. A method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF) in a patient population, comprising administering to the population a dosing regimen as follows: administering (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) at a starting dose of 400 mg QD (Week 1), with dose escalation allowed to 400 mg BID in Week 3 and 600 mg BID in Week 5, with the dosing period ending at Week 25; The criteria for dose escalation were patients who (a) had not achieved control of disease activity (CDA) or (b) had not reached the end of the consolidation phase (ECP); Control of disease activity was defined as the visit at which new lesions from PV or PF stopped forming and confirmed lesions from PV or PF began to heal; End of the consolidation phase was defined as a visit in which no new lesions from PV or PF had developed for at least 2 weeks and the majority of confirmed lesions from PV or PF had healed; During administration of PRN1008 to the patient population, the patient population also received corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to administration of 400 mg QD of PRN1008, the patient population had (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and was receiving corticosteroids. Also provided is a method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF) maintained on low-dose corticosteroid (LDCS) therapy comprising administering at a dose of ≦0.5 mg / kg / day.

[0233] Some embodiments of the present disclosure relate to a method of treating pemphigus in a human patient, comprising administering to the human patient a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 168 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day).

[0234] In some embodiments, the human patient is: Before administration of PRN1008, Subsensitized or recurrent pemphigus; and Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by:

[0235] In some embodiments, the method comprises treating pemphigus vulgaris. In some embodiments, the method comprises treating pemphigus foliaceus.

[0236] In some embodiments, the human patient is characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the human patient is characterized by naive or recurrent pemphigus foliaceus prior to administration of PRN1008.

[0237] In some embodiments, the method comprises treating pemphigus vulgaris, and the human patient is characterized by naive or recurrent pemphigus vulgaris prior to administration of PRN1008. In some embodiments, the method comprises treating pemphigus foliaceus, and the human patient is characterized by naive or recurrent pemphigus foliaceus prior to administration of PRN1008.

[0238] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0239] 1. A method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising: The study involves administering to a patient a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 168 days, during which the patient also receives a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to the 400 mg BID administration of PRN1008, the patient has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and is receiving a corticosteroid. Also provided are methods of maintaining the patient on low dose corticosteroid (LDCS) therapy, including administering at a dose of ≦0.5 mg / kg / day.

[0240] The present disclosure provides a method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising: Also provided is a method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF) comprising administering a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for at least 14 days.

[0241] Some embodiments of the present disclosure provide a method of achieving a primary endpoint in 17% to 37% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 14 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by The primary endpoint is about achieving the primary endpoint, which includes control of disease activity (CDA), defined as a check-up visit at which new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal.

[0242] In some embodiments, the method comprises achieving complete remission of the disease in 22% to 32% of the human patient population.

[0243] In some embodiments, the method comprises achieving complete remission of the disease in 27% of the human patient population.

[0244] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0245] In some embodiments, each member of the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0246] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008.

[0247] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone. In some embodiments, the first corticosteroid administered to the member of the human patient population is selected from the group consisting of prednisone, prednisolone, and methylprednisolone. In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0248] A method of achieving a primary endpoint in 27% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 14 days in combination with a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day). Also provided are methods of achieving a primary endpoint, including controlled disease activity (CDA), defined as a visit at which new lesions from PV or PF have ceased to form and confirmed lesions from PV and PF have begun to heal.

[0249] Some embodiments of the present disclosure provide a method of achieving a primary endpoint in 44% to 64% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 28 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by The primary endpoint will include control of disease activity (CDA), defined as a follow-up visit at which new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal. Regarding how the primary endpoint is achieved.

[0250] In some embodiments, the methods involve achieving complete remission of the disease in 49% to 59% of a human patient population.

[0251] In some embodiments, the method comprises achieving complete remission of the disease in 54% of a human patient population.

[0252] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0253] In some embodiments, each member of the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0254] In some embodiments, each member of the human patient population was characterized by naive or recurrent pemphigus vulgaris or naive or recurrent pemphigus foliaceus prior to administration of PRN1008.

[0255] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0256] Some embodiments of the present disclosure are directed to a method of achieving a primary endpoint in 54% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the human patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 28 days at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day). Prior to the administration of 400 mg BID of PRN1008, the patient population had (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points and was maintained on low-dose corticosteroid (LDCS) treatment, including administering corticosteroids at a dose of ≦0.5 mg / kg / day; the primary endpoint was control of disease activity (CDA), defined as a visit at which new lesions from PV or PF cease to form and confirmed lesions from PV and PF begin to heal.

[0257] Some embodiments of the present disclosure provide a method of achieving a primary endpoint in 63% to 83% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 84 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by The primary endpoint concerns how to achieve the primary endpoint, which includes control of disease activity (CDA), defined as a check-up visit at which new pemphigus lesions stop forming and confirmed pemphigus lesions begin to heal.

[0258] In some embodiments, the method comprises achieving the primary endpoint in 68% to 78% of the human patient population.

[0259] In some embodiments, the method comprises achieving the primary endpoint in 73% of the human patient population.

[0260] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0261] In some embodiments, each member of the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0262] In some embodiments, each member of the human patient population was characterized by non-sensitized or recurrent pemphigus vulgaris or non-sensitized or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by non-sensitized or recurrent pemphigus vulgaris.

[0263] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0264] A method of achieving a primary endpoint in 73% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 84 days in combination with corticosteroids at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day). Also provided are methods of achieving a primary endpoint, including controlled disease activity (CDA), defined as a visit at which new lesions from PV or PF have ceased to form and confirmed lesions from PV and PF have begun to heal.

[0265] Some embodiments of the present disclosure provide a method of achieving complete disease remission in 6% to 26% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 84 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day), wherein each member of the human patient population: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) Lloyd It is characterized by Complete remission refers to a method of achieving complete remission of the disease, defined as the absence of new, confirmed pemphigus lesions.

[0266] In some embodiments, the methods involve achieving complete remission of the disease in 11% to 21% of the human patient population.

[0267] In some embodiments, the methods include achieving complete remission of the disease in 15% to 17% of the human patient population.

[0268] In some embodiments, the method comprises achieving complete remission of the disease in 15% or 17% of the human patient population. In some embodiments, the method comprises achieving complete remission of the disease in 15% of the human patient population. In some embodiments, the method comprises achieving complete remission of the disease in 17% of the human patient population.

[0269] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0270] In some embodiments, each member of the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0271] In some embodiments, each member of the human patient population was characterized by non-sensitized or recurrent pemphigus vulgaris or non-sensitized or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by non-sensitized or recurrent pemphigus vulgaris.

[0272] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0273] A method of achieving complete disease remission in 15% or 17% of a human patient population being treated for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient population 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (B The method also provides a method for achieving complete remission of disease, including administering RN1008 400 mg BID (ID) for 84 days, where prior to administration of 400 mg BID, the patient population is (a) naive or recurrent PV; and (b) has a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points and is maintained on low-dose corticosteroid (LDCS) treatment, including administering corticosteroids at a dose of ≤0.5 mg / kg / day; complete remission means the absence of new, confirmed lesions from PV or PF.

[0274] Some embodiments of the present disclosure provide a method of achieving complete disease remission in 14% to 34% of a human patient population being treated for pemphigus, comprising: administering to each member of a human patient population a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 84 days, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); Each member of the patient population will be subject to an 84-day post-treatment period following administration of PRN1008, during which time neither PRN1008 nor corticosteroids will be administered, and each member of the human patient population will: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 45 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by Complete remission is defined as the absence of new, confirmed pemphigus lesions. Regarding methods for achieving complete remission.

[0275] In some embodiments, the method comprises achieving the primary endpoint in 19% to 29% of the human patient population.

[0276] In some embodiments, the method comprises achieving the primary endpoint in 23% to 25% of the human patient population.

[0277] In some embodiments, the method comprises achieving the primary endpoint in 23% or 25% of the human patient population. In some embodiments, the method comprises achieving the primary endpoint in 23% of the human patient population. In some embodiments, the method comprises achieving the primary endpoint in 25% of the human patient population.

[0278] In some embodiments, the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0279] In some embodiments, each member of the human patient population is being treated for pemphigus vulgaris or pemphigus foliaceus.

[0280] In some embodiments, each member of the human patient population was characterized by non-sensitized or recurrent pemphigus vulgaris or non-sensitized or recurrent pemphigus foliaceus prior to administration of PRN1008. In some embodiments, each member of the human patient population was characterized by non-sensitized or recurrent pemphigus vulgaris.

[0281] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0282] 1. A method of achieving complete disease remission in 23% or 25% of a human patient population undergoing treatment for pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising administering to the patient: The patient population received 400 mg of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 84 days, after which the patient population was subject to 84 days of post-treatment follow-up, during which follow-up the patient population received neither PRN1008 nor corticosteroids; throughout the administration of PRN1008 to the patient population, the patient population also received Prior to the administration of 400 mg QD of PRN1008, the patient population is maintained on low-dose corticosteroid (LDCS) treatment, including (a) naive or recurrent PV; and (b) Pemphigus Disease Activity Index (PDAI) skin scores of 8 to 45 points, and is administered a corticosteroid at a dose of ≤0.5 mg / kg / day. Methods of achieving complete remission of disease, meaning the absence of new, confirmed lesions from PV or PF, are also provided.

[0283] 1. A method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF) in a patient population, comprising administering to the population a dosing regimen as follows: (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) was administered at a starting dose of 400 mg QD (week 1), with allowed dose escalation to 400 mg BID in week 3 and 600 mg BID in week 5, completing the dosing period at 25 weeks; The conditions for dose escalation were either (a) patients who had not achieved control of disease activity (CDA) or (b) patients who had not reached the end of the consolidation phase (ECP); Control of disease activity was defined as the visit at which new lesions from PV or PF stopped forming and confirmed lesions from PV or PF began to heal; End of the consolidation phase was defined as a visit in which no new lesions from PV or PF had developed for at least 2 weeks and the majority of confirmed lesions from PV or PF had healed; A method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF), wherein, through administration of PRN1008 to the patient population, the patient population is also administered a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); and prior to the administration of 400 mg QD of PRN1008, the patient population has (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and is maintained on low-dose corticosteroid (LDCS) treatment, comprising administering a corticosteroid at a dose of ≦0.5 mg / kg / day.

[0284] 1. A method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF), comprising: The patient received a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily (BID) for 168 days, and throughout the administration of PRN1008, the patient also received no more than 0.5 mg / kg / day (≦0.5 mg / kg / day). Also provided is a method of treating a human patient suffering from pemphigus vulgaris (PV) or pemphigus foliaceus (PF) who is maintained on low-dose corticosteroid (LDCS) treatment comprising administering a corticosteroid at a dose of ≦0.5 mg / kg / day; and prior to the administration of 400 mg BID of PRN1008, the patient had (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points.

[0285] Some embodiments of the present disclosure provide a method of treating pemphigus in a human patient, comprising: administering to a human patient a 400 mg dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) twice daily, optionally in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); assessing whether the human patient has achieved control of disease activity and / or reached the end of the consolidation phase, and if the human patient has not achieved control of disease activity and / or reached the end of the consolidation phase, increasing the dose of PRN1008 to 500 mg BID or 600 mg BID; Includes: Control of disease activity (CDA) was defined as a check-up visit at which new pemphigus lesions stopped forming and confirmed pemphigus lesions began to heal; The present invention relates to a method of treating pemphigus in a human patient, wherein completion of the consolidation phase is defined as a medical visit in which no new pemphigus lesions have developed for a minimum of two weeks and the majority of confirmed pemphigus lesions have healed.

[0286] In some embodiments, the human patient is: Before administration of PRN1008, Subsensitivity or recurrent pemphigus; Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points; and A second corticosteroid at a maintenance dose of 0.5 mg / kg / day or less (≤0.5 mg / kg / day) It is characterized by:

[0287] In some embodiments, the methods comprise administering PRN1008 for 13 weeks.

[0288] In some embodiments, the first corticosteroid administered to the member of the human patient population and the second corticosteroid administered to the member of the human patient population are independently selected from prednisone, prednisolone, and methylprednisolone.In some embodiments, the first corticosteroid administered to the member of the human patient population is the same as the second corticosteroid administered to the member of the human patient population.In some embodiments, the first corticosteroid administered to the member of the human patient population is not the same as the second corticosteroid administered to the member of the human patient population.

[0289] 1. A method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF) in a patient population, comprising administering to the population a dosing regimen as follows: (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (PRN1008) was administered at a starting dose of 400 mg BID (week 1) with intrapatient dose titration allowed to 500 mg BID or 600 mg BID, completing the 13-week dosing period; The conditions for dose escalation were either (a) patients who had not achieved control of disease activity (CDA) or (b) patients who had not reached the end of the consolidation phase (ECP); Control of disease activity was defined as the visit at which new lesions from PV or PF stopped forming and confirmed lesions from PV or PF began to heal; End of the consolidation phase was defined as a visit in which no new lesions from PV or PF had developed for at least 2 weeks and the majority of confirmed lesions from PV or PF had healed; Also provided is a method of treating pemphigus vulgaris (PV) or pemphigus or pemphigus foliaceus (PF), wherein through administration of PRN1008 to a patient population, the patient population is also administered a corticosteroid at a dose of 0.5 mg / kg / day or less (≦0.5 mg / kg / day); prior to the administration of 400 mg QD of PRN1008, the patient population had (a) naive or recurrent PV; and (b) a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points and is maintained on low-dose corticosteroid (LDCS) treatment, comprising administering a corticosteroid at a dose of ≦0.5 mg / kg / day.

[0290] Pharmaceutical Composition: In some embodiments of the present disclosure, PRN1008 is administered as part of a pharmaceutical composition comprising: at least one compound selected from PRN1008 and a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0291] In some embodiments of the present disclosure, PRN1008 is orally administered as part of a pharmaceutical composition comprising: at least one compound selected from PRN1008 and a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0292] In some embodiments of the present disclosure, PRN1008 is administered in the form of at least one tablet comprising: at least one compound selected from PRN1008 and a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

[0293] In some embodiments, PRN1008 is administered with a glass of water.

[0294] In some embodiments, PRN1008 is administered with food.

[0295] In some embodiments, PRN1008 is administered without food.

[0296] The proportion and nature of any pharmaceutically acceptable excipients will be determined by the chosen route of administration and standard pharmaceutical practice. Except insofar as conventional pharmaceutically acceptable excipients are incompatible with PRN1008, such as by producing any undesirable biological effects or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, their use is contemplated within the scope of this disclosure.

[0297] Some non-limiting examples of materials that can serve as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and derivatives thereof, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) soluble fiber, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and sorbitol. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances utilized in pharmaceutical formulations.

[0298] Remington: The Science and Practice of Pharmacy, 21st ed., 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, pp. 1988-1999, Marcel Dekker, New York, also disclose additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for making and using them.

[0299] Those skilled in the art can readily select the appropriate form and route of administration depending on the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances.

[0300] Example The following examples are intended to be illustrative and are not intended to limit the scope of the disclosure in any way.

[0301] [Table 1-1] [Table 1-2] [Table 1-3] [Example]

[0302] An Open-Label, Phase 2, Pilot Study Examining the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Oral Treatment with the BTK Inhibitor PRN1008 in Patients With Newly Diagnosed or Recurrent Pemphigus Vulgaris The clinical study was an open-label, phase 2 pilot cohort study investigating the safety, clinical activity, pharmacokinetics, and pharmacodynamics of oral treatment with the BTK inhibitor PRN1008 in patients with newly diagnosed or recurrent pemphigus, such as newly diagnosed or recurrent pemphigus vulgaris. The study was conducted in accordance with ethical guidelines.

[0303] An important goal of drug development is to improve the risk-benefit ratio of treatment. The current standard of care for pemphigus and other immune-mediated diseases is high-dose CS alone or in combination with other immunosuppressants, which has a high risk of adverse events, delayed onset of action, long-term B cell depletion, and poor suitability for chronic administration. CS has limited long-term usefulness because the high doses required for efficacy are associated with serious adverse events.

[0304] The primary objectives of the study were: (1) to evaluate the clinical safety of PRN1008 in patients with pemphigus, e.g., pemphigus vulgaris (PV), over a 12-week (Part A) or 24-week (Part B) treatment period; and (2) to evaluate the clinical activity of PRN1008 in patients with pemphigus, e.g., PV, according to the criteria in the European Academy of Dermatology and Venereology (EADV) 2014 Pemphigus S2 Guideline (Hertl et al., 2015), which modified the definition of complete remission and excluded the 2-month durability portion of the definition. A secondary objective of the study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of PRN1008 in patients with pemphigus, e.g., PV. Exploratory endpoints of the study were to evaluate the relationship between PK and PD and between PK and PD and efficacy and safety in this patient population.

[0305] [Table 2]

[0306] In Part A (a 12-week treatment-duration study), the initial PRN1008 dosing was 400 mg BID, with intrapatient dose adjustments up to 600 mg BID allowed based on BTK occupancy and clinical response, as well as corticosteroid rescue treatment, if necessary (Table 1). In Table 1, "well tolerated" is defined as the absence of grade 3 or higher gastrointestinal AEs or grade 2 non-gastrointestinal AEs, including liver function changes, related to PRN1008 therapy. Low-dose corticosteroids (corticosteroids ≤ 0.5 mg / kg / day; corticosteroids were prednisone or equivalent) could be administered in combination with PRN1008.

[0307] The maximum PRN1008 dose permitted in Part A was 600 mg BID after dose adjustment. Patients were treated under a corticosteroid tapering protocol that included: (1) maintaining the corticosteroid dose for 2 weeks after disease control was achieved, followed by reducing the corticosteroid dose by 15% every 3 weeks; or (2) following the glucocorticoid tapering schedule disclosed in Table 1 of Werth VP et al., Arch Dematol. 2008 January;144(1):25-32 (hereafter referred to as the Werth tapering). Typically, subjects in Part A received 12 weeks of twice-daily PRN1008 treatment, beginning on Day 1 and ending on Study Day 85, with an additional 12 weeks of follow-up (total duration of participation for an individual subject was approximately 28 weeks). Clinical response and tolerability were typically assessed at each visit.

[0308] [Table 3]

[0309] In Part B (24-week treatment period), unless the patient was eligible to cross over from Part A to Part B, initial PRN1008 dosing was 400 mg QD, with intrapatient dose escalation to 400 mg BID allowed for inadequate clinical response after the Week 3 visit (and then again to 600 mg BID after the Week 5 visit, if necessary) (Table 2). Inadequate clinical response in Table 2 was determined at the investigator's discretion. Generally, clinical response was indicated by any improvement seen in the first 2 weeks with CDA achieved by the Week 5 visit. Typically, subjects in Part B received PRN1008 once or twice daily for 24 weeks, starting on Day 1 and ending on Study Day 169, with a follow-up visit 4 weeks later (total duration of participation for an individual subject is approximately 32 weeks). Low-dose corticosteroids (corticosteroids ≦0.5 mg / kg / day, where the corticosteroid was prednisone or equivalent) could be administered in combination with PRN1008. Clinical response and tolerability were typically determined at each visit.

[0310] PRN1008 initial dose selection: 400 mg BID (Part A): The 400 mg BID starting dose was based on a dose known to result in approximately 70% BTK occupancy at trough (average daily occupancy of approximately 85%), adjusted by the results of a relative bioavailability study, with the tablet having approximately 70% of the exposure of an equivalent dose of the liquid formulation. Adequate BTK occupancy with 400 mg BID dosing of IR tablets has been confirmed in most patients with pemphigus studied to date. To confirm target achievement, BTK occupancy measurements after the first dose were processed promptly and provided to the treating physician in time for the follow-up visit on Day 15 (Part A only). This dose level demonstrated a sufficient safety margin for exposure in chronic toxicity studies.

[0311] 400 mg qd (Part B): A dose-response relationship between predose BTK occupancy and clinical efficacy has been observed in some, but not all, animal studies. Because it was unclear whether a once-daily PRN1008 dose would provide sufficient pharmacodynamic benefit, a 400 mg QD dose was tested in Part B, with the option for rapid escalation to higher doses after the week 3 visit. This dose level provided a sufficient safety margin for exposure in chronic toxicity studies.

[0312] Maximum dose of 600 mg bid: A dose level 50% higher than the target upper dose level of 400 mg bid was chosen to achieve higher exposure. The 500 mg / kg bw was chosen arbitrarily based on previous clinical safety data in healthy volunteers at 100 mg / kg bw and sufficient safety margins for exposure in animal toxicity studies.

[0313] Study population: The study population consisted of male or female patients with newly diagnosed (i.e., naïve to an effective induction treatment regimen) or recurrent biopsy-proven mild-to-severe PV (PDAI 8-60) who were clinically tolerated for initial PRN1008 monotherapy. Patients without mucosal involvement but with a medical history suggestive of PV were allowed to enter the study, so it is possible that some patients with clinical features suggestive of pemphigus foliaceus (PF), distinct from this disease, were enrolled.

[0314] Patients were considered to have withdrawn from the study early if they withdrew from the study before receiving one or more doses of study medication.

[0315] For Part A, 52 patients were screened for eligibility over a maximum 28-day period. Twenty-five patients were excluded: six were unable to provide informed consent and agree to the screening schedule; six screened positive for viruses (hepatitis B and C or HIV); five screened positive for TB; four were out of age range or did not have biopsy-confirmed mild-to-moderate PV; and four were excluded for other reasons. Twenty-seven patients were enrolled and received PRN1008 (400 mg BID to 600 mg BID); all started at 400 mg BID; three patients underwent dose escalation (one patient to 500 mg BID and two patients to 600 mg BID). One patient discontinued early due to an unrelated AE (acute respiratory failure) before the primary endpoint CDA adjudication. Two patients discontinued early after the primary endpoint CDA adjudication, and two unrelated AEs (pancreatic pseudocyst; chest pain) were reported between the primary endpoint CDA adjudication and completion of treatment. Twenty-four enrolled patients underwent a 12-week post-treatment evaluation.

[0316] For Part B, 18 patients were screened for eligibility over a maximum of 28 days. Fifteen patients were enrolled and received 400 mg QD, with intrapatient dose titration allowed (400 mg BID, 600 mg BID). One patient discontinued at week 9 due to a worsening of pemphigus that began during screening after stopping MMF and continued, resulting in hospitalization at week 9.

[0317] Baseline demographic characteristics for patients enrolled in Parts A and B are summarized in Table 3. In Table 3, moderate-severe included patients with severe recurrent disease according to PDAI severity quartiles for recurrent disease versus mild-moderate newly diagnosed disease.

[0318] [Table 4]

[0319] Inclusion Criteria (Part A and Part B unless noted below): The following inclusion criteria were used to inform patient enrollment in this study. 1. Male or female patients aged 18-80 years with biopsy-confirmed (positive direct immunofluorescence and H&E microscopic appearance) mild to moderate PV (PDAI 8-45) in Part A and mild to severe PV (PDAI 8-60) in Part B. 2. Newly diagnosed or relapsed patients in whom initial PRN1008 monotherapy or combination therapy with low-dose corticosteroids (≤0.5 mg / kg prednisolone or equivalent) is clinically tolerated, provided that a favorable clinical response to PRN1008 is anticipated to allow tapering of the corticosteroid treatment regimen. 3. BMI > 17.5 and < 40 kg / m 2 (Part A only) 4. Adequate hematological, hepatic, and renal function (absolute neutrophil count ≥ 1.5 × 10 9 / L, Hgb>9g / dL, platelet count ≥100×10 9 / L, AST / ALT ≤ 1.5 × ULN, albumin ≥ 3 g / dL, creatinine ≤ ULN (Part A) and creatinine ≤ 1.5 × ULN (Part B). 5. Female patients of reproductive potential must agree to use effective contraception (hormonal contraception that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, condoms, or sexual abstinence) for the duration of active treatment in the study. Postmenopausal women should have menopause confirmed by FSH testing, unless surgically sterile. 6. Able to provide written informed consent and agree to the assessment schedule.

[0320] Exclusion criteria: The following exclusion criteria were used to inform patient enrollment in this study. 1. Previous use of BTK inhibitors Patients enrolled in the previous version of the protocol and still in their 12-week active treatment period with PRN1008 were initially eligible to continue treatment at their current dose level under the amended protocol for an additional 12 weeks, for a total of 24 weeks, after review and signing of an EC-approved patient consent. Patients who completed Part A and did not discontinue the study due to a medical condition that could compromise safety assessments or due to a PRN1008-related adverse event could be screened for participation in Part B. 2. Pregnant or breastfeeding women 3. ECG findings of QTc >450 msec (men) or >470 msec (women), uncontrolled atrial fibrillation (i.e., symptomatic patients or ventricular rate >100 beats / min on ECG), or other clinically significant abnormalities 4. History of any type of malignancy other than surgically removed non-melanoma skin cancer or in situ cervical cancer within 5 years prior to the date of dosing 5. Use of immune response modifiers during the following periods prior to Day 1: other immune response modifiers other than corticosteroids as concomitant therapy, not detailed in this exclusion section; 1 week: cyclophosphamide; 4 weeks: IVIG, Kineret (anakinra), and Enbrel (etanercept); 12 weeks: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatacept), Actemra (tocilizumab), Cimzia (certolizumab), Cosentyx (secukinumab), plasma exchange; 6 months: Rituxan / MabThera (rituximab), ofatumumab, any other anti-CD20 antibodies, other long-acting biologics 6. Prednisone (low-dose corticosteroids) greater than 0.5 mg / kg per day within the 2 weeks prior to Day 1 7. Use of proton pump inhibitors such as omeprazole and esomeprazole (it is permissible to switch patients to an H2 receptor blocker before the first dose of PRN1008) 8. Concomitant use of a strong to moderate inducer or inhibitor of CYP3A (Appendix 2) within 3 days or 5 half-lives (whichever is longer) of study drug administration 9. Use of CYP3A sensitive substrate drugs (Appendix 3) with a narrow therapeutic index within 3 days or 5 half-lives (whichever is longer) of study drug administration, including but not limited to alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine 10. Received any investigational drug (or is currently using an investigational device) within 30 days or at least 5 elimination half-lives of each (whichever is longer) prior to receiving the first dose of the investigational drug. 11. History of substance abuse within the past 12 months 12. Alcoholism or excessive alcohol use, defined as regular consumption of more than approximately 3 standard drinks per day 13. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection preventing adequate study drug absorption 14. History of anorexia nervosa in the past 5 years or a period of being underweight (BMI<17.5) for 3 months or more 15. Donation of 1 or more units of blood or blood products within 4 weeks prior to Day 1 16. History of solid organ transplantation 17. History of epilepsy or other forms of seizures within the past 5 years 18. Screen positive for HIV, Hepatitis B (surface and core antibodies not associated with vaccination), or Hepatitis C (anti-HCV antibodies confirmed by Hep C RNA) 19. Positive interferon gamma release assay (IGRA) (e.g., T-spot TB test, QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold Plus (QFT Plus)) at screening, unless the patient has latent TB and all three of the following conditions are true: a. Chest x-ray shows no evidence of active tuberculosis (TB) disease b. Absence of clinical signs and symptoms of pulmonary and / or extrapulmonary TB disease c. Record of receipt of one of the following prophylaxis regimens: i. Oral daily isoniazid for 6 months or ii. Oral daily rifampin (RIF) for 4 months or iii. Weekly isoniazid and rifapentine (3HP) for 3 months On a case-by-case basis, after review and approval by the sponsor, a local TB test that is negative and deemed equivalent to one of the above tests may be used for eligibility purposes, e.g., QuantiFERON®-TB Gold or QuantiFERON-TB. If the Gold Plus (QFT Plus) is positive and the on-site blood test or T-spot TB test is negative, the on-site result may be used to enroll the patient, with sponsor approval. 20. History of serious infections requiring intravenous therapy and with the potential for recurrence 21. Live vaccine within 28 days prior to baseline or plan to receive it during the study 22. Any other clinically significant disease, condition, or medical history that, in the opinion of the investigator, interferes with the subject's safety, study assessments, and / or study procedures

[0321] Previous Therapy: Use of immune response modifiers within the following periods prior to Day 1 was not permitted: (1) 1 week for cyclophosphamide; (2) 4 weeks for Kineret® (anakinra), intravenous gamma globulin (IVIG), and Enbrel® (etanercept); (3) 12 weeks for Remicade® (infliximab), Humira® (adalimumab), Simponi® (golimumab), Orencia® (abatacept), Actemra® (tocilizumab), Cimzia® (certolizumab), Cosentyx™ (secukinumab), plasma exchange; and (4) 6 months for Rituxan® / MabThera® (rituximab), ofatumumab, any other anti-CD20 antibody, or any other long-acting biologic.

[0322] Combination therapy: Concomitant use of immunosuppressive medications other than low-dose corticosteroids was avoided unless rescue criteria were invoked. Concomitant use of known strong to moderate inducers or inhibitors of CYP3A within 14 days or 5 half-lives (whichever is longer) of PRN1008 dosing was avoided. Use of CYP3A-sensitive substrates with narrow therapeutic indices within 14 days or 5 half-lives (whichever is longer) of PRN1008 dosing was avoided, including but not limited to alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine. Proton pump inhibitors were not permitted.

[0323] The use of oral prednisone was considered acceptable in some circumstances. For study entry, the oral prednisone dose in the 2 weeks prior to Day 1 could not exceed 0.5 mg / kg per day (inhaled and mucosal [for symptomatic treatment of oral lesions] corticosteroids were permitted). If patients entered the study on low-dose corticosteroids, the regimen could be maintained for the first 2 weeks of PRN1008 therapy. At the Day 15 review, a favorable clinical response to PRN1008 could initiate corticosteroid tapering using a Werth tapering regimen. In some circumstances, corticosteroids could be added or the dose increased, with or without discontinuing PRN1008, if clinically appropriate.

[0324] judgement: After providing written informed consent, subjects typically completed screening assessments within 28 days prior to the first dose of PRN1008: (1) medical history and concomitant medication review; (2) PDAI, ABSIS assessment; (3) inclusion and exclusion criteria review; (4) Measurement of height and weight; (5) Physical examination; (6) 12-lead ECG; (7) Vital signs (blood pressure, heart rate, respiratory rate, and temperature); (8) Laboratory tests (hematology, coagulation, serum chemistry, and urinalysis) for HIV, Hepatitis B (surface and core antigens and antibodies), Hepatitis C (anti-HCV antibodies confirmed by Hep C RNA); (9) TB screening with T-spot TB test, QuantiFERON®-TB Gold, or QuantiFERON®-TB Gold Plus (QFT Plus); (10) Serum pregnancy test for women of childbearing potential; (11) FSH (only in postmenopausal women who are not surgically sterile); (12) Skin biopsy if not already performed: H&E staining of the lesion, direct immunofluorescence around the lesion.

[0325] Pemphigus disease activity was monitored using PDAI and ABSIS assessments. For most subjects in Parts A and B, an abbreviated physical examination, PDAI, and ABSIS assessments were performed at the following times: (1) Day 1, Week 1 (pre-dose); (2) Day 15, Week 3 (± 3 days); (3) Day 29, Week 5 (± 3 days); (4) Day 57, Week 9 (± 7 days); (5) Day 85, Week 13 (± 7 days); (6) Day 113, Week 17 (± 7 days); (7) Day 141, Week 21 (± 7 days); (8) Day 169, Week 25 (± 7 days); (9) Day 197, Week 29 (± 7 days); and (10) any unscheduled visit. When appropriate, photography was used to document skin disease changes.

[0326] Subject quality of life was monitored using ABQOL and TABQOL assessments. For most subjects in Parts A and B, ABQOL and TABQOL assessments were performed at the following assessments: (1) Day 1, Week 1 (pre-dose); (2) Day 15, Week 3 (± 3 days); (3) Day 29, Week 5 (± 3 days); (4) Day 57, Week 9 (± 7 days); (5) Day 85, Week 13 (± 7 days); (6) Day 113, Week 17 (± 7 days); (7) Day 141, Week 21 (± 7 days); (8) Day 169, Week 25 (± 7 days); (9) Day 197, Week 29 (± 7 days); and (10) any unscheduled visit.

[0327] Specific assessments to assess treatment safety included: (1) frequency and type of AEs; (2) clinical tests; (3) the SNAQ appetite questionnaire; and (4) vital signs. Typically, patients were under observation in the clinic for 2 hours after administration of the first PRN1008 dose and until PK samples were taken.

[0328] Primary endpoint: The primary safety endpoint was the incidence of treatment-emergent AEs (TEAEs), including clinically significant changes in physical examination, laboratory tests, and vital signs.

[0329] The primary efficacy endpoint was the proportion of subjects able to achieve control of disease activity (CDA) within 4 weeks of initiating PRN1008 treatment without requiring a dose of prednisone >0.5 mg / kg.

[0330] Secondary endpoints: The following clinical activity endpoints were also determined: (1) the proportion of subjects able to achieve CDA without corticosteroids within 4 weeks; (2) the proportion of subjects able to achieve complete response (CR) without corticosteroids within 12 weeks (and 24 weeks in Part B); (3) the proportion of subjects able to achieve CR without requiring a dose of prednisone greater than 0.5 mg / kg within 12 weeks (and 24 weeks in Part B); (4) time to CDA; (5) time to CR; (6) time to end of the intensification phase; (7) time to relapse after discontinuation of PRN1008 treatment; (8) cumulative corticosteroid use over the first 12 weeks (and 24 weeks in Part B); and (9) Pemphigus Disease Area Indicator (PDIA) score at each follow-up visit. (10) change from baseline in Autoimmune Bullous Disease Quality of Life (ABQOL) and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) scores at each follow-up visit; and (11) change from baseline in appetite (SNAQ score) at each follow-up visit.

[0331] Clinical activity endpoints were as defined by the EADV 2014 pemphigus S2 guideline (Hertl et al. 2015), except that CR was defined as CR at a single time point rather than ≥2 months.

[0332] PK / PD scale: PK endpoints examined included plasma concentrations of PRN1008 at approximately the time of maximum concentration on day 1 and at various subsequent times during outpatient dosing. PD endpoints examined included individual BTK occupancy percentage in peripheral blood mononuclear cells (PBMCs) at 2 and 24 hours after the first PRN1008 dose and at various subsequent times during outpatient dosing, as well as change from baseline in anti-dsg1-3 autoantibody levels by ELISA at various time points. Exploratory PK / PD analyses investigated the effect of covariates, if any, on PK and / or PD, and the relationship between PK, PD, and efficacy in this population.

[0333] Analysis population: Four study populations were defined: a screening population; a safety population; an efficacy population; and a pharmacokinetic population.

[0334] All participants who provided informed consent and assessed screening measures for study participation were included in the screening population. All participants who received at least one dose of PRN1008 were included in the safety analysis (safety population). The safety population was defined for all safety analyses.

[0335] All patients who received at least one dose of PRN1008 were included in the efficacy analysis (efficacy population). Subject response and disease progression were determined using PDAI, ABSIS, ABQOL, and TABQOL scores.

[0336] The pharmacokinetic population included participants who provided sufficient plasma concentration data to allow PK analysis. Participants could be excluded from the PK population if they significantly violated the inclusion or exclusion criteria, significantly deviated from the protocol, or had unavailable or incomplete data, all of which could affect the analysis.

[0337] Clinical Adverse Events: An adverse event (AE) is any undesirable medical occurrence in a participant receiving a medicinal product or in a clinical trial participant that does not necessarily have a causal relationship to the intervention. Thus, an AE can be any unfavorable, unintended sign (including, for example, abnormal laboratory findings), symptom, or disease temporarily associated with the use of an investigational product, regardless of whether it is considered product-related. Investigators were instructed to report in detail in source documents all AEs encountered during the clinical study, from the participant's consent date through the follow-up visit. Because it was anticipated that there may be fluctuations in pemphigus disease activity intended to be captured in other measures, investigators were also instructed to report any pre-existing conditions that worsened during the study, excluding the disease under study, as AEs.

[0338] Investigators were instructed to grade AEs according to the NCI CTCAE, Version 4.0 or higher. For any AE not in the CTCAE, the following intensity grading could be used: Grade 1: Mild; no or mild symptoms; clinical or laboratory findings only; no intervention required. Grade 2: Moderate; minimal, local or non-invasive intervention required; limitations in age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; requires hospitalization or prolonged hospitalization; is disabling; limits self-care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention required. Grade 5: Death related to an AE.

[0339] Investigators were instructed to use the study participant's information, the circumstances surrounding the event, and an assessment of any potential alternative causes to determine whether the AE was considered related to the study drug and to indicate a corresponding "yes" or "no." Investigators were asked to follow the following guidelines to be considered in determining whether an AE was related to the study drug: (1) the temporal relationship between the occurrence of the event and the initiation of the study drug; (2) considering the course of the event, particularly the effects of dose reduction, discontinuation of the study drug, or reintroduction of the study drug (if applicable); (3) known association of the event with the study drug or similar treatment; (4) known association of the event with the disease under study; (5) the presence in the study participant of risk factors or use of concomitant medications known to increase the occurrence of the event; and (6) the presence of non-treatment-related factors known to be associated with the occurrence of the event.

[0340] A serious adverse event (SAE) is any experience (clinical AE or abnormal laboratory test) that suggests a significant risk, contraindication, side effect, or caution. An SAE must meet at least one of the following criteria at any dose level: (1) fatal (resulting in death); (2) life-threatening; (3) requiring hospitalization for treatment or prolonged hospitalization; (4) resulting in permanent or significant disability / incapacity; (5) resulting in a congenital anomaly / birth defect; or (6) medically significant or requiring intervention to prevent any of the outcomes listed above.

[0341] Research Design Part A: Part A was a multicenter, open-label, single-arm phase 2 study (NCT02704429) designed to evaluate the efficacy and safety of PRN1008 in patients with pemphigus. Patients from 13 centers in Australia, Croatia, France, Greece, and Israel were screened for inclusion. Fifty-two patients in Australia, Croatia, France, Greece, and Israel were screened, with 25 not meeting the eligibility criteria. The high screening failure rate was due to patients testing positive for hepatitis B or C (n=6) or tuberculosis (n=5). Twenty-seven patients were enrolled and included in the safety analysis. One patient was excluded due to a non-treatment-related AE, leaving a total of 26 patients in the modified intention-to-treat (mITT) population used for the primary efficacy analysis. Two other patients withdrew from the study due to non-treatment-related AEs, leaving a total of 24 patients who completed the study.

[0342] The mean patient age was 52.1 (range: 37-72), and the majority of patients were Caucasian (81.5%) and female (55.6%). Nine patients (33.3%) were newly diagnosed, and 18 (66.7%) had recurrent disease. The mean time from diagnosis to screening was 6 years (range: 0-25). Eleven patients had mild-to-moderate pemphigus, and 16 patients had moderate-to-severe pemphigus. Twenty-six patients received concomitant CS medications at some point during the study. A total of 22 patients had the PV phenotype (13 anti-dsg3+, 10 anti-dsg1 / 3). +), three had the PF phenotype (anti-dsg1+), and one patient was double-negative for anti-dsg1 / 3. The median CS dose at study entry was 14 mg / day, with a range of 0 to 30 mg / day.

[0343] Patients received an initial dose of 400 mg PRN1008 twice daily (BID), which could be titrated up to 600 mg BID at the investigator's discretion. Treatment duration was 12 weeks, with an additional 12 weeks of post-treatment follow-up. Three patients had their dose increased due to worsening disease activity. One patient achieved CDA on day 15 and was increased to 500 mg bid with CS on day 34. Two additional patients were increased to 600 mg bid; one on day 23 with a 25 mg CS dose (CDA achieved on day 29), and one on day 57.

[0344] Patients were permitted to receive CS at 0.5 mg / kg / day or less in addition to the study drug regimen unless disease "rescue" was required. Patients were monitored throughout the study for vital signs, adverse events (AEs), concomitant medications, PK / PD, and other laboratory tests.

[0345] The primary efficacy endpoint was the proportion of patients who achieved control of disease activity (CDA) within 4 weeks of initiating PRN1008 treatment at a dose of ≤0.5 mg / kg / day CS (Murrell DF et al., 2008). CDA was defined as the time when new lesions ceased to form and confirmed lesions began to heal. The primary safety endpoint was the incidence of treatment-emergent adverse events (TEAEs), including clinically significant changes in physical examination, laboratory tests, and vital signs. Secondary endpoints included PK / PD data measured by BTK occupancy in peripheral blood mononuclear cells (PBMCs) 2 and 24 hours after the first PRN1008 dose, as well as changes from baseline in anti-dsg1 and anti-dsg3 autoantibody levels at various time points.

[0346] Due to the small sample size, all p-values ​​obtained from inferential analyses were considered informative. In general, all significance tests were two-sided at the 0.05 significance level. All tests were performed without adjusting for multiplicity or multiple comparisons. Two-sided 80% and 95% CIs for the efficacy endpoint response rates are presented.

[0347] All but one patient had therapeutic levels of BTK occupancy in peripheral leukocytes (target ≥70%). High occupancy was achieved on day 1 after the first dose, confirming that an adequate initial dose was used. The mean day-1 BTK occupancy at 2 hours post-dose was 88%, compared with a pre-dose mean of 87% at steady state. Rapid systemic clearance and slow off-kinetics resulted in a minimum plasma level (trough) of 9.5 ng / mL at 12 hours post-dose, with a high BTK occupancy of 87% maintained.

[0348] Fourteen of 26 (54%) patients achieved CDA with low-dose CS by day 29 (after a 4-week period) (Figure 1). This endpoint occurred in 12 of 23 (52%), 1 of 1 (100%), and 1 of 2 (50%) patients in the 400, 500, and 600 mg BID dosing subgroups, respectively. A total of three patients achieved CDA without the use of CS before the week 5 visit (Figure 2). Nineteen of 26 (73%) patients achieved CDA by day 85 with low-dose CS (Figures 1 and 2).

[0349] Six of 26 (23%) patients achieved a CR during the study period (Figure 3). Four patients (15%) achieved a CR by day 85 at CS doses ≤ 0.5 mg / kg / day, and two additional patients achieved a CR by day 141 at CS ≤ 0.5 mg / kg / day. Of the patients who completed the study, four of 24 (16.7%) achieved a CR during the treatment period, and another Two patients (i.e., a total of 6 of 24, 25%) achieved a CR during follow-up (by day 141) with a CS ≤ 0.5 mg / kg / day. The mean CS dose was 14 mg / day (SD = 11) at baseline and 12 mg / day (SD = 10) after 12 weeks of treatment for all patients. For patients who achieved a CR, the mean CS dose at the time the patient achieved a CR was 8 mg (range: 1-20 mg). The median duration of CR was 96 days after treatment, during which the mean CS dose was 8 mg / day (range: 0.7-20 mg / day).

[0350] A 70% median reduction in PDAI scores and an associated reduction in anti-dsg3 antibodies was seen over 12 weeks of treatment (Figures 4 and 5). PDAI score reductions were seen as early as 2 weeks into treatment in patients with moderately severe disease. In 11 patients with milder disease, PDAI scores declined over the first 4 weeks of treatment, and all patients had a PDAI score of 5 or less at the 85-day visit. A median reduction in autoantibody levels of up to 65% was observed, including in patients with high levels of autoantibodies at baseline.

[0351] Results were similar in all subgroups, including new cases versus chronic cases, anti-dsg1 and -3 antibody titers <100 versus ≥100, and mild versus moderate-to-severe pemphigus patients. CDA rates in recurrent and newly diagnosed patients were 13 of 18 (72%) and 6 of 8 (75%), respectively. Among anti-dsg3 antibody-positive patients, the CDA rate was slightly higher (64%) than in the overall mITT population.

[0352] Overall, PRN1008 rapidly improved clinical symptoms, with >50% of patients in Part A achieving CDA within 4 weeks and an overall median reduction in PDAI score of 70%. Efficacy in subgroups ranged from 43 to 64%, suggesting that treatment success was not affected by disease characteristics and may be effective in all patients diagnosed with pemphigus. 90% of patients did not require dose escalation to achieve a response. The high proportion of patients (54%) who achieved CDA by week 4 despite the lack of reduction in anti-dsg3 suggests that this may be the result of a rapid anti-inflammatory effect and may be independent of autoantibody reduction. By week 12, reductions were observed in both PDAI score and anti-dsg3 levels. This observation may be due to PRN1008's three simultaneous mechanisms of action: rapid anti-inflammatory effect, neutralization of pathogenic autoantibodies, and blockade of autoantibody production.

[0353] Notably, two-thirds of the study population in Part A were patients with recurrent pemphigus who had been living with the condition for a significant period of time (average: 6 years) and who were potentially refractory to multiple treatments. Additionally, over 50% of enrolled patients had PDAI scores consistent with moderate-to-severe pemphigus. Most other pemphigus treatments have only been studied in newly diagnosed patients or patients who had been treated for up to 2 years (Chams-Davatchi C et al., 2013). In this study, PRN1008 demonstrated efficacy in a population that is very difficult to treat and closely represents the real-world demographics of this condition.

[0354] PRN1008 also demonstrates the potential for reduced CS use compared with current standard of care. Patients achieved symptomatic improvement with little to no CS (average reduction from baseline of 14 mg / day to 8 mg / day during CR), which is preferable to the usual standard of care for pemphigus (typically 1 mg / kg / day or at least 60 mg / day) (Gregoriou S et al., 2015; Cholera M et al., 2016). Three patients achieved CDA before week 5 without CS use, and four additional patients achieved CR at week 13 without CS use. Only three patients required dose escalation beyond the standard 400 mg bid, and only four patients required CS rescue >0.5 mg / kg 12 weeks after discontinuing PRN1008. It is possible that a longer duration of PRN1008 therapy may allow for further reduction or even cessation of CS use. This, if realized, may reduce the CS-induced AEs common with current therapy. This will reduce the risk of CS and mitigate the adverse consequences of long-term, high-intensity CS therapy (Hwang JL et al., 2014;Rostaing L et al., 2016).

[0355] Twenty of 27 patients (74%) in the safety population experienced a TEAE. TEAEs reported by >10% of patients are shown in Appendix 17. AEs judged to be related to study drug included nausea (15%), upper abdominal pain (11%), and headache (11%). Most AEs were mild to moderate in severity (94 / 97 were grade 1 or 2) and were often transient.

[0356] Three patients experienced serious adverse events (SAEs). The first and only treatment-related SAE was cellulitis (grade 3) on day 26 in a patient with type 2 diabetes and 9 years of recurrent pemphigus. After a 3-day course of IV antibiotics, which stopped the study drug, the patient was discharged and completed the full 12 weeks of treatment. The second SAE was a pancreatic pseudocyst discovered on day 29, after which the patient was withdrawn from the study for elective surgery. The third SAE was acute respiratory failure (day 8) due to inflammation of an undiagnosed congenital pulmonary sequestration. The patient did not recover and died 34 days after his last exposure to PRN1008; the cause of death was determined to be cerebral herniation and cerebral artery embolism following pulmonary surgery.

[0357] Safety results of PRN1008 in Part A demonstrate a favorable risk / benefit profile. The majority of TEAEs reported in this study were mild and transient, with no reported cases of AEs commonly associated with marketed BTKis, such as major bleeding, atrial fibrillation, or thrombocytopenia / neutropenia.

[0358] Limitations of the Part A study include those typically associated with open-label trial designs, such as the lack of a control group. Therefore, the data should be interpreted with caution, and placebo-controlled studies are needed to provide a more robust assessment. The study duration was short, with 12 weeks of treatment and 12 weeks of follow-up, and longer-term data are needed. The sample size of 27 patients was small. However, pemphigus is a relatively rare disease, and therefore, any study in this disease area will likely be relatively modest in size. Although approximately half of the study population was enrolled from Greece, the clinical and demographic characteristics of patients in the ITT population may be broadly representative of patients with pemphigus.

[0359] Research Design Part B: Part B was a multicenter, open-label, single-arm Phase 2 study (NCT02704429) designed to further evaluate the efficacy and safety of PRN1008 in patients with pemphigus. Patients received an initial dose of 400 mg PRN1008 once daily (QD), with dose adjustments up to 600 mg BID at the investigator's discretion. Treatment duration was 24 weeks, with an additional 4 weeks of post-treatment follow-up. One patient withdrew at week 5 due to worsening pemphigus.

[0360] In Part B, treatment with PRN1008 resulted in a high CDA rate (Figures 6, 7, 8A, and 8B). Patients receiving 400 mg QD dosing were able to achieve CDA at 4 weeks with low-dose corticosteroids, but at a lower rate compared with BID dosing. The overall CDA rate at 12 weeks was 80% (12 of 15 patients).

[0361] Patients on the 400 mg QD dose had a lower complete remission rate compared with the BID dose at 12 weeks (Figures 9A and 9B). However, by 24 weeks, a 94% reduction in median PDAI activity score and a 79% reduction in mean PDAI activity score were observed for patients enrolled in Part B (Figures 10 and 11). The median PDAI went from 12 on day 1 to 4 at 12 weeks and 1 at 24 weeks, with 10 of 15 patients (67%) achieving a complete remission of 1 at 24 weeks. Or a PDAI of 0 was reached.

[0362] Additionally, 24 weeks of PRN1008 treatment reduced daily corticosteroid use (Figure 11). The cumulative steroid dose increased between the first and second 12 weeks in Part A, while the reverse was true in Part B.

[0363] Overall, PRN1008 was well tolerated in Part B and continued to maintain a positive benefit / risk profile for patients with pemphigus. All treatment-related AEs were mild to moderate and transient. Part B treatment-related adverse events were consistent with those observed in Part A, with the most common AEs being gastrointestinal in origin. In Part B, two of 15 patients reported mild related infections (one event each: grade 1 nasopharyngitis; grade 1 tracheitis). Treatment-related AEs with an incidence greater than 10% were mild to moderate (grades 1 and 2) nausea, abdominal distension, infection, and oropharyngeal pain.

[0364] Certain documents are referenced in this application in short citation form. A more detailed listing of the references is provided below. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med., 369(1):32–42, 2013. Bizikova P, Olivry T, Mamo LB, Dunston SM. Serum autoantibody profiles of IgA,IgE and IgM in canine pemphigus foliaceus. Vet Dermatol 2014;25:471~e75. Bizikova P、Dean GA、Hashimoto T、Olivry T. Cloning and establishment of canine desmocollin-1 as a major autoantigen in canine pemphigus foliaceus. Vet Immunol Immunopathol 2012;149:197~207. Development Report #DVR0210、A Pilot Study of the Efficacy of a Bruton’s Tyrosine Kinase Inhibitor(BTKi) in the Treatment of Dogs with Pemphigus Foliaceus (PF). Principia Biopharma,Inc.、South San Francisco、CA、94080、U.S.A. Evans EK、Tester R、Aslanian S、Karp R、Sheets M、Labenski MT、Witowski SR、Lounsbury H、Chaturvedi P、Mazdiyasni H、Zhu Z、Nacht M、Freed MI、Petter RC、Dubrovskiy A、Singh J、Westlin WF. Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans. J Pharmacol Exp Ther、346(2):219~28、2013. Hertl,M.、Jedlickova,H.、Karpati,S.ら(2015)、Pemphigus. S2 Guideline for diagnosis and treatment - guided by the European D ermatology Forum(EDF) in cooperation with the European Academy of Dermatology and Venereology(EADV). Journal of the European Academy of Dermatology and Venereology、29:405~414. doi:10.1111 / jdv.12772. Horvath,B.、Huizinga,J.、Pas,H.H.、Mulder,A.B.、Jonkman,M.F.、Low Dose rituximab is effective in pemphigus. Br J Dermatol.166(2):405~12、2012. Imbruvica[package insert].Pharmacyclics,Inc.、Sunnyvale、CA;2015. 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November 2013;169(5):1000~6. Tsukada, S., Saffran, D.C., Rawlings, D.J., Parolini, O., Allen, R.C., Klisak, I., Sparkes, R.S., Kubagawa, H., Mohandas, T., Quan, S. et al., Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell, 72:279~290, 1993. Drug Development and Drug Interactions: Table of Substrates,Inhibitors and Inducers. US Food and Drug Administration. http: / / www.fda.gov / drugs / developmentapprovalprocess / developmentresources / drugin teractionslabeling / ucm093664.htm# April 7, 2016. . Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., The Gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature、361:226~233、1993. 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Pemphigus vulgaris: update on etiopathogenesis, oral manifestations, and management. Crit Rev Oral Biol Med 2002;13:397 - 408. Scully C, Paes De Almeida O, Porter SR, Gilkes JJ. Pemphigus vulgaris: the manifestations and long-term management of 55 patients with oral lesions. Br J Dermatol 1999;140:84 - 9. Amagai M, Stanley JR. Desmoglein as a target in skin disease and beyond. J Invest Dermatol 2012;132:776 - 84. Diaz LA、Giudice GJ. End of the century overview of skin blisters. Arch Dermatol 2000;136:106~12. Murrell DF、Pena S、Joly Pら、Diagnosis and Management of Pemphigus:recommendations by an International Panel of Experts. Journal of the American Academy of Dermatology 2018. Kasperkiewicz M、Ellebrecht CT、Takahashi Hら、Pemphigus. Nat Rev Dis Primers 2017;3:17026. Joly P、Maho-Vaillant M、Prost-Squarcioni Cら、First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus(Ritux 3):a prospective,multicentre,parallel-group,open-label randomised trial. Lancet 2017;389:2031~40. RITUXAN(rituximab) Highlights of Prescribing Information. 2018.、https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 103705s5450lbl.pdf.) Cianchini G、Corona R、Frezzolini A、Ruffelli M、Didona B、Puddu P. Treatment of Severe Pemphigus With Rituximab: Report of 12 Cases and a Review of the Literature. JAMA Dermatology 2007;143:1033~8. Harman KE、Brown D、Exton LSら、British Association of Dermatologists’ guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol 2017;177:1170~201. Amagai M、Ikeda S、Shimizu Hら、A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol 2009;60:595~603. Martin LK、Werth V、Villanueva E、Segall J、Murrell DF. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev 2009:Cd006263. Crofford LJ、Nyhoff LE、Sheehan JH、Kendall PL. The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol 2016;12:763~73. Pal Singh S、Dammeijer F、Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer 2018;17:57. Volmering S、Block H、Boras M、Lowell CA、Zarbock A. The Neutrophil Btk Signalosome Regulates Integrin Activation during Sterile Inflammation. Immunity 2016;44:73~87. Khan WN、Alt FW、Gerstein RMら、Defective B cell development and function in Btk-de ficient mice. Immunity 1995;3:283~99. Montalban X、Arnold DL、Weber MSら、Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med 2019;380:2406~17. Norman P. Investigational Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs 2016;25:891~9. Tam CS、LeBlond V、Novotny Wら、A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenstrom macroglobulinemia. Future Oncol 2018;14:2229~37. Crawford JJ, Johnson AR, Misner DL, et al., Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical Development. J Med Chem 2018;61:2227 - 45. Min TK, Saini SS. Emerging Therapies in Chronic Spontaneous Urticaria. Allergy Asthma Immunol Res 2019;11:470 - 81. Gillooly KM, Pulicicchio C, Pattoli MA, et al., Bruton’s tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care. PLoS One 2017;12:e0181782. Nadeem A, Ahmad SF, Al-Harbi NO, et al., Inhibition of Bruton’s tyrosine kinase and IL-2 inducible T-cell kinase suppresses both neutrophilic and eosinophilic airway inflammation in a cockroach allergen extract-induced mixed granulocytic mouse model of asthma using preventative and therapeutic strategy. Pharmacol Res 2019;148:104441 Drug Record Kinase Inhibitors. In: Services NIoHUSDoHH ed., 2019. Khan Y、O’Brien S. Acalabrutinib and its use in treatment of chronic lymphocytic leukemia. Future Oncol 2019;15:579~89. Paydas S. Management of adverse effects / toxicity of ibrutinib. Crit Rev Oncol Hematol 2019;136:56~63. IMBRUVICA(ibrutinib) Highlights of Prescribing Information. US Food and Drug Administration、2013.、https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2015 / 205552s002lbl.pdf.) Rigg RA、Aslan JE、Healy LDら、Oral administration of Bruton’s tyrosine kinase inhibitors impairs GPVI-mediated platelet function. Am J Physiol Cell Physiol 2016;310:C373~80. Tang CPS、McMullen J、Tam C. Cardiac side effects of bruton tyrosine kinase(BTK) inhibitors. Leuk Lymphoma 2018;59:1554~64. Smith PF、Krishnarajah J、Nunn PAら、A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton’s tyrosine kinase,in healthy volunteers. Br J Clin Pharmacol 2017;83:2367~76. Serafimova IM、Pufall MA、Krishnan Sら、Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat Chem Biol 2012;8:471~6. Hill R BJ、Bisconte A、Tam D、Owens T、Brameld Kら、Preclinical Characterization of PRN1008, a Novel Reversible Covalent Inhibitor of BTK that Shows Efficacy in a RAT Model of Collagen-Induced Arthritis. EULAR. Rome2015. Smith PF K、Nunn PA、Hill RJ、Karr D、Tam Dら、A Phase 1 Clinical Trial of PRN1008, An Oral,Reversible,Covalent BTK Inhibitor Demonstrates Clinical Safety and Therapeutic Levels of BTK Occupancy Without Sustained Systemic Exposure. EULAR 2015. Rome2015. Langrish C BJ、Francesco M、Xing Y、Shu J、LaStant J、Owens T、Brameld K、Outerbridge C、Bisconte A、White S、Hill R、Gourlay S、Goldestein D、Nunn P Pre-clinical data on the anti-inflammatory and autoantibody inhibitory effects of the reversible,covalent Bruton’s tyrosin kinase inhibitor PRN1008 for autoimmune diseases [IN PRESS].Journal of Immunology 2019. Langrish CL、Bradshaw JM、Owens TDら、PRN1008、a Reversible Covalent BTK Inhibitor in Clinical Development for Immune Thrombocytopenic Purpura. Blood 2017;130:1052~. Hill R BJ、Bisconte A、Tam D、Owens T、Brameld K、Smith P、Funk J、Goldstein D、Nunn P Preclinical Characterization of PRN1008, a Novel Reversible Covalent Inhibitor of BTK That Shows Efficacy in a Rat Model of Collagen-Induced Arthritis. The Annual European Congress of Rheumatology EULAR. Rome、Italy:EULAR;2015. Murrell DF ea. Final Results of the Believe-PV Proof of Concept Study of PRN1008 in Pemphigus. American Academy of Dermatology Annual Meeting. Washington DC2019. CALQUENCE(acalabrutinib) Highlights of Prescribing Information. US Food and Drug Administration、2017.、https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2017 / 210259s000lbl.pdf.) Boulard C、Duvert Lehembre S、Picard-Dahan Cら、Calculation of cut-off values based on the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Pemphigus Disease Area Index (PDAI) pemphigus scoring systems for defining moderate,significant and extensive types of pemphigus. Br J Dermatol 2016;175:142~9. Murrell DF、Dick S、Ahmed ARら、Consensus statement on definitions of disease,end points,and therapeutic response for pemphigus. J Am Acad Dermatol 2008;58:1043~6. Anhalt GJ、Diaz LA. Research Advances in Pemphigus. JAMA 2001;285:652~4. Chams-Davatchi C, Mortazavizadeh A, Daneshpazhooh M, et al. Randomized double blind trial of prednisolone and azathioprine,vs.prednisolone and placebo, in the treatment of pemphigus vulgaris. J Eur Acad Dermatol Venereol 2013;27:1285~92. 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[0365] Any claim or description containing "or" or "and / or" between at least one member of a group is construed as including all or part of the group unless indicated to the contrary or apparent from the context. Unless otherwise specified, a group is considered satisfied when one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one or all group members are present in, employed in, or otherwise relevant to a given product or process.

[0366] When ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can take any particular value or subrange within the stated range in different embodiments of this disclosure, down to one-tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0367] The foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding. It is therefore to be understood that the above description is intended to be illustrative and not limiting. The scope of the present disclosure should, therefore, be determined not with reference to the above description, but instead with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. Use of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment of recurrent pemphigus, wherein the pharmaceutical is administered to a human patient in a dose of 400 mg twice daily for at least 14 days.

2. The use according to Claim 1, wherein the pharmacopoeia is administered to a human patient at a dose of 400 mg twice daily for 14 to 84 days.

3. The use according to claim 1 or 2, wherein the pharmacopoeia is administered to a human patient in combination with a first corticosteroid at a dose of 0.5 mg / kg / day or less.

4. The use according to claim 3, wherein the first corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

5. A use according to any one of claims 1 to 4, wherein the pharmaceutical is administered to a human patient having a Pemphigus Disease Activity Index (PDAI) skin score of 8 to 60 points.

6. The use according to any one of claims 1 to 5, wherein the human patient is administered a second corticosteroid in a maintenance dose of 0.5 mg / kg / day or less before administration of the pharmaceutical agent.

7. A use according to any one of claims 1 to 6, wherein the pharmaceutical comprises the (E) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile.

8. A use according to any one of claims 1 to 6, wherein the pharmaceutical comprises the (Z) isomer of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]pento-2-ennitrile.

9. A use according to any one of claims 1 to 6, wherein the pharmaceutically isomer comprises a mixture of the (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]penta-2-ennitrile.

10. A use according to any one of claims 1 to 9, wherein the pharmacopoeia is for the treatment of recurrent pemphigus vulgaris.

11. A use according to any one of claims 1 to 9, wherein the pharmacopoeia is for the treatment of recurrent pemphigus foliaceus.

12. A use according to any one of claims 1 to 11, wherein the pharmaceutical agent reduces the average daily corticosteroid use by human patients.

13. A use according to any one of claims 1 to 12, wherein the pharmacopoeia cures at least 50% of established pemphigus lesions.

14. A use according to any one of claims 1 to 13, wherein the pharmaceutical product prevents the formation of new pemphigus lesions.

15. A use according to any one of claims 1 to 14, wherein the pharmacopoeia reduces the pemphigus disease activity index skin score, preferably by at least 20%.

16. A use according to any one of claims 1 to 15, wherein the pharmaceutical agent gives a pemphigus disease activity index skin score of 0 or 1 after administration.

17. A use according to any one of claims 1 to 16, wherein the pharmacopoeia achieves control of disease activity of recurrent pemphigus.

18. A use according to any one of claims 1 to 16, wherein the pharmacopoeia achieves the termination of the sclerotic phase of recurrent pemphigus.

19. The use according to any one of claims 1 to 17, wherein the pharmaceutical product is administered orally to a human patient.

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