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Myasthenia Gravis is an autoimmune disease that causes muscle weakness and fatigue. It occurs when the communication between nerve cells and muscles is disrupted. This impairment prevents critical muscle contractions from occurring, resulting in muscle weakness. This disease is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. The main symptom of Myasthenia Gravis is weakness in the voluntary skeletal muscles. There are three types of Myasthenia Gravis- Transient Neonatal Myasthenia Gravis, Juvenile Myasthenia Gravis, and Congenital Myasthenia Gravis (CMG).
According to the NORD, the myasthenia gravis prevalence is estimated to be 14-40 per 100,000 people in the United States, and women are more likely to be affected than men. As per DelveInsight analysis, the Myasthenia Gravis diagnosed prevalent cases were found to be 40,723 in the US in 2020, with the Class II (mild generalized) accounting for the maximum prevalence followed by Class IV (severe generalized), Class I (ocular), Class III (moderate generalized), and Class V (Intubated), respectively. There are several therapies in the market to address the Myasthenia Gravis burden, and many companies are still working on their drug candidates to cope with Myasthenia Gravis. The disease presents some unmet needs such as lack of understanding related to the role of thymus gland and development of novel biomarkers for ease in diagnostic procedure.
Myasthenia Gravis Treatment Landscape
The Myasthenia Gravis treatment is divided into the first-line of therapy and second-line of treatment. The first line of therapy treatment includes Symptomatic treatments (Anticholinesterase agents such as pyridostigmine bromide, neostigmine, and ambenonium), Chronic Immunomodulating treatments (Immunomodulators in combination with Glucocorticosteroids, Azathioprine, Ciclosporin A, Methotrexate, MMF, Tacrolimus, Rituximab, etc.). The second line of therapy consists of Rapid Immunomodulating treatments (Plasmapheresis and intravenous immune globulin). Apart from these, Surgical treatment (Thymectomy) is also used for Myasthenia Gravis treatment.
Myasthenia Gravis Approved Therapies
The current Myasthenia Gravis therapeutics market has many FDA-approved drugs for the treatment of Myasthenia Gravis. These drugs are playing a vital role in the lives of Myasthenia Gravis patients for a long time. Some of the approved drugs are:
Prograf (tacrolimus), developed by Astellas Pharma, is an immunosuppressant used in conjunction with other medications to keep your body from rejecting a heart, liver, or kidney transplant. Prograf is available for oral administration in the form of capsules (tacrolimus capsules USP) containing 0.5 mg, 1 mg, or 5 mg of anhydrous tacrolimus USP. It is also available as a sterile solution (tacrolimus injection) containing 5 mg anhydrous tacrolimus USP in 1 mL for intravenous infusion only. Some Prograf formulations are available in generic form as the patent of Prograf is expired. The drug was launched in Japan in 2000. Prograf is indicated for the prevention of organ rejection in kidney, liver, and heart transplants.
Mestinon (pyridostigmine bromide)
Mestinon, developed by Valeant Pharmaceuticals, is a prescription medication used to treat Myasthenia Gravis symptoms as a pretreatment for Soman Nerve Gas Exposure and reverse the effects of nondepolarizing muscle relaxants. Mestinon can be used alone or in combination with other medications. Mestinon (pyridostigmine) is available in three dosage forms- Syrup, Conventional Tablets, and Timespan Tablets. Mestinon was first launched in the United States in 1955. The patent of the drug is expired and is available for generic medicine.
Mitsubishi Tanabe Pharma’s product Venoglogulin IH is an immunoglobulin used to boost the body’s natural defense system (immune system) to reduce the risk of infection in people who have a weakened immune system. This medication is made from healthy human blood that contains a high concentration of certain defensive substances (antibodies) that aid in the fight against infections. This medication is administered by injection under the skin or slowly into a vein as directed by the doctor. It was first launched in Japan in 2011.
Soliris is a first-in-class terminal complement inhibitor developed by Alexion Pharmaceuticals. Soliris inhibits the activation of specific complement system proteins (C5a and C5b), which are involved in the pathophysiology of several rare diseases. Soliris is indicated for the treatment of patients with Paroxysmal Nocturnal Hemoglobinuria (PNH), Atypical Hemolytic Uremic Syndrome (aHUS), Generalized Myasthenia Gravis (gMG) in adults, and Neuromyelitis Optica Spectrum Disorder (NMOSD). Soliris is in clinical trials to prove its efficacy in the treatment of pediatric refractory gMG. Soliris has received some of the pharmaceutical industry’s most prestigious awards for innovation, including the Prix Galien USA Award for Best Biotechnology Product in 2008 and the Prix Galien France Award for Drugs for Rare Diseases in 2009.
During 2007-2011, Soliris got FDA approval for all the patients with Atypical Hemolytic Uremic Syndrome (aHUS) and Paroxysmal Nocturnal Hemoglobinuria (PNH). In 2014, Eculizumab was designated as an orphan drug by the European Commission and the US Food and Drug Administration to treat patients with Myasthenia Gravis. In 2017, Soliris (Eculizumab) was approved by the MHLW in Japan, the European Commission in Europe and the FDA in the United States to treat patients with generalized Myasthenia Gravis (gMG). The latter are Anti-Acetylcholine Receptor (AChR) antibody-positive. The FDA has approved Alexion’s Soliris (Eculizumab) to treat adults with Neuromyelitis Optica Spectrum Disorder (NMOSD) in 2019. However, the patent expiry for the Soliris at hand is approaching fast, expected in 2022, in the US, while the drug has already met its deadline in Europe. Still, the orphan drug designation has managed to grant the drug extended market exclusivity.
Soliris Sales and Annual Cost of Therapy (ACOT)
Soliris has always been a blockbuster drug of Alexion Pharmaceuticals. The company is generating a tremendous amount of revenue every year from the Soliris drug. The company made a profit of USD 3144.1 million through the sales of Soliris across all the regions (the US, Europe, Asia Pacific, and ROW) and for all the indications mentioned above in 2017, while in 2018, the total sales made by this drug was USD 3563 million. The maximum sale of Soliris was recorded in the US region (USD 2014 million and 2259.7 million, respectively) in the years 2019 and 2020, which was double of the sales generated by the Europe region.
Soliris is available in the injection form, and the recommended amount of this drug is 900 and 1200mg, while the annual cost of therapy is more than USD 400,000 per year. The high cost of Soliris —only approved drug in the 7MM — presents an unmet need for pocket friendly effective treatment options.
Myasthenia Gravis Pipeline Overview
There are several Myasthenia Gravis therapies in the pipeline that are in different stages of development for Myasthenia Gravis treatment. Major pharmaceutical companies across the globe, such as UCB Pharma, Alexion, Grifols, and others, are testing their drug candidates with novel MoA that can be used as first-line of therapy or second-line of treatment for the Myasthenia Gravis treatment.
|Drug||Molecule||Phase||Company||MoA||LOT||Expected Launch Year|
|Uplizna (Inebilizumab cdon)||Monoclonal antibody||Phase III||VielaBio (now acquired by Horizon Therapeutics)||Anti-CD19 mAb||Second-line||–|
|Rozanolixizumab||Monoclonal antibody||Phase III||UCB Pharma||Block the interaction of FcRn and IgG||Second-line||2022|
|Zilucoplan (RA101495)||Peptide||Phase III||RaPharma/UCB Pharma||Complement C5 inhibitor||First-line||2023|
|Efgartigimod (ARGX-113)||Monoclonal antibody||Phase III (BLA accepted, PDUFA target action date is in December 2021)||Argenx||FcRn-antagonist||Second-line||2022|
|Firdapse (amifampridine)||Antineoplastics; Small molecules||Phase III||Catalysts Pharmaceuticals||neuronal potassium channel blocker||First-line||2022|
|ULTOMIRIS IV(Ravulizumab)||Monoclonal antibody||Phase III||Alexion||C5 inhibitor||Second-line||2025|
|IGIV-C (GAMUNEX)||Immunoglobulin Immunostimulants||Phase III (received EU approval to treat severe acute exacerbations of Myasthenia Gravis)||Grifols||ComplementC5 inhibitor||–||–|
|Nipocalimab||Monoclonal antibody||Phase III||Janssen Pharmaceutical Companies||IgG1 anti-FcRn||–||–|
|Satralizumab||Monoclonal antibody||Phase III||Hoffmann-La Roche||Interleukin 6 receptor antagonists||–||–|
Market Potential of the Upcoming Myasthenia Gravis Therapies
Currently, a significant portion of the Myasthenia Gravis market is grabbed by the top-selling drug, Soliris. To give this drug competition and try to impact the current Myasthenia Gravis therapeutics market, key companies such as Catalysts Pharmaceuticals, Ra Pharmaceuticals, Argenx, and others are evaluating their drug candidates for Myasthenia Gravis.
Firdapse (Amifampridine), being developed by Catalysts Pharmaceuticals, is an oral, nonspecific, voltage-dependent potassium (K+) channel blocker that causes presynaptic membrane depolarization and slows or inhibits repolarization. This action causes slow voltage-dependent calcium (Ca2+) channels to open, allowing Ca2+ to enter the cell. In turn, it causes synaptic vesicles containing acetylcholine (ACh) to exocytose, releasing more ACh into the synaptic cleft and improving neuromuscular transmission and muscle function. As per DelveInsight analysis, Firdapse will grab the market size of more than USD 500 million by 2028 in the United States. Firdapse is approved for use in patients with LEMS in the United States and the European Union. Firdapse was designated as an orphan drug by the US Food and Drug Administration in September 2016 to treat MuSK-MG. Firdapse is still in development for other indications such as Lupus nephritis and Rheumatoid arthritis.
Efgartigimod developed by Argenx is an investigational antibody fragment intended to reduce disease-causing immunoglobulin G (IgG) antibodies while also blocking the IgG recycling process. Efgartigimod binds to the neonatal Fc receptor (FcRn), widely expressed throughout the body and essential in rescuing IgG antibodies from degradation. In a phase II study, 75 percent of patients treated with Efgartigimod had a clinically meaningful and statistically significant improvement in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores (at least a two-point reduction from baseline) for at least six weeks, compared to 25 percent of placebo patients (p = 0.0391). Treatment with Efgartigimod resulted in clinical improvement over placebo on all four predefined clinical efficacy scales – MG-ADL, QMG, and Myasthenia Gravis Composite (MGC). According to DelveInsight analysis, Efgartigimod is expected to give tough competition to Firdapse. Currently, Efgartigimod is in registrational phase for generalized Myasthenia Gravis. If Efgartigimod gets the FDA approval, it will be the first and only approved FcRn antagonist to treat generalized Myasthenia Gravis. The other indications for which Efgartigimod is in development are Primary Immune Thrombocytopenia, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), and Pemphigus Vulgaris.
Zilucoplan (RA101495), developed by Ra Pharmaceuticals acquired by UCB Pharma, is a synthetic peptide that binds to complement 5 (C5), blocking its activity and preventing the overactivation of the complement system — a collection of more than 50 blood proteins that serve as part of the body’s immune defenses — which is thought to be involved in the formation of harmful autoantibodies in Myasthenia Gravis. In a phase II study, patients treated with Zilucoplan improved significantly in both QMG (Quantitative myasthenia gravis score) and MG-ADL compared to placebo recipients. Higher-dose recipients improved faster and for a more extended period than lower-dose recipients. If approved, Zilucoplan is also expected to create a competitive market for the approved and emerging therapies. In 2019, Zilucoplan was designated as an orphan drug by the United States Food and Drug Administration (FDA) to treat Myasthenia Gravis. The Phase III results for Myasthenia Gravis are expected in Q4 2021. Immune-Mediated Necrotizing Myopathy, Paroxysmal Nocturnal Hemoglobinuria (PNH), Amyotrophic Lateral Sclerosis, and COVID-19 are the indications for which the Zilucoplan is still in development.
The current treatment for Myasthenia Gravis focuses on immune system regulation and suppression on a broad scale. These treatments have been well researched and found to be successful in many myasthenia patients, albeit at the cost of considerable side effects due to the immune system’s overall impact. Future treatment approaches will focus on targeted immunotherapies that attempt to improve results while reducing adverse effects. New biologics targeting B cells, complement, and the FcRn receptor are getting us closer to successfully tailored immunotherapies for myasthenia gravis, promising an exciting future for antibody-mediated neurological diseases.