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
Fusion protein
subcutaneousPhase II

Cystic Fibrosis: Emerging Pipeline Landscape

Cystic Fibrosis is an autosomal, recessive inheritable genetic disease that causes severe damage to the respiratory and digestive systems. This damage often results from a buildup of thick, sticky mucus in the organs. It occurs as a result of a defect in what’s called the “cystic fibrosis transmembrane conductance regulator” gene, or CFTR gene. This gene controls the movement of water and salt in and out of your body’s cells. A sudden mutation causes the abnormality in CFTR gene and commonly affected the various organs including the lungs, pancreas, liver, and intestines. The symptoms of cystic fibrosis can vary depending on the person and the severity of the condition. The age at which symptoms develop can also differ. Symptoms may appear at infancy, but for other children, symptoms may not begin until after puberty or even later in life. As time passes, the symptoms associated with the disease may get better or worse.

Around 70,000-80,000 people worldwide are suffering from the Cystic Fibrosis. Cystic Fibrosis has the highest incidence and prevalence in Caucasian populations and is less common in other population groups. Every year, around 1,000 people are diagnosed with Cystic Fibrosis in the United States.

Several pharmaceutical companies are developing the novel drugs for the treatment of Cystic Fibrosis. The pipeline landscape of the cystic fibrosis is robust with the involvement of several drugs such as vancomycin hydrochloride inhalation powder, OligoG, ELX-02 and VX-561 etc. 

The pharmaceutical companies involved in developing emerging drugs against Cystic Fibrosis are as follows:

Savara Pharmaceuticals (AeroVanc)

AeroVanc (vancomycin hydrochloride inhalation powder) is an inhaled dry powder form of vancomycin for the treatment of the persistent (MRSA) lung infection in people living with Cystic Fibrosis. AeroVanc is in Phase III stage of development for the treatment of the Methicillin-resistant Staphylococcus aureus (MRSA) lung infection in Cystic Fibrosis. AeroVanc is effective in improving the clinical efficacy, and reducing the adverse effects due to lessor systemic drug exposure in comparison to the intravenous antibiotic treatment.

AlgiPharma (OligoG)

OligoG is a dry powder drug that has been shown to decrease the thickness of mucus in the lungs and may help individuals with cystic fibrosis clear mucus easier. OligoG help in improving the effectiveness of some antibiotics. It is administered using a dry powder inhaler and also developed as a liquid for use with a nebulizer

Currently, Phase IIb trial is currently running in Australia, with another Phase 2b scheduled to start in Europe H1 2020. The drug candidate OligoG for Cystic Fibrosis has Orphan Drug designation from both the European Medicines Agency and the FDA

Eloxx Pharmaceuticals, Inc. (ELX-02)

ELX-02, is a small molecule drug candidate designed to restore production of full-length functional proteins. It is in the early stages of clinical development focusing on cystic fibrosis and nephropathic cystinosis. ELX-02 is an investigational drug that has not been approved by any global regulatory body.

Furthermore, ELX-02, is a eukaryotic ribosomal selective glycoside (ERSG) designed to increase the read-through activity in patients with nonsense mutations and enable the production of sufficient amounts of full-length functional protein to restore activity.

Its Phase II program has been given a score of “high priority” by the European Cystic Fibrosis Society-Clinical Trial Network (ECFS-CTN).

Laurent Pharmaceuticals Inc. (LAU-7b)

LAU-7b is a novel and improved solid dosage form of fenretinide, requiring. once-a-day oral administration. It was recently tested in adult patients with Cystic Fibrosis in a dose-ascending where Phase Ib study, showing a good safety and tolerability, and promising pharmacokinetic and pharmacodynamic results.

The company is currently recruiting patients for its Phase II safety and efficacy study in adult patients with Cystic Fibrosis. The goal of the Phase II trial is to evaluate LAU-7b’s effect on the preservation of lung function, by reducing persistent unresolved inflammation in the lung and stimulating its return to homeostasis. The study would enroll 136 adults with Cystic Fibrosis for a treatment duration of 6 months and will involve more than 30 clinical sites in the USA and Canada.

Corbus Pharmaceuticals Inc. (Lenabasum)

Lenabasum is a rationally-designed, oral, small-molecule that selectively binds as an agonist to the cannabinoid receptor type 2 (CB2). It has a direct effect on fibroblasts to limit the production of fibrogenic growth factors and extracellular connective tissue that lead to tissue fibrosis. Lenabasum treatment has resulted in lowering the and longer time to pulmonary exacerbations in Phase II cystic fibrosis study. The Lenabasum had demonstrated the safety and tolerability profile in clinical studies. It has demonstrated safety and tolerability profile in clinical studies

Vertex Pharmaceuticals Incorporated (VX-561)

VX-561 is a deuterated form of ivacaftor that replaces one or more hydrogen atoms with deuterium. It is designed to keep CFTR proteins at the cell surface open longer to improve the flow of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.

Vertex Pharmaceuticals Incorporated (VX-121 + TEZACAFTOR + VX-561)

VX-121 and tezacaftor act by increasing the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the CFTR protein. VX-561 (deuterated ivacaftor) is designed to keep CFTR proteins at the cell surface open longer to improve the flow of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.

SolAeroMed Inc (S-1226)

S-1226 is a novel fast-acting bronchodilator, with airway lubricant properties to remove mucus.  It acts as a cough suppressant and is an anti-inflammatory agent. S-1226 is based on amalgation of Perflubron (a synthetic surfactant derivative) and carbon dioxide. When combined in inhalation therapy as S-1226 delivered by nebulization these compounds offer significant promise to treat respiratory diseases where breathing is compromised due to bronchoconstriction, excess mucus production, and/or impaired mucus motility. It has demonstrated the safety and efficacy for the treatment of Cystic Fibrosis.

Cystic Fibrosis Emerging Pipeline Landscape

Company NameProduct nameStage of developmentMechanism of ActionRoute of administration
Savara Inc.Vancomycin inhalation powderPhase IIICell wall inhibitorsInhalation
AlgiPharma ASOligoG DPIPhase IIBacterial growth inhibitorsInhalation
Eloxx Pharmaceuticals, Inc.ELX-02Phase IIRibosomal protein modulatorsSubcutaneous
Corbus Pharmaceuticals Inc.LenabasumPhase IICannabinoid receptor CB2 agonistsOral
Laurent Pharmaceuticals Inc.LAU-7bPhase IIRetinoic acid receptor agonistsOral
Vertex Pharmaceuticals IncorporatedVX-121 + TEZACAFTOR + VX-561 Phase IIRegulated CFTR geneOral
SolAeroMed Inc.S-1226Phase IICell membrane permeability enhancers    Inhalation
Vertex Pharmaceuticals Incorporated VX-561Phase IIRegulated CFTR geneOral