Myasthenia Gravis: Emerging Therapies

Myasthenia Gravis is a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles that worsens after periods of activity and improves after periods of rest. These muscles are responsible for functions involving breathing and moving parts of the body, including the arms and legs. It is characterized by muscular fatigue leading to extreme weakness. The fatigue is caused by the loss of ability to convert nerve impulses into muscle contraction. The disease affects muscles controlling voluntary movement including those associated with actions such as swallowing and breathing and usually begins in a mild form. Typical first symptoms are associated with the eyelid, sight, swallowing, and speech. Focal MG usually develops more or less rapidly into generalized MG with symptoms that appear in the arms and abdomen and subsequently in the legs and respiratory muscles.

Various diagnostic tests such as electro-diagnostics, diagnostic imaging, pulmonary function tests, and other tests are used for the diagnosis of Myasthenia Gravis. Thymectomy, Monoclonal antibody, Anticholinesterase medications, and Immunosuppressive drugs are recommended for the treatment of myasthenia gravis. Several pharmaceutical companies such as CuraVac, argenx BVBA, Cartesian Therapeutics, Momenta Pharmaceuticals, Inc., RemeGen, and others are involved in the development of novel therapies for the treatment of Myasthenia Gravis.

CuraVac (CV-MG01)

Myasterix (CV-MG01) is an investigational therapeutic vaccine being developed by Curavac to alleviate the symptoms of myasthenia gravis. Myasterix is likely to have fewer side effects and a simpler method of administration than other therapies. The Myasterix vaccine induces the body to produce a different type of antibody, which binds to autoantibodies and T-cell receptors associated with myasthenia gravis. Obstructing receptors of the anti-AChR T-cells with the Mysterix-produced antibody prevents autoimmune production of anti-AChR antibodies. This is expected to unblock the AChR, restoring neuromuscular communication via acetylcholine successfully binding to its receptor.

Myasterix, is currently investigated under a clinical trial study. The Study CV-0002 is the first clinical trial administering CV-MG01 in humans. This clinical trial is a safety and proof-of-concept study (proof of mechanism of action) intended to assess the safety, tolerability, and immunogenic response following three subcutaneous injections of CV-MG01 as a potential therapeutic vaccine / active immunotherapy in myasthenia gravis (MG) patients.

Argenx BVBA (ARGX-113/ Efgartigimod)

Efgartigimod is designed as a first-in-class investigational antibody fragment to target the neonatal Fc receptor (FcRn). Efgartigimod is being evaluated for the treatment of patients with severe autoimmune diseases with confirmed presence of pathogenic immunoglobulin G, IgG autoantibodies, where a severe unmet medical need exists.

Cartesian Therapeutics (Descartes-08)

Descartes-08 is a CD8+ CAR-T investigational therapy that targets cells expressing B-cell Maturation Antigen (BCMA), a protein expressed by all plasma cells. Descartes-08 is engineered to have a defined and predictable half-life, enabling repeat dosing to maximize potency while minimizing the risk of toxicity

UCB Biopharma S.P.R.L. (Rozanolixizumab)

Rozanolixizumab is a subcutaneously administered, humanized monoclonal antibody that specifically binds, with high affinity, to human FcRn. It has been designed to block the interaction of FcRn and IgG, inhibiting IgG recycling and inducing the removal of pathogenic IgG autoantibodies. Rozanolixizumab is under clinical development with the aim of improving the lives of people with pathogenic IgG-autoantibody-driven autoimmune diseases, including ITP, myasthenia gravis (MG) and chronic inflammatory demyelinating polyneuropathy (CIDP), by driving removal of pathogenic IgG autoantibodies

Momenta Pharmaceuticals, Inc.( M281/ Nipocalimab)

Nipocalimab (M281) is a fully human, anti-FcRn (neonatal Fc receptor), aglycosylated IgG1 monoclonal antibody. Nipocalimab (M281) has the potential of improving the clinical signs and symptoms of MG by blocking FcRn-mediated IgG recycling, thereby reducing pathogenic autoantibodies including the most common autoantibodies, anti-AChR and anti-MuSK. Nipocalimab, is investigated under clinical trial. The purpose of this study is to evaluate the safety, tolerability, and efficacy of M281 administered to participants with generalized myasthenia gravis (gMG) who have an insufficient clinical response to ongoing standard of care therapy.

Immunovant Sciences GmbH (IMVT-1401)

The investigational drug product candidate, IMVT-1401 (formerly known as RVT-1401), is a novel, fully human monoclonal antibody targeting the neonatal Fc receptor (FcRn). IMVT-1401 has the potential to address a variety of IgG-mediated autoimmune diseases as a subcutaneous injection. The FcRn receptor facilitates IgG recycling. IMVT-1401 enhances the degradation of IgG by targeting FcRn and preventing endogenous IgG from binding. This increased catabolism of IgG may curtail the harmful immune response exhibited by auto-antibodies.

Catalyst Pharmaceuticals, Inc. (Amifampridine Phosphate)

Amifampridine, a neuronal potassium channel blocker, is used for the treatment of MuSK-positive myasthenia gravis. Currently, Catalyst is enrolling patients into a phase III trial examining amifampridine  for the treatment of Myasthenia Gravis. The MuSK Trial is a phase III, randomized, double-blind, placebo-controlled, parallel-group study evaluating the safety, tolerability, and efficacy of amifampridine in patients with MuSK-MG and a small sample of patients with AChR-MG. Amifampridine has received the Orphan Drug Designation from the Food and Drug Administration FDA for the treatment of patients with myasthenia gravis.

RemeGen (RC18)

Investigational candidate RC18 is a fusion antibody created by RemeGen scientists to target signaling factors involved in the development and survival of B cells, the cell responsible for generating antibodies. RC18 is a fusion of a TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactors) protein and the IgG protein.

RC18 binds to BLyS (B lymphocyte stimulator) and APRIL (a proliferation-inducing ligand), preventing these cell-signaling molecules from binding to TACI proteins on the surface of the B cell. This inhibits the development and survival of mature B cells, preventing the formation of autoantibodies.

Emerging Pipeline Landscape of Myasthenia Gravis

Company NameProduct NameMechanism of ActionRoute of AdministrationStage of development
CuraVacCV-MG01Acetylcholine ModulatorsSubcutaneousPhase I/II
argenx BVBAARGX-113FcRn/ Neonatal Fc receptor AntagonistsIntravenousPhase III
Cartesian TherapeuticsDescartes-08CD8 + CART TherapyIntravenousPhase I/II
UCB Biopharma S.P.R.L.Rozanolixizumab/UCB7665Anti-(FcRn) antibodySubcutaneous Phase III
Momenta Pharmaceuticals, Inc.M281/ NipocalimabAnti-FcRn AntibodyIntravenousPhase II
Immunovant Sciences GmbHIMVT-1401  Neonatal Fc Receptor AntagonistsSubcutaneousPhase II
DAS-MG, IncDAS-001Acetylcholinesterase InhibitorsNAPhase II
Catalyst Pharmaceuticals, Inc.Amifampridine PhosphateNeuronal Potassium Channel BlockerOralPhase III
RemeGenRC18
Fusion protein
BLyS/APRIL
subcutaneousPhase II

Myasthenia Gravis Awareness Month

June is the Myasthenia Gravis Awareness Month that creates awareness regarding the myasthenia gravis (MG), supports the people living with Myasthenia Gravis, and creates connections for the MG community. This awareness month aims to boost the efforts regarding the fundraising, research, and advocacy to support people affected by Myasthenia Gravis.

Myasthenia Gravis is a disorder that occurred due to the breakdown in the communication between nerves and muscles because of an immunological problem. It caused the weakness and easy fatigue of the skeletal muscles used for the movement. It is characterized by the trouble talking, problems in walking up stairs or lifting objects, facial paralysis, difficulty in swallowing or chewing, fatigue, hoarse voice, drooping of eyelids, and double vision.

According to the National Organization for Rare Disorders (NORD), the prevalence of Myasthenia Gravis is approximately 14-40 per 100,000 individuals in the United States. It is most frequent among females in comparison to males. It affects people of any age group. It is most common in young adult women under 40 and older adult men over 60 years.

Emerging Therapies: Multiple Sclerosis

Multiple sclerosis (MS) is a condition that can affect the brain and spinal cord, causing a wide range of potential symptoms, including problems with vision, arm or leg movement, sensation, or balance. It is a chronic autoimmune inflammatory disease of the central nervous system that damage and scars the sheath, and potentially the underlying nerves. Multiple sclerosis is affecting 2.3 million people worldwide, with females more affected than males.

According to the National Institute for Neurological Disorders and Stroke (NINDS), approximately, 250,000-350,000 people are suffering from the Multiple Sclerosis in the United States. The majority of the people with multiple sclerosis are diagnosed between the ages of 20 and 50, with at least two to three times more women than men being diagnosed with the disease. The most common symptoms associated with MS include fatigue, difficulty walking, vision problems, problems controlling the bladder, etc. The average life expectancy is slightly reduced for people with MS. The progress, severity, and specific symptoms of MS in any one person cannot yet be predicted.  

There are various diversify companies involved in the discovery and development of a potentially robust clinical pipeline for the treatment of Multiple Sclerosis. Merck Healthcare KGaA, Novartis, Sanofi, TG Therapeutic, Biogen, MedDay Pharmaceuticals SA, and Hoffmann-La Roche are the major market players

Actelion (Ponesimod)

Ponesimod is an investigational selective sphingosine-1-phosphate receptor 1 (S1P1) modulator that inhibits S1P protein activity and reduce the number of circulating lymphocytes that can cross the blood-brain barrier. The Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen) had submitted the New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for ponesimod for the treatment of adult patients with relapsing multiple sclerosis (MS).

Merck Healthcare KGaA (Evobrutinib)

Evobrutinib is an investigational oral inhibitor of Bruton’s tyrosine kinase (BTK) which is thought to be important in the development and functioning of various immune cells including B lymphocytes and macrophages. Currently, clinical research study is ongoing on Evobrutinib. The study would evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Teriflunomide (Aubagio), administered orally once daily in participants with Relapsing Multiple Sclerosis (RMS).

Hoffmann-La Roche (Ocrelizumab)

Ocrelizumab is a humanized monoclonal antibody that selectively targets the CD20-positive B-cells implicated in the inflammatory and neurodegenerative processes of multiple sclerosis (MS), to effectively impact disease progression while maintaining immunosurveillance.

A clinical trial of Phase-III study is being conducted to treat MS. This is a single arm, open label, multicenter extension study in participants on ocrelizumab therapy at the end of Treatment period of the Roche P-trial. Participants would receive the treatment with ocrelizumab as single 600 mg infusions every 24 weeks for two years.

TG Therapeutics, Inc. (Ublituximab)

Ublituximab (TG-1101) is a monoclonal antibody that targets CD20 positive B-cells, a component of the body’s immune system. When it attaches to the B-cell it triggers immune reactions (including antibody-dependent cellular cytotoxicity, ADCC, and antibody-dependent cellular phagocytosis that result in the death of the targeted B-cell).

While ublituximab is a novel patented molecule, it’s mechanism of action is similar to the approved anti-CD20 monoclonal antibodies. Ublituximab has been bioengineered to remove certain sugar molecules from the anti-CD20 antibody, which are naturally occurring. The removal of the sugar molecules in a process called glycoengineering have enhanced the potency of ublituximab with data showing 50-100x greater activity than non-bioengineered anti-CD20 antibodies.

MedDay Pharmaceuticals SA (MD1003)

MD1003 is a highly concentrated oral formulation of biotin currently under clinical investigation as a treatment for primary and secondary progressive multiple sclerosis (PPMS and SPMS). It is being developed by MedDay. It is a promising treatment that exhibits the pro-myelinogenic effects and enhances the supply of energy for nerve impulse transmission.

Biogen (Opicinumab)

Opicinumab is a human monoclonal antibody that targets LINGO-1, a protein that suppresses the redevelopment of axons (brain cells that send functional information throughout the body) and re-formation of myelin sheaths (fibers that protect the axons). Axons and myelin sheaths are lost or damaged in patients with MS, leading to loss of physical and cognitive function. By blocking LINGO-1, opicinumab is formulated to promote regeneration of axons and myelin.

The Phase II, double-blind AFFINITY study is assessing the effectiveness of opicinumab as an add-on therapy in people with relapsing or secondary-progressive forms of MS (RMS or SPMS).

Novartis (Ofatumumab)

Ofatumumab is a fully human anti-CD20 monoclonal antibody (mAb) self-administered by a once-monthly subcutaneous injection in development for RMS. Ofatumumab works by binding to the CD20 molecule on the B-cell surface, distinct from that of other anti-CD20 antibodies, and induces potent B-cell lysis and depletion. The selective mechanism of action and subcutaneous administration of ofatumumab allows precise delivery to the lymph nodes, where B-cell depletion in MS is needed, while sparing those in the spleen that help maintain protective immunity. Once-monthly dosing of ofatumumab also allows faster repletion of B-cells, and offers more flexibility as no first dose observations or laboratory monitoring is required. Novartis obtained rights for ofatumumab from Genmab in all indications, including MS, in December 2015.

Novartis (BAF312)

Siponimod is an investigational, selective modulator of specific subtypes of the sphingosine-1-phosphate (S1P) receptor. Siponimod binds to the S1P1 sub-receptor on lymphocytes, which prevents them from entering the central nervous system (CNS) of patients with multiple sclerosis. This leads to the anti-inflammatory effects of siponimod. Siponimod also enters the CNS and binds to the S1P5 sub-receptor on specific cells in the CNS (oligodendrocytes and astrocytes). By binding to these specific receptors, siponimod has the potential to modulate damaging cell activity, and preclinical studies suggest that it may prevent synaptic neurodegeneration and promote remyelination in the central nervous system.

Sanofi (Teriflunomide)

Teriflunomide is the first original ‘once-daily’ oral ‘disease modifying therapy’ (DMT) for Multiple Sclerosis. It offers an effective, safe and a convenient option that is indicated as a first-line treatment for relapsing forms of Multiple Sclerosis that must be taken once a day, with or without food.

Emerging Pipeline Landscape of Multiple Sclerosis (MS)

Company nameProduct NameStage of developmentRoute of administrationMechanism of action
Merck Healthcare KGaAEvobrutinib + TeriflunomidePhase IIIOralBTK inhibtor
ActelionPonesimodPhase IIIOralS1P1 immunomodulator
NovartisBAF312 (Mayzent™)  Phase IIIOralS1P1 Modulator
Novartis OfatumumabPhase IIISubcutaneousanti-CD20
MedDay Pharmaceuticals MD1003Phase IIIOralEnzyme modulators
F. Hoffmann-La Roche AG Ocrelizumab/ RG1594Phase IIIIntavenousanti- CD20 positive B- cells
Sanofi TeriflunomidePhase IIIOralDihydroorotate dehydrogenase inhibitors
Sanofi AlemtuzumabPhase IIIIntravenous dihydro-orotate dehydrogenase inhibitor
TG TherapeuticsUblituximabPhase IIIOralanti- CD20
BiogenOpicinumabPhase IIIntravenousanti-LINGO