Methods for treating myasthenia gravis using TACI-Fc fusion protein

Abstract

The present invention provides a pharmaceutical preparation, dosage scheme, administration interval and administration method for treating myasthenia gravis using TACI-Fc fusion protein.The results show that the TACI-Fc fusion protein of the present invention has relatively good clinical therapeutic effect and safety in treating patients with myasthenia gravis.

Description

[Technical field]

[0001] The present invention relates to pharmaceutical agents, dosage schemes, dosing intervals and methods of administration for treating myasthenia gravis. [Background technology]

[0002] Myasthenia gravis (MG) is an acquired autoimmune disease mediated by anti-acetylcholine receptor antibodies (AchR-Ab), which depends on cellular immunity, involves complement, and affects the postsynaptic membrane of the neuromuscular junction, causing impaired transmission at the neuromuscular junction and resulting in reduced skeletal muscle contractility. A small proportion of MG patients are mediated by anti-muscle specific tyrosine kinase antibodies (MuSK-Ab) and anti-low-density lipoprotein receptor-related protein 4 antibodies (LRP4-Ab). In MG patients, skeletal muscles of the whole body may be affected. However, in the early stages of the disease, weakness of the extraocular muscles, throat muscles, or limbs may occur alone. It often begins with weakness of one muscle group, gradually affecting other muscle groups, and finally resulting in generalized weakness. In some patients, muscle weakness can affect the entire body within a short period of time, and even develop a myasthenic crisis, in which case the respiratory muscle weakness can cause respiratory distress and death by asphyxiation within a short period of time. 80% to 90% of patients with MG have abnormalities of the thymic tissue, mainly manifested as thymic hyperplasia, cysts, necrosis, hypertrophy, and various types of thymomas.

[0003] The incidence of myasthenia gravis is related to the age, sex, and race of the population and varies between countries and regions. MG can occur in both sexes at any age, while the incidence is higher in women than in men under 40 years of age, equal in both sexes between 40 and 50 years of age, and slightly higher in men than women over 50 years of age. Pediatric MG is uncommon in the West but is widespread in Asian countries, with approximately 50% of patients under the age of 15. Statistics show that in the United States, 20 people per 100,000 people suffer from myasthenia gravis, while in China, the incidence of MG is approximately 0.68 / 100,000.

[0004] Myasthenia gravis is a lifelong disease for patients, and there is no cure for it to date. Currently, the main treatments for MG are as follows: (1) Cholinesterase inhibitors (e.g., pyridostigmine bromide, neostigmine, etc.): These drugs can inhibit the decomposition of acetylcholine and increase the availability of acetylcholine in the synapse. Although the therapeutic response is usually good for MG subgroups, the therapeutic effect varies greatly for individuals, and they can only alleviate symptoms without eliminating the underlying etiology. Moreover, a single drug cannot be used for a long period of time, and the therapeutic effect for MuSK-MG patients is low. (2) Immunosuppressants (e.g., cyclophosphamide, cyclosporine A, mycophenolate mofetil, tacrolimus, methotrexate, azathioprine, etc.): These drugs improve muscle strength by inhibiting the production of abnormal antibodies, but they may cause serious side effects. (3) Intravenous injection of immunoglobulin: This method is mainly suitable for patients with MG in acute disease progression and preoperative preparation, and can be combined with slow-acting immunosuppressants or high-dose corticosteroids that may induce myasthenic crisis. Usually, the therapeutic effect appears about 5 to 10 days after use and can last for about 2 months. (4) Plasma exchange: This method uses a device to remove harmful antibodies from plasma and replace it with high-quality plasma or plasma substitute. This method is mainly used for patients in acute disease progression and myasthenic crisis before thymectomy, perioperative management, and the initial stage of immunosuppressive treatment, and can temporarily relieve the symptoms of myasthenia gravis patients, but if not combined with other treatments, the therapeutic effect does not exceed 2 months, and even if it is used repeatedly for a long period of time, the long-term effect does not increase. (5) Thymectomy: This therapy is suitable for patients with generalized myasthenia gravis who have developed the disease at the age of 16 to 60 years and have no contraindications to surgery. (6) Other treatment methods include, for example, respiratory muscle training and muscle strength training for patients with mild MG. In short, the general treatment regimens for MG have certain risks and limitations, and the therapeutic effects are insufficient. From the perspective of pathogenesis, MG is an antibody-mediated disease, so there is an urgent need to develop effective new targeted drugs.

[0005] In recent years, three targeted biologics approved by the FDA for the treatment of MG include eculizumab (October 23, 2017), efgartigimod (December 17, 2021) and ravulizumab (April 28, 2022).

[0006] Eculizumab (Soliris) is a recombinant human monoclonal antibody that inhibits terminal complement C5 and can prevent the production of membrane attack complex (MAC) by anti-AChR antibodies. In a 26-week follow-up study of refractory MG, the dose of eculizumab was 900 mg on day 1 and weeks 1, 2, and 3, 1200 mg on week 4, and 1200 mg every 2 weeks thereafter. Thereafter, a maintenance dose of 1200 mg was administered every 2 weeks. Vaccination against Neisseria meningitidis is required. From the results of the study, statistical differences between the treatment and placebo groups were observed only for dichotomous outcomes (MG exacerbation, need for rescue treatment) from baseline to the end of follow-up, with no difference in the primary endpoint (MG daily activity score). The effect of this treatment appeared within 4 to 8 weeks. The most common side effects in the study were headache and upper respiratory tract infection. Although eculizumab has been approved for patients with refractory MG, its use is likely to be severely limited by its very high price (at least 450,000 euros per year).

[0007] Ravulizumab (ULTOMIRIS), an improved long-acting formulation based on the first-generation C5 monoclonal antibody eculizumab, has an extended half-life compared to eculizumab and is currently approved for the treatment of adult patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG). The safety and efficacy of ravulizumab in complement inhibitor-naïve adult patients with gMG was evaluated in a 26-week international phase III randomized, double-blind, placebo-controlled, multicenter study. The study enrolled 175 patients from North America, Europe, Asia, and Japan who had been diagnosed with MG within at least 6 months prior to screening, were seropositive for anti-AChR antibodies, had an MG-ADL total score of at least 6 at study entry, and were classified as Myasthenia Gravis Foundation of America (MGFA) clinically classified as II-IV at screening. In this study, patients were randomized in a 1:1 ratio to receive either ravulizumab or placebo for a total of 26 weeks. Patients received a single weight-based loading dose on day 1, followed by regular weight-based maintenance doses every 8 weeks starting on day 15. The study evaluated the change from baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) total score (primary endpoint) at week 26, as well as multiple secondary endpoints evaluating disease-related and quality of life improvements. Data showed that the study met its primary endpoint. From baseline to week 26, the ravulizumab group had a statistically significant change in MG-ADL total score compared to the placebo group (ravulizumab group -3.1 vs placebo -1.4, treatment difference -1.6, p<0.001). Additionally, the ULTOMIRIS arm also demonstrated clinically meaningful and statistically significant improvements in the prospectively defined secondary endpoints of quantitative myasthenia gravis (QMG) total score (physician assessment of the clinical severity of MG) and the proportion of patients with at least a 5-point improvement in QMG from baseline to week 26 (p<0.001 and p=0.005, respectively). Compared with the placebo arm, the ULTOMIRIS arm was three times more likely to achieve an improvement in QMG score of at least 5 points (30.0% vs 11.3%).These improvements in MG-ADL and QMG scores were observed as early as week 1 and were sustained through week 26. During the randomized controlled period (26 weeks), adverse events were comparable between the ravulizumab and placebo groups. The most common side effects included headache (ravulizumab 18.6%, placebo 25.8%), diarrhea (ravulizumab 15.1%, placebo 12.4%), and nausea (ravulizumab 10.5%, placebo 10.1%). The most common serious adverse events included MG crisis (ravulizumab 1.2%) and MG exacerbation (placebo 3.4%). However, ravulizumab also faces the problem of high cost.

[0008] Wifugart (efgartigimod) is an antibody fragment that binds to the neonatal Fc receptor (FcRn) and prevents FcRn from transferring immunoglobulin G (IgG) back into the bloodstream. The drug causes a reduction in overall levels of IgG, including the abnormal AChR antibodies present in myasthenia gravis, and is approved for the treatment of generalized myasthenia gravis (gMG) in adults who test positive for anti-acetylcholine receptor (AChR) antibodies. Wifugart's safety and efficacy were evaluated in a 26-week clinical study of 167 myasthenia gravis patients randomized to receive Wifugart or placebo. The study found that more myasthenia gravis patients who had antibodies (68%) showed a treatment response within the first cycle of Wifugart compared to patients who received placebo (30%) on measures assessing the impact of myasthenia gravis on daily functioning. More Wifugart patients showed a response to muscle weakness compared to patients who received placebo. The most common side effects associated with the use of Wifugart include respiratory infections, headaches, and urinary tract infections, but Wifugart can cause a decrease in IgG levels, which may significantly increase the risk of infection.

[0009] Since the 1960s, myasthenia gravis has been considered a "second cancer", in which patients suffer from fatigue and weakness throughout their lives, gradually progressing to death. Although the field of MG treatment has developed rapidly in recent years, there remains enormous unmet clinical need in the field of myasthenia gravis treatment not only in China but also worldwide. Summary of the Invention [Problem to be solved by the invention]

[0010] In the present invention, it has been surprisingly discovered that TACI-Fc fusion protein produces a remarkable therapeutic effect when treating patients with myasthenia gravis. [Means for solving the problem]

[0011] Specifically, the present invention provides a method for treating myasthenia gravis, comprising administering to a patient suffering from said myasthenia gravis a therapeutically effective amount of a TACI-Fc fusion protein comprising (i) the extracellular domain of TACI or a fragment thereof that binds to Blys and / or APRIL, and (ii) a fragment of a human immunoglobulin constant domain.

[0012] Specifically, the present invention also provides a method for treating myasthenia gravis, comprising: (1) determining whether a patient has received a standard treatment regimen for myasthenia gravis; and (2) administering an effective amount of a TACI-Fc fusion protein to a patient with myasthenia gravis if the patient has already received a standard treatment regimen for myasthenia gravis, including a cholinesterase inhibitor alone, a cholinesterase inhibitor in combination with a glucocorticoid or other immunosuppressant as specified in the regimen, a glucocorticoid in combination with other immunosuppressant as specified in the regimen, or a cholinesterase inhibitor in combination with a corticosteroid and other immunosuppressant as specified in the protocol.

[0013] Specifically, the present invention also provides the use of a TACI-Fc fusion protein in the manufacture of a medicament for treating a patient with myasthenia gravis.

[0014] Preferably, the TACI extracellular domain, or a Blys and / or APRIL binding fragment thereof, comprises the amino acid sequence shown in SEQ ID NO:1. SEQ ID NO:1 SRVDQEERFP QGLWTGVAMR SCPEEQYWDP LLGTCMSCKT ICNHQSQRTC AAFCRSLSCR 60 KEQGKFYDHL LRDCISCASI CGQHPKQCAY FCENKLRSPV NLPPEL 106

[0015] More preferably, the human immunoglobulin constant region comprises an amino acid sequence as set forth in SEQ ID NO:2, or an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO:2. SEQ ID NO:2 DKPHTCPLCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD 60 GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK 120 GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKATPPVLDS 180 DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 227

[0016] More preferably, the constant region of said human immunoglobulin comprises an amino acid modification corresponding to one or more of sites 3, 8, 14, 15, 17, 110, 111 or 173 of SEQ ID NO: 2. The modification is preferably an amino acid substitution, deletion or insertion.

[0017] More preferably, said substitutions are selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

[0018] More preferably, the constant region of said human immunoglobulin comprises the amino acid sequence shown in SEQ ID NO:3. SEQ ID NO:3 DKTHTCPPCP APEAEGAPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD 60 GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPS SIEKTISKAK 120 GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 180 DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 227

[0019] More preferably, said human immunoglobulin is IgG1.

[0020] More preferably, the TACI-Fc fusion protein is Telitaccept, the amino acid sequence of which is shown in SEQ ID NO:4. SEQ ID NO:4 SRVDQEERFP QGLWTGVAMR SCPEEQYWDP LLGTCMSCKT ICNHQSQRTC AAFCRSLSCR 60 KEQGKFYDHL LRDCISCASI CGQHPKQCAY FCENKLRSPV NLPPELDKTH TCPPCPAPEA 120 EGAPSVFLFP PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE 180 QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPSSIEK TISKAKGQPR EPQVYTLPPS 240 RDELTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK 300 SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK 333

[0021] More preferably, the TACI-Fc fusion protein is administered at a dose of about 0.1 to 10 mg / kg per administration.

[0022] More preferably, the TACI-Fc fusion protein is administered in a dose of 160 to 240 mg, more preferably 160 mg or 240 mg per administration.

[0023] More preferably, the TACI-Fc fusion protein is used 2-4 times per month, or twice a month, 3 times a month, or 4 times a month.

[0024] More preferably, the TACI-Fc fusion protein is administered once a week.

[0025] More preferably, the treatment lasts for about 2 to 50 weeks. More preferably, the treatment lasts for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, or 50 weeks.

[0026] More preferably, the TACI-Fc fusion protein is administered subcutaneously, intramuscularly, or intravenously, and the administration site is preferably the thigh, abdomen, or upper arm, hi some specific embodiments, the TACI-Fc fusion protein is administered by subcutaneous, intramuscular, or intravenous injection.

[0027] More preferably, the TACI-Fc fusion protein is injected at the same or a different site each time. In some specific embodiments, the TACI-Fc fusion protein is injected at the same site each time. In other specific embodiments, the TACI-Fc fusion protein is injected at a different site each time.

[0028] More preferably, said myasthenia gravis is generalized myasthenia gravis (gMG).

[0029] More preferably, the myasthenia gravis is positive for anti-acetylcholine receptor antibody (AchR-Ab).

[0030] More preferably, the myasthenia gravis is positive for anti-muscle specific tyrosine kinase antibody (MuSK-Ab).

[0031] More preferably, said myasthenia gravis corresponds to type II or III according to the clinical classification of the Myasthenia Gravis Foundation of America (MGFA).

[0032] More preferably, the myasthenia gravis is characterized by a quantitative myasthenia gravis score (QMG) of 8 points or more, with at least 2 points or more in 4 or more items.

[0033] More preferably, the patient is an adult patient with generalized myasthenia gravis (gMG) diagnosed as positive for anti-acetylcholine receptor antibody (AchR-Ab) or positive for anti-muscle specific tyrosine kinase antibody (MuSK-Ab), receiving a stable standard treatment regimen, and corresponding to type II or III according to the Myasthenia Gravis Foundation of America (MGFA) clinical classification, with a quantitative myasthenia gravis (QMG) score of 8 or more at screening, and with at least four item scores of at least 2 or more.

[0034] Generalized myasthenia gravis is an autoimmune disease that affects the neuromuscular junction and causes symptoms of muscle weakness. Scale scoring allows the severity of the patient's condition to be quantitatively evaluated, allowing for a more intuitive assessment of the patient's condition, which is useful for clinical observation and drug efficacy evaluation. In the present invention, the effectiveness of treatment is evaluated using the quantitative myasthenia gravis scale (QMG) and a table of MG clinical absolute scores.

[0035] The QMG mainly measures the muscle strength and endurance of patients and was proposed by the Myasthenia Gravis Foundation of America in 2000. When used, it requires the assistance of measuring devices such as a handheld dynamometer and a stopwatch. The QMG includes 13 items: diplopia, ptosis, facial muscle strength, swallowing, articulation, left and right arm lift, vital capacity (VC) / predicted vital capacity, head lift, left and right hand grip strength, and lower limb lift in the supine position. The total score ranges from 0 to 39, with higher scores indicating more severe disease. The QMG should be evaluated 8 hours after the last dose of a cholinesterase inhibitor.

[0036] The clinical absolute score of myasthenia gravis mainly reflects the severity of muscle weakness and fatigue in the muscle groups affected by MG. The scale mainly includes eight items: upper eyelid muscle weakness score, upper eyelid fatigue test, horizontal eye movement restriction score, upper limb fatigue test, lower limb fatigue test, facial muscle weakness score, chewing and swallowing function score, and respiratory muscle function score. The total score ranges from 0 to 60, with higher scores indicating more severe disease. The clinical absolute score of myasthenia gravis should be assessed 8 hours after the last dose of a cholinesterase inhibitor.

[0037] The Myasthenia Gravis Foundation of America (MGFA) strongly recommended that the QMG scale be applied to prospective clinical studies related to MG in 2000. The MG clinical absolute score method, in which the high or low clinical absolute score reflects the severity of muscle weakness and fatigue in the affected muscle groups of MG patients, can sensitively reflect changes in the clinical condition and is an ideal quantitative method for observing changes in the condition of MG patients.

[0038] More preferably, the patient is an adult patient or a pediatric patient.

[0039] More preferably, the patient has been on a stable standard of care regimen for myasthenia gravis, which in some specific embodiments includes a cholinesterase inhibitor alone, a cholinesterase inhibitor in combination with a glucocorticoid or other immunosuppressant as specified in the regimen, a glucocorticoid in combination with other immunosuppressant as specified in the regimen, or a cholinesterase inhibitor in combination with a corticosteroid and other immunosuppressant as specified in the protocol.

[0040] The TACI-Fc fusion protein provided by the present invention exhibits unexpected clinical efficacy and favorable safety profile in treating patients with myasthenia gravis. [Brief description of the drawings]

[0041] [Figure 1] FIG. 1 shows the time course analysis of the change in QMG score relative to baseline. [Diagram 2] Figure 2 shows the percentage of subjects who achieved various degrees of improvement in QMG scores at each visit. [Diagram 3] FIG. 3 shows a time course analysis of the change in MG clinical absolute score versus baseline. [Figure 4] FIG. 4 shows a time course analysis of the percent change in immunoglobulin IgG levels relative to baseline. [Diagram 5] FIG. 5 shows a time course analysis of the percentage change in immunoglobulin IgA levels relative to baseline. [Figure 6] FIG. 6 shows a time course analysis of the percent change in immunoglobulin IgM levels relative to baseline. [Figure 7] FIG. 7 shows a time course analysis of the percentage change in CD19+ B cell counts relative to baseline. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. For definitions and terms in this field, those skilled in the art can refer specifically to Current Protocols in Molecular Biology (Ausubel).

[0043] The three-letter and one-letter codes for amino acids used in the present invention are as described in J. Biol. Chem, 243, p. 3558 (1968).

[0044] The present invention provides the use of a transmembrane activator, calcium regulator and cyclophilin ligand interactor (TACI)-immunoglobulin fusion protein (i.e., a TACI-Fc fusion protein) in the treatment of myasthenia gravis. The TACI-immunoglobulin fusion protein provided herein comprises 1) a polypeptide comprising at least a region identical to the TACI extracellular domain or a fragment thereof capable of binding to BlyS and / or APRIL, and 2) a human immunoglobulin constant chain. U.S. Patent Nos. 5,969,102, 6,316,222 and 6,500,428, and U.S. Patent Application Nos. 09 / 569,245 and 09 / 627,206, the contents of which are incorporated herein by reference, describe the extracellular domain of TACI and certain fragments of the TACI extracellular domain capable of interacting with TACI ligands, including BlyS and APRIL. Chinese Patent Publication CN101323643A describes a TACI-Fc fusion protein comprising a fragment of amino acids 13-118 of the extracellular domain of TACI.

[0045] The immunoglobulin portion of the TACI-immunoglobulin fusion proteins provided herein is preferably IgG1 and may include a heavy chain constant region, e.g., a human heavy chain constant region. A preferred IgG1 heavy chain constant region of the invention is an IgG1 Fc fragment containing the CH2 and CH3 regions, which may be a wild-type IgG1 Fc fragment or a mutated IgG1 Fc fragment.

[0046] The TACI-Fc fusion protein can be administered to a patient by any suitable route, including, but not limited to, intravenous, intramuscular, or subcutaneous administration.

[0047] The formulations of TACI-Fc fusion proteins provided herein are prepared and stored in lyophilized, sterile, solution form. Such formulations may contain other active ingredients, excipients, or other components, such as sodium chloride, phosphate buffer, sodium hydroxide, etc. TACI-Ig formulations may be administered to a patient in combination with other drugs and may be administered prior to, concurrently with, or following other treatments.

[0048] The term "treatment" in relation to the present invention relates to a given disease or condition. "Treatment" includes, but is not limited to, for example, inhibiting the disease or condition so as to arrest the progression of the disease or condition, alleviating the disease or condition so as to cause the disease or condition to regress, or alleviating symptoms caused by the disease or condition so as to alleviate, prevent or treat the symptoms of the disease or condition. EXAMPLES

[0049] Hereinafter, the embodiments of the present invention will be described in detail in conjunction with examples. However, those skilled in the art will understand that the following examples are used to explain the present invention and should not be considered as limiting the scope of the present invention.

[0050] Example 1 Clinical Trial of Treating Myasthenia Gravis with Teritacicept

[0051] 1. Research method This was a multicenter, randomized, open clinical study aimed to preliminary evaluate the efficacy and safety of telitacicept in the treatment of patients with generalized myasthenia gravis. Patients with generalized MG who were AChR-Ab positive or MuSK-Ab positive and were receiving standard treatment regimens, had a QMG score of 8 or higher, and were classified as type II / III MGFA were enrolled in the study. Subjects were randomly assigned to receive either 160 mg or 240 mg telitacicept. The study drug was administered once weekly for a total of 24 doses.

[0052] 2. Selected patients Subjects were adult patients with generalized myasthenia gravis (gMG) diagnosed as positive for anti-acetylcholine receptor antibody (AchR-Ab) or anti-muscle specific tyrosine kinase antibody (MuSK-Ab), receiving a stable standard treatment regimen, and were required to have Myasthenia Gravis Foundation of America (MGFA) clinical classification type II or III, a quantitative myasthenia gravis score (QMG) of 8 or more points at screening, and at least four item scores of at least 2 points.

[0053] 3. Treatment given Participants were randomly assigned to receive either 160 mg or 240 mg telitacicept, which was administered by subcutaneous injection in the thigh, abdomen, or upper arm once weekly for a total of 24 doses, with each injection administered at a different site.

[0054] 4. Evaluation criteria

[0055] 4.1 Indicators of treatment effect

[0056] 4.1.1 Main treatment effect measures Mean change in QMG score from baseline at week 24.

[0057] 4.1.2 Secondary treatment effect indicators Mean change from baseline in myasthenia gravis clinical absolute score at weeks 12 and 24. Mean change in QMG score at week 12 from baseline.

[0058] 4.1.3 Safety Endpoint Incidence and severity of adverse events.

[0059] 5. Demographics and Baseline Characteristics The study had three analysis populations: ● Full Analysis Set (FAS): The full analysis set refers to the set of all cases who were randomized and used the investigational drug at least once. Per Protocol Set (PPS): The per protocol set is a data population generated by subjects who are sufficiently compliant with the protocol, including treatment received, availability of primary endpoint measures, and lack of significant violations of the larger protocol. ● Safety data analysis set (SS): This is actual data for subjects who received treatment at least once and for whom safety indicators were recorded. The incidence of adverse reactions is calculated using the number of cases in the safety analysis set as the denominator.

[0060] In this study, 41 patients were screened and 29 were randomly assigned to a group. All 29 patients completed the 24-week study observation period and were all included in the full analysis set (FAS), per protocol set (PPS), and safety analysis set (SS). In the telitacicept 160 mg group, there were 14 patients in the FAS, 14 patients in the PPS, and 14 patients in the SS. In the telitacicept 240 mg group, there were 15 patients in the FAS, 15 patients in the PPS, and 15 patients in the SS.

[0061] The mean age of the 29 subjects was 44.1 years, and 55.2% were female. All subjects were positive for AChR antibodies. Twenty-eight subjects were tested for MuSK-Ab levels (one subject in the telitacicept 160 mg group was not tested), and all had negative results. The median disease duration was 25.4 months, the mean QMG score was 18.9 points, and the mean MG clinical absolute score was 24.0 points. Sixteen subjects (55.2%) had a MGFA clinical classification of type II, and 13 subjects (44.8%) had a MGFA clinical classification of type III. Nine (31.0%) subjects were treated with a cholinesterase inhibitor alone, 13 (44.8%) subjects were treated with a combination of a cholinesterase inhibitor and a glucocorticoid / other immunosuppressant as specified, and 7 (24.1%) subjects were treated with a combination of a cholinesterase inhibitor, glucocorticoid, and other immunosuppressant.

[0062] 6. Treatment Efficacy Results

[0063] 6.1 Analysis of treatment effects The treatment effects were analyzed by the FAS and PPS. All 29 subjects randomized in this study were included in the FAS and PPS, and the analysis results of the FAS and PPS were the same, so the following description of the efficacy results does not distinguish between the FAS and PPS.

[0064] 6.2 Primary endpoints of treatment efficacy The primary outcome measure for this study was the mean change in QMG score from baseline to week 24. Analysis of covariance (ANCOVA) was used with group as the fixed effect and baseline value as the covariate.

[0065] At week 24, the change from baseline in subjects' QMG scores (mean ± SD) was -7.7 ± 5.34 in the 160 mg telitacicept group and -9.6 ± 4.29 in the 240 mg telitacicept group. See Table 1.

[0066] [Table 1]

[0067] ANCOVA was used to compare the difference in least squares means (LSMEANS) of change from baseline in QMG score at week 24 for the telitacicept 160 mg and 240 mg groups. At week 24, the LSMEANS of change from baseline in QMG score for the telitacicept 160 mg group was -7.96 (95% CI: -10.07 to -5.85) and the LSMEANS of change from baseline in QMG score for the telitacicept 240 mg group was -9.37 (95% CI: -11.40 to -7.33). The difference in LSMEANS between the two groups was -1.40 (95% CI: -4.34 to 1.53). See Table 2.

[0068] [Table 2]

[0069] 6.3 Secondary treatment effect evaluation indicators

[0070] 6.3.1 Mean change from baseline in QMG score at week 12 The mean change in QMG score from baseline at week 12 was one of the secondary efficacy measures of this study, and differences between groups were compared using t-tests.

[0071] At week 12, the change from baseline in subjects' QMG scores (mean ± SD) was -5.8 ± 5.85 in the 160 mg teritacicept group and -9.5 ± 5.03 in the 240 mg teritacicept group. See Table 3.

[0072] [Table 3]

[0073] 6.3.2 Mean change from baseline in MG clinical absolute score at weeks 12 and 24 The mean change in MG clinical absolute score from baseline at weeks 12 and 24 was one of the secondary efficacy measures of this study, and between-group differences were compared using t-tests.

[0074] At week 12, the subject MG clinical absolute score change from baseline (mean ± SD) was -10.4 ± 4.40 in the 160 mg teritacicept group and -11.2 ± 9.88 in the 240 mg teritacicept group. At week 24, the subject MG clinical absolute score change from baseline (mean ± SD) was -13.8 ± 7.30 in the 160 mg teritacicept group and -14.1 ± 9.78 in the 240 mg teritacicept group. See Table 4.

[0075] [Table 4]

[0076] 6.4 Other treatment outcomes

[0077] 6.4.1 Analysis of changes over time in QMG scores from baseline The results of the analysis of changes in QMG scores over time relative to baseline are shown in Figure 1. From week 4, the QMG scores of subjects in the telitacicept 160 mg group and the telitacicept 240 mg group continued to decrease significantly relative to baseline through week 24.

[0078] 6.4.2 Proportion of subjects with improved QMG scores The percentage of subjects who achieved various degrees of improvement in QMG score at each visit (i.e., reduction in QMG score of ≥3, ≥4, ≥5, ≥6, ≥7, and ≥8 points, respectively) is shown in Figure 2 .

[0079] The percentage of subjects who showed any degree of improvement in QMG score was higher in the 240 mg telitacicept group than in the 160 mg group at week 4 through week 24. At week 24, the percentage of subjects who showed an improvement of 3 or more points in QMG score was 92.9% and 100.0% in the 160 mg and 240 mg groups, respectively. The percentage of subjects who showed an improvement of 4 or more points in QMG score was 78.6% and 93.3%, respectively. The percentage of subjects who showed an improvement of 5 or more points in QMG score was 57.1% and 86.7%, respectively. The percentage of subjects who showed an improvement of 6 or more points in QMG score was 50.0% and 80.0%, respectively. The percentage of subjects who showed an improvement of 7 or more points in QMG score was 42.9% and 73.3%, respectively. The percentage of subjects who improved by 8 or more points in QMG score was 42.9% and 66.7%, respectively.

[0080] 6.4.3 Time course analysis of MG clinical absolute score change from baseline The results of the time course analysis of the change from baseline in MG clinical absolute score are shown in Figure 3. From week 4, the subjects' MG clinical absolute scores from baseline in both the telitacicept 160 mg group and the telitacicept 240 mg group continued to decrease significantly through week 24.

[0081] 6.4.4 Immunological indicators

[0082] 6.4.4.1 Immunoglobulins (IgG, IgA, IgM) The results of the time course analysis of the percent change in immunoglobulin (IgG, IgA, IgM) levels relative to baseline are shown in Figures 4 to 6. From week 4, subjects' IgG, IgA, and IgM levels (g / L) significantly decreased in the telitacicept 160 mg and 240 mg groups, continuing through week 24.

[0083] At week 24, the percent change (mean ± SD) in subjects' IgG levels relative to baseline was -26.827 ± 17.127 in the teritacicept 160 mg group and -30.595 ± 13.037 in the teritacicept 240 mg group.

[0084] At week 24, the subject's percent change in IgA levels relative to baseline (mean ± SD) was -52.475 ± 17.954 in the teritacicept 160 mg group and -56.850 ± 14.781 in the teritacicept 240 mg group.

[0085] At week 24, the percent change (mean ± SD) in subjects' IgG levels relative to baseline was -61.747 ± 17.299 in the teritacicept 160 mg group and -68.203 ± 10.821 in the teritacicept 240 mg group.

[0086] 6.4.4.2 CD19+B cells The results of a time course analysis of the percent change in CD19+ B cell count relative to baseline are shown in Figure 7. Compared to baseline, the median CD19+ B cell count in subjects receiving 240 mg telitacicept initially increased and then tended to decrease. At week 24, the median subject CD19+ B cell count significantly decreased relative to baseline. The median CD19+ B cell count in subjects receiving 160 mg telitacicept fluctuated, but no trend of change was evident.

[0087] 6.5 Efficacy Results In this study, teritacicept 160 mg and 240 mg demonstrated sustained improvements in clinical efficacy for the treatment of patients with generalized myasthenia gravis. After subjects were treated with 160 mg or 240 mg of teritacicept once weekly, there was a sustained decline in QMG scores and MG clinical absolute scores from week 4 to week 24. At week 24, compared to baseline, subjects in the teritacicept 160 mg group had a mean decline in QMG scores of 7.7 points, and subjects in the teritacicept 240 mg group had a mean decline in QMG scores of 9.6 points. At week 24, compared to baseline, subjects in the teritacicept 160 mg group had a mean decline in MG clinical absolute scores of 13.8 points, and subjects in the teritacicept 240 mg group had a mean decline in MG clinical absolute scores of 14.1 points. At week 24, 92.9% of subjects in the 160 mg teritacicept group had an improvement of 3 or more points in their QMG score, and 100% of subjects in the 240 mg teritacicept group had an improvement of 3 or more points in their QMG score. Additionally, both 160 mg and 240 mg teritacicept significantly reduced subjects' IgG, IgA, and IgM levels.

[0088] 6.6 Safety Results In this study, teritacicept 160 mg and 240 mg were administered once weekly to patients with generalized myasthenia gravis and showed good treatment safety. Adverse events / reactions were mostly mild to moderate in severity (CTCAE grade 1 and grade 2). However, only one subject in the teritacicept 160 mg group experienced one CTCAE grade 3 adverse event (low lymphocyte count). There were no CTCAE grade 4 or grade 5 adverse events / reactions. There were no adverse events / reactions that led to discontinuation of the study drug, withdrawal from the study, or subject death, and no serious adverse reactions. During the study, one subject in the teritacicept 160 mg group experienced a serious adverse event, infectious pneumonia, but the researchers determined that the adverse event was not due to the study drug and the subject recovered after treatment without discontinuing the study drug. All adverse reactions that occurred in this study were foreseeable risks of telitacicept, and no indications of new safety risks were identified.

[0089] 6.7 Conclusion In this study, telitacicept 160 mg and 240 mg demonstrated favorable clinical therapeutic effects and safety in treating patients with generalized myasthenia gravis.

[0090] It should be noted that the above description is merely a preferred embodiment, and is used only as an example, and does not limit the combination of features necessary to implement the present invention. The titles described are not meant to limit the various embodiments of the present invention. Terms such as "contain", "include" and "include" are not meant to limit. Furthermore, unless otherwise specified, if a noun is not modified by a number, its plural is included. The term "or" means "and / or". Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0091] All publications and patents mentioned in this application are incorporated herein by reference. Various modifications and variations made to the methods and combinations described in this invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described through specific preferred embodiments, it should be understood that the invention for which protection is sought should not be unduly limited to these specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that become apparent to those skilled in the art are intended to be encompassed within the scope of the claims of this application.

Claims

1. In patients with myasthenia gravis, (i) the extracellular domain of TACI or a fragment thereof that binds to Blys and / or APRIL; (ii) a fragment of a constant region of a human immunoglobulin; and A method for treating myasthenia gravis, comprising administering a therapeutically effective amount of a TACI-Fc fusion protein comprising:

2. The method of claim 1, wherein the TACI extracellular domain or a fragment that binds to Blys and / or APRIL comprises the amino acid sequence shown in SEQ ID NO:

1.

3. 2. The method of claim 1, wherein the constant region of the human immunoglobulin comprises an amino acid sequence as set forth in SEQ ID NO:2 or an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO:

2.

4. 4. The method of claim 3, wherein the constant region of the human immunoglobulin comprises amino acid modifications corresponding to one or more of sites 3, 8, 14, 15, 17, 110, 111 and 173 of SEQ ID NO:

2.

5. 5. The method of claim 4, wherein the modification is an amino acid substitution, deletion or insertion.

6. 6. The method of claim 5, wherein the substitutions are selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, P111S and A173T.

7. The method of claim 6, wherein the human immunoglobulin is IgG1 or the constant region comprises the amino acid sequence shown in SEQ ID NO:

3.

8. The method of claim 1, wherein the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:

4.

9. The method of claim 9, wherein the TACI-Fc fusion protein is Telitaccept.

10. The method according to claim 9, wherein the TACI-Fc fusion protein is administered at a dose of about 0.1 to 10 mg / kg each time.

11. The method according to claim 9, characterized in that the TACI-Fc fusion protein is administered in a dose of 160-240 mg, preferably 160 mg or 240 mg each time.

12. The method according to claim 10 or 11, characterized in that the targeted TACI-Fc fusion protein is administered 2-4 times per month and / or continuously for about 2-50 weeks.

13. The method of claim 12, wherein the TACI-Fc fusion protein is administered by subcutaneous, intramuscular or intravenous routes, or via administration sites in the thigh, abdomen or upper arm.

14. The method according to claim 13, wherein the myasthenia gravis is generalized myasthenia gravis (gMG), or myasthenia gravis positive for anti-acetylcholine receptor antibody (AchR-Ab), or myasthenia gravis positive for anti-muscle specific tyrosine kinase antibody (MuSK-Ab), or myasthenia gravis type II or III according to the clinical classification of the Myasthenia Gravis Foundation of America (MGFA).

15. The method according to claim 14, wherein the myasthenia gravis is characterized by a quantitative myasthenia gravis score (QMG) of 8 or more and four or more item scores of at least 2 or more.

16. 16. The method of claim 15, wherein the patient is an adult or pediatric patient, or a patient who has previously received a standard treatment regimen for stable myasthenia gravis.

17. 16. The method of claim 15, wherein the standard of care regimen includes a cholinesterase inhibitor alone, a cholinesterase inhibitor in combination with a glucocorticoid or other immunosuppressant as specified in the regimen, a glucocorticoid in combination with other immunosuppressant as specified in the regimen, or a cholinesterase inhibitor in combination with a corticosteroid and other immunosuppressant as specified in the protocol.

18. 1. A method for treating a myasthenia gravis patient who has received a standard treatment regimen for myasthenia gravis, comprising: (1) determining whether the patient has received a standard treatment regimen for myasthenia gravis; and (2) administering an effective amount of a TACI-Fc fusion protein to the myasthenia gravis patient if the patient has already received a standard treatment regimen for myasthenia gravis.

19. 20. The method of claim 18, wherein the standard of care regimen includes a cholinesterase inhibitor alone, a cholinesterase inhibitor in combination with a glucocorticoid or other immunosuppressant as specified in the regimen, a glucocorticoid in combination with other immunosuppressant as specified in the regimen, or a cholinesterase inhibitor in combination with a corticosteroid and other immunosuppressant as specified in the protocol.

20. Use of a TACI-Fc fusion protein in the manufacture of a medicament for treating a patient with myasthenia gravis.

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