Treatment methods for myasthenia gravis using TACI-Fc fusion proteins

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 medicaments, dosage regimens, administration intervals and administration methods for treating myasthenia gravis.

BACKGROUND ART

[0002] Myasthenia gravis (MG) is an acquired autoimmune disease mediated by anti-acetylcholine receptor antibodies (AchR-Ab), dependent on cellular immunity, involving complement, affecting the postsynaptic membrane of the neuromuscular junction, causing transmission disorders at the neuromuscular junction and resulting in reduced skeletal muscle contractility. A small number 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). MG patients may have their systemic skeletal muscles affected. However, in the initial stage of onset, weakness of the extraocular muscles, throat muscles, or limb muscles may occur alone. It often starts with weakness in a certain muscle group, gradually affects other muscle groups, and eventually leads to systemic muscle weakness. In some patients, muscle weakness spreads throughout the body in a short period of time, and may further develop myasthenic crisis, in which case the weakness of respiratory muscles leads to dyspnea, and there is a risk of suffocation and death in a short period of time. 80% to 90% of MG patients have abnormalities in thymus tissue, which mainly manifest as thymic hyperplasia, cysts, necrosis, hypertrophy, and various types of thymomas.

[0003] The incidence of myasthenia gravis varies by country and region, and is related to the age, sex, and race of the population. MG can occur in men and women of all ages, but the incidence is higher in women than in men under 40, is equal between 40 and 50 years old, and becomes slightly higher in men than in women after 50. Childhood MG is rare in Western countries but is prevalent in Asian countries, with approximately 50% of patients under 15 years old. Statistics show that in the United States, 20 people per 100,000 livelihoods have myasthenia gravis, while in China, the incidence is approximately 0.68 per 100,000 people.

[0004] Myasthenia gravis is a lifelong disease for patients, and there is currently no cure. Currently, the main treatments for MG are as follows: (1) Cholinesterase inhibitors (e.g., pyridostigmine bromide, neostigmine, etc.): These drugs inhibit the breakdown of acetylcholine and can increase the availability of acetylcholine in synapses. They generally respond well to the MG subgroup, but the treatment effect varies greatly from person to person. They only alleviate symptoms without addressing the underlying etiology, and long-term use of a single drug is not possible. They have a low therapeutic effect on MuSK-MG patients. (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 can cause serious side effects. (3) Intravenous immunoglobulin injection: This method is mainly suitable for MG patients in the acute disease progression and preoperative preparation stages, and can be used in combination with slow-acting immunosuppressants or high doses of corticosteroids that may induce myasthenic crisis. The therapeutic effect usually appears about 5-10 days after use and can last for about 2 months. (4) Plasma exchange: This method involves using a device to remove harmful antibodies from the plasma and replacing them with high-quality plasma or surrogate plasma. This method is mainly used for patients in the acute disease progression stage and myasthenic crisis, before thymectomy, during perioperative management, and in the initial stages of immunosuppressive therapy, and can temporarily alleviate the symptoms of patients with myasthenia gravis. However, if not used in combination with other treatments, the therapeutic effect does not last more than 2 months, and repeated use over a long period does not improve the long-term effect. (5) Thymectomy: This therapy is suitable for patients with systemic myasthenia gravis that develops between the ages of 16 and 60, and for whom there are no contraindications to surgery. (6) Other treatment methods include, for example, respiratory muscle training and muscle strengthening exercises for patients with mild MG. In short, general treatment regimens for MG have certain risks and limitations, and their therapeutic effects are not sufficient. From an etiological standpoint, since MG is an antibody-mediated disease, there is an urgent need for the development of effective new targeted drugs.

[0005] In recent years, three targeted biological agents used to treat myasthenia gravis (MG) have been approved by the FDA: eculizumab (October 23, 2017), efgaltigimod (December 17, 2021), and ravulizumab (April 28, 2022).

[0006] Eculizumab (brand name: Soliris) is a recombinant human monoclonal antibody that inhibits terminal complement C5, preventing the production of membrane attack complexes (MACs) by anti-AChR antibodies. In a 26-week follow-up study of refractory myositis (MG), the eculizumab dose was 900 mg on day 1 and weeks 1, 2, and 3, 1200 mg at week 4, and then 1200 mg every two weeks thereafter. A maintenance dose of 1200 mg every two weeks was then administered. Vaccination against Neisseria meningitidis is required. From baseline to the end of follow-up, statistical differences between the treatment group and the placebo group were observed only in two outcomes (MG exacerbation and need for salvage treatment), and there was no difference in the primary endpoint (daily MG activity score). The effect of this treatment appeared within 4–8 weeks. The most common side effects in the trial were headache and upper respiratory tract infections. Eculizumab has been approved for patients with refractory myasthenia gravis, but its use is likely to be severely limited by its extremely high price (at least €450,000 per year).

[0007] Ravulizumab (Ultomiris) is an improved, long-acting formulation based on the first-generation C5 monoclonal antibody eculizumab. Compared to eculizumab, ravulizumab has an extended half-life and is currently approved for the treatment of adult patients with generalized myasthenia gravis (gMG) who are positive for anti-acetylcholine receptor (AChR) antibodies. The safety and efficacy of ravulizumab in adult gMG patients with no prior complement inhibitor use were evaluated in a 26-week international, phase III, randomized, double-blind, placebo-controlled, multicenter study. This study enrolled 175 patients from North America, Europe, Asia, and Japan who were diagnosed with MG within at least 6 months prior to screening, were serologically positive for anti-AChR antibodies, had an MG-ADL total score of at least 6 at the time of study enrollment, and were classified as clinically classified II-IV by the Myasthenia Gravis Foundation (MGFA) at the time of screening. In this study, patients were randomly assigned 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 from day 15. This study evaluated the change from baseline in the total MG-ADL score (primary endpoint) at week 26, as well as several secondary endpoints assessing disease-related and quality-of-life improvements. The data demonstrated that this study met the primary endpoint. From baseline to week 26, the ravulizumab group showed a statistically significant change in the total MG-ADL score compared to the placebo group (ravulizumab: -3.1, placebo: -1.4, treatment difference: -1.6, p<0.001). Furthermore, in prospectively defined secondary endpoints—the total quantitative myasthenia gravis (QMG) score (physician assessment of clinical severity of MG) from baseline to week 26 and the percentage of patients with at least a 5-point improvement in QMG—the ravulizumab group also showed clinically meaningful and statistically significant improvements (p<0.001 and p=0.005, respectively). Compared to the placebo group, the ravulizumab group had three times as many patients with at least a 5-point improvement in QMG score (30.0% vs 11.3%).These improvements in MG-ADL and QMG scores were observed as early as week 1 and persisted until week 26. During the randomized control period (26 weeks), adverse events were comparable between the ravulizumab and placebo groups. The most common side effects were headache (18.6% in the ravulizumab group, 25.8% in the placebo group), diarrhea (15.1% in the ravulizumab group, 12.4% in the placebo group), and nausea (10.5% in the ravulizumab group, 10.1% in the placebo group). The most common serious adverse events were MG crisis (1.2% in the ravulizumab group) and MG exacerbation (3.4% in the placebo group). However, ravulizumab also faces the problem of its high price.

[0008] Efgartigimod is an antibody fragment that binds to the neonatal Fc receptor (FcRn), preventing FcRn from circulating immunoglobulin G (IgG) back into the bloodstream. This drug causes a reduction in overall levels of IgG, including 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. The safety and efficacy of efgartigimod were evaluated in a 26-week clinical study involving 167 patients with myasthenia gravis who were randomly assigned to receive either efgartigimod or placebo. This study found that, in measures to assess the impact of myasthenia gravis on daily living activities, patients with more antibodies (68%) showed a therapeutic response within the first cycle of efgartigimod compared to those who received placebo (30%). More patients who received efgartigimod showed a response to muscle weakness compared to those who received placebo. The most common side effects associated with the use of Wifgart include respiratory infections, headaches, and urinary tract infections. However, because Wifgart can cause a decrease in IgG levels, the risk of infection may be significantly increased.

[0009] Since the 1960s, myasthenia gravis has been considered a "second cancer," with patients suffering from lifelong fatigue and weakness, gradually progressing to death. Although the field of MG treatment has developed rapidly in recent years, there remains a huge unmet clinical need in the treatment of myasthenia gravis, not only in China but also globally. [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] In this invention, we have surprisingly discovered that TACI-Fc fusion proteins produce remarkable therapeutic effects when used to treat patients with myasthenia gravis. [Means for solving the problem]

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

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

[0013] Specifically, the present invention also provides the use of TACI-Fc fusion proteins in the manufacture of pharmaceuticals for the treatment of patients with myasthenia gravis.

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

[0015] More preferably, the human immunoglobulin constant region comprises the amino acid sequence shown in SEQ ID NO: 2, or comprises 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 with SEQ ID NO: 2. Sequence ID 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 the human immunoglobulin includes an amino acid modification corresponding to one or more sites among 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, the substitution is selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, P111S, and A173T.

[0018] More preferably, the constant region of the human immunoglobulin includes the amino acid sequence shown in SEQ ID NO: 3. Sequence ID 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, the human immunoglobulin is IgG1.

[0020] More preferably, the TACI-Fc fusion protein is teritacicept, the amino acid sequence of which is shown in SEQ ID NO: 4. Sequence ID 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 each time.

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

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

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

[0025] More preferably, the treatment lasts for approximately 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, and 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. In some specific embodiments, the TACI-Fc fusion protein is administered by subcutaneous injection, intramuscular injection, or intravenous injection.

[0027] More preferably, the TACI-Fc fusion protein is injected at the same or different sites 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 different sites each time.

[0028] More preferably, the 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 muscle-specific tyrosine kinase antibody (MuSK-Ab).

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

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

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

[0034] Generalized myasthenia gravis is an autoimmune disease that affects the neuromuscular junction, causing symptoms of muscle weakness. Scale scoring allows for quantitative assessment of the severity of a patient's condition, enabling a more intuitive evaluation of the patient's state and proving useful for clinical observation and drug efficacy assessment. This invention evaluates the effectiveness of treatment using a quantitative myasthenia gravis scale (QMG) and a table of MG clinical absolute scores.

[0035] The Quasi-Myasthenic Magnification Test (QMG) primarily measures a patient's muscle strength and endurance. Proposed in 2000 by the Myasthenia Gravis Foundation of America, it requires the assistance of measuring devices such as a handheld dynamometer or stopwatch when used. The QMG includes 13 items: diplopia, ptosis, facial muscle strength, swallowing, articulation, left and right arm raises, vital capacity (VC) / predicted vital capacity, head elevation, left and right hand grip strength, and lower limb elevation in a supine position. The total score ranges from 0 to 39 points, with higher scores suggesting a more severe condition. The QMG should be evaluated 8 hours after the last administration of a cholinesterase inhibitor.

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

[0037] The Myasthenia Gravis Foundation (MGFA) strongly recommended in 2000 that the QMG scale be applied to prospective clinical studies related to MG. The MG clinical absolute score method reflects the severity of muscle weakness and fatigue in the affected muscle groups of MG patients, and can sensitively reflect changes in clinical status, making it 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 receiving a standard treatment regimen for stable myasthenia gravis. In some specific embodiments, the standard treatment regimen includes the use of a cholinesterase inhibitor alone, a combination of a cholinesterase inhibitor with a glucocorticoid or other immunosuppressant specified in the regimen, a combination of a glucocorticoid and other immunosuppressant specified in the regimen, or a combination of a cholinesterase inhibitor with a corticosteroid and other immunosuppressant specified in the protocol.

[0040] The TACI-Fc fusion protein provided by this invention exhibits unexpected clinical efficacy and good safety in the treatment of patients with myasthenia gravis. [Brief explanation of the drawing]

[0041] [Figure 1] Figure 1 shows an analysis of the change in QMG score over time relative to the baseline. [Figure 2] Figure 2 shows the percentage of subjects whose QMG score improved to varying degrees after each visit. [Figure 3] Figure 3 shows the time-course analysis of the change in MG clinical absolute score relative to baseline. [Figure 4] Figure 4 shows the time-course analysis of the percentage change in immunoglobulin IgG levels relative to baseline. [Figure 5] Figure 5 shows the time course analysis of the percentage change in immunoglobulin IgA levels relative to baseline. [Figure 6] Figure 6 shows the time course analysis of the percentage change in immunoglobulin IgM levels relative to baseline. [Figure 7] Figure 7 shows the time course analysis of the percentage change in CD19+ B cell count relative to baseline. [Modes for carrying out the invention]

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

[0043] The three-letter and one-letter codes for amino acids used in this invention are as described in J.biol.chem, 243, p3558 (1968).

[0044] The present invention provides the use of transmembrane activator, calcium regulator, and cyclophylline ligand interactor (TACI)-immunoglobulin fusion proteins (i.e., TACI-Fc fusion proteins) in the treatment of myasthenia gravis. The TACI-immunoglobulin fusion proteins provided in the present invention comprise 1) a polypeptide comprising a region at least partially identical to the extracellular domain of TACI 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 Applications 09 / 569,245 and 09 / 627,206 (the contents of which are incorporated herein by reference) describe the extracellular domain of TACI and specific fragments of the extracellular domain of TACI capable of interacting with TACI ligands, the TACI ligands including BlyS and APRIL. Chinese Patent Publication No. CN101323643A describes a TACI-Fc fusion protein containing amino acid fragments from positions 13 to 118 of the TACI extracellular domain.

[0045] The immunoglobulin portion of the TACI-immunoglobulin fusion protein provided in the present invention is preferably IgG1, and may include a heavy chain constant region, such as the human heavy chain constant region. The preferred IgG1 heavy chain constant region of the present invention is an IgG1 Fc fragment containing CH2 and CH3 regions, and may be a wild-type IgG1 Fc fragment or a mutated IgG1 Fc fragment.

[0046] TACI-Fc fusion proteins can be administered to patients via any appropriate route. These routes include, but are not limited to, intravenous, intramuscular, or subcutaneous administration.

[0047] The TACI-Fc fusion protein formulations provided in this invention are manufactured and stored in lyophilized, sterile, solution form. Such formulations may contain other active ingredients, excipients, or other components such as sodium chloride, phosphate buffer, or sodium hydroxide. TACI-Ig formulations can be administered to patients in combination with other drugs and can be administered before, concurrently with, or after other treatments.

[0048] The term "treatment" in relation to the present invention relates to a given disease or illness. "Treatment" includes, but is not limited to, suppressing a disease or illness to prevent its progression, reducing a disease or illness to cause it to regress, or reducing, preventing, or treating symptoms caused by a disease or illness. [Examples]

[0049] The embodiments of the present invention will be described in detail below, along with examples, but those skilled in the art will understand that the following examples are used to illustrate the present invention and should not be considered to limit the scope of the invention.

[0050] Example 1: Clinical trial to treat myasthenia gravis with teritacicept

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

[0052] 2. Selected patients Subjects were defined as adult patients with generalized myasthenia gravis (gMG) who were diagnosed with positive acetylcholine receptor antibody (AchR-Ab) or muscle-specific tyrosine kinase antibody (MuSK-Ab), were receiving a stable standard treatment regimen, and were classified as type II or III according to the Myasthenia Gravis Foundation of America (MGFA) clinical classification, had a quantitative myasthenia gravis score (QMG) of 8 or higher at screening, and scored at least 2 on four or more items.

[0053] 3. Treatment administered Participants were randomly assigned to receive either teritacicept 160 mg or teritacicept 240 mg. Teritacicept was administered subcutaneously once a week for a total of 24 times, via the thigh, abdomen, or upper arm. Each injection was administered at a different site.

[0054] 4. Evaluation Criteria

[0055] 4.1 Indicators of treatment effectiveness

[0056] 4.1.1 Indicators of the effectiveness of the primary treatment Mean change in QMG score at week 24 relative to baseline.

[0057] 4.1.2 Indicators of secondary therapeutic effects Mean change in clinical absolute score for myasthenia gravis at weeks 12 and 24 relative to baseline. Mean change in QMG score at week 12 relative to baseline.

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

[0059] 5. Demographic and Baseline Characteristics This study included the following three populations for analysis: ●Farest Analysis Set (FAS): The farest analysis set refers to the set of all cases that were randomized and received the investigational drug at least once. ● Protocol-compliant subjects (PPS): A protocol-compliant subjects is a data set generated from subjects who have fully complied with the protocol, provided that compliance includes treatment received, availability of primary endpoint indicator measurements, and minimal violations of the overall clinical trial protocol. ●Safety data analysis population (SS): This is actual data from patients who received treatment at least once and whose safety indicators were recorded. The incidence of adverse reactions is calculated using the number of cases in the safety analysis population as the denominator.

[0060] In this trial, 41 patients were screened, and 29 were randomly assigned to groups. All 29 patients completed the 24-week observation period and were included in the largest analysis population (FAS), the protocol-fit population (PPS), and the safety data analysis population (SS). In the teritacicept 160 mg group, there were 14 patients in the FAS, 14 in the PPS, and 14 in the SS. In the teritacicept 240 mg group, there were 15 patients in the FAS, 15 in the PPS, and 15 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. All 28 subjects underwent MuSK-Ab level testing (one subject in the teritacicept 160 mg group was not tested), and the results were all negative. The median duration of illness for the subjects was 25.4 months, the mean QMG score was 18.9 points, and the mean MG clinical absolute score was 24.0 points. The clinical classification of MGFA in 16 subjects (55.2%) was type II, and the clinical classification of MGFA in 13 subjects (44.8%) was type III. Nine subjects (31.0%) were treated with cholinesterase inhibitors alone, thirteen subjects (44.8%) were treated with a combination of cholinesterase inhibitors and glucocorticoids / other designated immunosuppressants, and seven subjects (24.1%) were treated with a combination of cholinesterase inhibitors, glucocorticoids, and other immunosuppressants.

[0062] 6. Results of treatment effectiveness

[0063] 6.1 Analysis of Treatment Effectiveness Treatment efficacy was analyzed using FAS and PPS. All 29 randomized subjects in this study were included in both FAS and PPS, and the analysis results for FAS and PPS were identical; therefore, FAS and PPS will not be distinguished in the following explanation of efficacy results.

[0064] 6.2 Evaluation Indicators (Endpoints) for the Primary Treatment Efficacy The primary treatment efficacy indicator in this study was the mean change in QMG score at week 24 relative to baseline. Analysis of covariance (ANCOVA) was performed with the group as a fixed effect and the baseline value as a covariate.

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

[0066] [Table 1]

[0067] Using ANCOVA, the difference in the least two-squares mean (LSMEANS) of the change in QMG score from baseline at week 24 was compared between the teritacicept 160 mg group and the teritacicept 240 mg group. At week 24, the LSMEANS of the change in QMG score from baseline was -7.96 (95% CI: -10.07 to -5.85) in the teritacicept 160 mg group, and -9.37 (95% CI: -11.40 to -7.33) in the teritacicept 240 mg group. 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 Evaluation Indicators for Secondary Therapeutic Effects

[0070] 6.3.1 Mean change in QMG score at week 12 relative to baseline The mean change in QMG score at week 12 relative to baseline was used as one of the secondary indicators of treatment efficacy in this study, and group differences were compared using a t-test.

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

[0072] [Table 3]

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

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

[0075] [Table 4]

[0076] 6.4 Results of other treatment effects

[0077] 6.4.1 Time-series analysis of the change in QMG score relative to baseline Figure 1 shows the results of the time-course analysis of the change in QMG scores relative to baseline. From week 4, the QMG scores of subjects in both the teritacicept 160 mg group and the teritacicept 240 mg group continued to decrease significantly relative to baseline until week 24.

[0078] 6.4.2 Percentage of subjects with improved QMG score Figure 2 shows the percentage of subjects whose QMG score improved to varying degrees at each visit (i.e., their QMG score decreased by ≥3, ≥4, ≥5, ≥6, ≥7, and ≥8 points, respectively).

[0079] From weeks 4 to 24, the proportion of subjects showing varying degrees of QMG score improvement was higher in the teritacicept 240mg group than in the 160mg group. At week 24, the proportion of subjects in the teritacicept 160mg group and teritacicept 240mg group who had improved their QMG score by 3 points or more was 92.9% and 100.0%, respectively. The proportion of subjects who had improved their QMG score by 4 points or more was 78.6% and 93.3%, respectively. The proportion of subjects who had improved their QMG score by 5 points or more was 57.1% and 86.7%, respectively. The proportion of subjects who had improved their QMG score by 6 points or more was 50.0% and 80.0%, respectively. The proportion of subjects who had improved their QMG score by 7 points or more was 42.9% and 73.3%, respectively. The percentage of subjects whose QMG score improved by 8 points or more was 42.9% and 66.7%, respectively.

[0080] 6.4.3 Time-course analysis of the change in clinical absolute scores of MG relative to baseline Figure 3 shows the results of the time-course analysis of the change in clinical absolute scores of MG relative to baseline. From week 4, the clinical absolute scores of subjects in both the teritacicept 160 mg group and the teritacicept 240 mg group showed a significant and sustained decrease relative to baseline until week 24.

[0081] 6.4.4 Immunological indicators

[0082] 6.4.4.1 Immunoglobulins (IgG, IgA, IgM) Figures 4-6 show the results of the time-course analysis of the rate of change in immunoglobulin (IgG, IgA, IgM) levels relative to baseline. From week 4, the IgG, IgA, and IgM levels (g / L) of subjects in the teritacicept 160 mg and 240 mg groups continued to decrease significantly until week 24.

[0083] At week 24, the percentage change (%) (mean ± SD) in the subject's 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 percentage 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 percentage change (%) (mean ± SD) in the subject's 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 Figure 7 shows the results of a time-course analysis of the percentage change in CD19+ B cell count relative to baseline. Compared to baseline, the median CD19+ B cell count in subjects treated with 240 mg of teritacicept initially increased, then showed a tendency to decrease. At week 24, the median CD19+ B cell count in subjects was significantly lower than baseline. The median CD19+ B cell count in subjects treated with 160 mg of teritacicept fluctuated, but no clear trend in change was observed.

[0087] 6.5 Results of effectiveness This study demonstrated sustained improvement in clinical efficacy of teritacicept 160 mg and 240 mg in the treatment of patients with generalized myasthenia gravis. After receiving either 160 mg or 240 mg of teritacicept once weekly, subjects experienced a continuous decline in their QMG score and MG clinical absolute score from week 4 to week 24. At week 24, compared to baseline, subjects in the teritacicept 160 mg group showed a mean decrease of 7.7 points in their QMG score, and subjects in the teritacicept 240 mg group showed a mean decrease of 9.6 points in their QMG score. At week 24, compared to baseline, subjects in the teritacicept 160 mg group showed a mean decrease of 13.8 points in their MG clinical absolute score, and subjects in the teritacicept 240 mg group showed a mean decrease of 14.1 points in their MG clinical absolute score. At week 24, 92.9% of subjects in the teritacicept 160 mg group showed a QMG score improvement of 3 points or more, and 100% of subjects in the teritacicept 240 mg group showed a QMG score improvement of 3 points or more. Furthermore, both teritacicept 160 mg and teritacicept 240 mg significantly reduced IgG, IgA, and IgM levels in subjects.

[0088] 6.6 Safety Results In this study, teritacicept 160 mg and teritacicept 240 mg administered once weekly to patients with systemic myasthenia gravis demonstrated good treatment safety. The severity of adverse events / reactions was mostly mild to moderate (CTCAE grade 1 and grade 2). However, one patient in the teritacicept 160 mg group experienced a CTCAE grade 3 adverse event (decreased lymphocyte count). No CTCAE grade 4 or grade 5 adverse events / reactions occurred. No adverse events / reactions led to discontinuation of the study drug, withdrawal from the study, or death of any patient, and no serious adverse reactions occurred. During the study period, one patient in the teritacicept 160 mg group experienced a serious adverse event, infectious pneumonia. However, the researchers determined that this adverse event was not caused by the investigational drug and treated the patient without discontinuing the investigational drug, after which the patient recovered. All adverse reactions observed in this study were foreseeable risks of teritacicept, and no signs of new safety risks were identified.

[0089] 6.7 Conclusion In this study, teritacicept 160 mg and 240 mg demonstrated favorable clinical efficacy and safety in the treatment of patients with systemic myasthenia gravis.

[0090] The above description is merely a preferred embodiment and is used for illustrative purposes only, and does not limit the combination of features necessary to carry out the present invention. The titles described herein do not mean to limit the various embodiments of the present invention. Terms such as “contains,” “includes,” and “includes” do not mean limiting. Furthermore, unless otherwise specified, if a noun is not modified by a number, it is considered to encompass multiple nouns. The terms “or” and “or” mean “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 referenced in this application are incorporated herein by reference. Various modifications and variations made to the methods and combinations described in the present invention will be obvious 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 unjustly limited to these specific embodiments. In practice, various variations of the modes described for carrying out the invention, which will be obvious to those skilled in the art, are intended to be included within the claims of this application.

Claims

1. (i) the extracellular domain of TACI, or a fragment thereof that binds to BLys and / or APRIL, (ii) Fragments of the constant region of human immunoglobulin, A composition for the treatment of myasthenia gravis in patients suffering from myasthenia gravis, characterized by containing a TACI-Fc fusion protein, Here, the constant region fragment of the human immunoglobulin comprises an Fc fragment containing the CH2 and CH3 domains of the human immunoglobulin, and includes the amino acid sequence shown in SEQ ID NO: 2, or includes 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 with SEQ ID NO:

2.

2. The composition according to claim 1, characterized in that the fragment that binds to the TACI extracellular domain or BLys and / or APRIL includes the amino acid sequence shown in SEQ ID NO:

1.

3. The composition according to claim 2, characterized in that the fragment of the constant region of the human immunoglobulin comprises amino acid modifications corresponding to one or more sites among sites 3, 8, 14, 15, 17, 110, 111, and 173 of SEQ ID NO:

2.

4. The composition according to claim 3, characterized in that the modification is the substitution, deletion, or insertion of one or more amino acids.

5. The composition according to claim 4, characterized in that the substitution is selected from the group consisting of P3T, L8P, L14A, L15E, G17A, A110S, P111S, and A173T.

6. The composition according to claim 5, characterized in that the human immunoglobulin is IgG1, or the fragment of the constant region comprises the amino acid sequence shown in SEQ ID NO:

3.

7. The composition according to claim 1, characterized in that the TACI-Fc fusion protein has the amino acid sequence shown in SEQ ID NO:

4.

8. The composition according to claim 1, characterized in that the TACI-Fc fusion protein is teritacicept.

9. The composition according to claim 8, characterized in that the TACI-Fc fusion protein is administered at a dose of approximately 0.1 to 10 mg / kg each time.

10. The composition according to claim 8, characterized in that the TACI-Fc fusion protein is administered in a dose of 160 to 240 mg, preferably 160 mg or 240 mg, each time.

11. The composition according to claim 9 or 10, characterized in that the TACI-Fc fusion protein is used 2 to 4 times over a one-month period and / or administered continuously for about 2 to 50 weeks.

12. The composition according to claim 11, characterized in that the TACI-Fc fusion protein is administered once a week.

13. The composition according to claim 11, characterized in that the TACI-Fc fusion protein is administered via a subcutaneous, intramuscular, or intravenous route, or administered through an administration site of the thigh, abdomen, or upper arm.

14. The composition according to claim 13, characterized in that the myasthenia gravis is generalized myasthenia gravis (gMG), or type II or type III myasthenia gravis according to the clinical classification of the Myasthenia Gravis Foundation of America (MGFA).

15. The composition according to claim 14, characterized in that the myasthenia gravis has a quantitative myasthenia gravis score (QMG) of 8 or more, and at least 2 or more item scores for four or more items.

16. The composition according to claim 15, characterized in that the patient is an adult patient or a pediatric patient, or a patient who has previously received a standard treatment regimen for stable myasthenia gravis.

17. The composition according to claim 16, characterized in that the standard treatment regimen includes the use of a cholinesterase inhibitor alone, the combination of a cholinesterase inhibitor with a glucocorticoid or other immunosuppressant specified in the regimen, the combination of a glucocorticoid and other immunosuppressant specified in the regimen, and the combination of a cholinesterase inhibitor with a corticosteroid and other immunosuppressant specified in the protocol.

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