Myasthenia gravis treatments: what’s on the horizon?

Myasthenia gravis is a chronic autoimmune condition that causes muscle weakness. While there is no cure yet, there are treatments that offer symptom relief. However, in the past decade, this has changed with drugs being approved to target the root cause of the rare disease – the most recent being Johnson & Johnson’s monoclonal antibody.

Johnson & Johnson’s Imaavy scores approval for myasthenia gravis

The monoclonal antibody in question is nipocalimab, now known by its brand name, Imaavy. It was greenlit by the U.S. Food and Drug Administration (FDA) this month, which was underpinned by compelling findings from an ongoing study. The drug achieved the longest primary endpoint any trial has ever produced for an FcRn blocker in patients with myasthenia gravis.

FcRn blockers are medicines that block the Fc receptor. In myasthenia gravis, autoantibodies – antibodies that mistakenly target the body’s own cells and proteins – especially IgG antibodies, attack acetylcholine receptors at the junction where nerves and muscles connect. Acetylcholine receptors are proteins that bind to the neurotransmitter acetylcholine, which plays a crucial role in muscle movement and memory. Another protein that is targeted by autoantibodies is muscle-specific kinase (MuSK), which is also vital for the formation of neuromuscular junctions.

Targeting these proteins causes muscles to feel weak and get tired quickly and results in a host of symptoms such as arm and leg muscle fatigue, double vision, drooping eyelids, and issues with speaking, chewing, swallowing, and breathing.

As FcRn is crucial for recycling IgG back into the bloodstream, the therapeutic approach of inhibiting Fc receptors aims to cut IgG recycling at the source so that these autoantibodies can no longer strike the acetylcholine receptors. 

Nipocalimab is the first and only FcRn blocker to exhibit superiority on the MG-ADL scale. This is a tool that measures the ability to perform tasks such as talking, chewing, swallowing, breathing, the ability to brush teeth or comb hair, and the ability to arise from a chair, as well as the extent of symptoms of double vision and eyelid droop on a scale of zero to three.

When the drug was combined with standard of care and given to adult patients with the myasthenia gravis autoantibodies, it significantly improved disease management over a period of 24 weeks, compared to a placebo plus standard care. Also, in another late-stage trial in antibody-positive children aged between 12 and 17 years, a 69% decrease in IgG was observed over 24 weeks, a marked reduction in IgG levels.

David Lee, head of Global Immunology Therapeutic Area at Johnson & Johnson Innovative Medicine, called the FDA win a “historic milestone” for more than 240 million people living with autoantibody diseases in the U.S., many of whom didn’t have treatments that worked for them until now. In fact, the approval covers the broadest population of people living with myasthenia gravis – patients aged 12 and older – who have the anti-acetylcholine receptor (AChR) or anti-muscle-specific kinase (MuSK) antibodies. People with these antibodies make up 90% of the total antibody-positive myasthenia gravis population, according to Johnson & Johnson.

In a bid to make the drug affordable in the U.S., the pharma giant is launching the Imaavy withMe program, wherein insured patients who are prescribed Imaavy may be eligible to receive their first treatment in as quickly as one week and may pay as little as $0 per infusion. However, when the rollout will begin has not been confirmed.

Amgen’s Uplizna: en route to approval

Meanwhile, there are a few clinical candidates that are on the road to approval for the neuromuscular condition. One of these is Uplizna, which became the first and only FDA-approved drug for IgG4-related disease, a chronic inflammatory condition that can affect nearly any organ system, last month. It first hit the market five years ago when it was given the FDA go-ahead to treat neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disease that affects the central nervous system.

Now, it is in the clinic to check off clearance for yet another rare autoimmune disease, myasthenia gravis. Amgen-owned Uplizna, or inebilizumab, is a humanized IgG1 monoclonal antibody that works by targeting the CD19 cell surface antigen, typically found on immune cells called B cells. Its mechanism of action is to deplete the cells that produce the autoantibodies. 

A phase 3 trial saw Uplizna hit the primary endpoint. The drug was given to patients with AChR- and MuSK-positive patients, just like nipocalimab, but AChR-positive patients were followed for 52 weeks and the latter for 26 weeks. It demonstrated a “durable and sustained efficacy” based on change in the baseline on the MG-ADL scale.

Around 72.3% of patients who are AChR-positive had a three-point or greater than three-point improvement in the MG-ADL score, compared to 45.2% in the placebo group. The Quantitative Myasthenia Gravis (QMG) score – another measure for the disease – was also tallied, and the results were encouraging. 

Among the AChR-positive patients in the Uplizna group, 69.2% improved by at least three points in the QMG score, compared to 41.8% in the placebo group, over 26 weeks. However, in the MuSK-positive group, the mean change from baseline in the QMG score at week 26 showed a trend favoring Uplizna, but it was not statistically significant.

“Patients living with generalized myasthenia gravis deserve an effective treatment option that provides long-term symptom relief. Once approved, Uplizna is expected to offer a new option for patients earlier in their treatment plan,” Jay Bradner, executive vice president of Research and Development and chief scientific officer at Amgen, had said in a press release about the trial.

Myasthenia gravis treatments: CAR-T cell therapies in the clinic  

While monoclonal antibodies have paved the way to addressing autoimmune conditions, CAR-T cell therapies are picking up pace. American company Cartesian Therapeutics’ Descartes-08 is an autologous mRNA CAR-T cell therapy, meaning that it uses a patient’s own T cells that have been modified with mRNA to help them better target and fight their disease. Particularly for myasthenia gravis, Descartes-08 targets B-cell maturation antigen (BCMA), a cell surface protein involved in regulating immune responses, in order to help modulate the overactive immune activity seen in autoimmune diseases like myasthenia gravis.

The therapy reaped positive results after it changed the trial’s primary endpoint from the MG-ADL scale to the Myasthenia Gravis Composite (MGC) scale last year. Around 71% of the patients who were given Descartes-08 had a “clinically meaningful improvement” in the MGC score after three months compared to 25% in the placebo group. 

Later, the company’s updated results revealed that deepening responses were observed over time, with a 5.5-point reduction in MG-ADL after four months, and the drug elicited durable responses throughout the twelfth month. Descartes-08 also maintained its safety profile. A phase 3 trial is planned to begin soon.

Another CAR-T cell therapy in the space is California-based Kyverna Therapeutics’ KYV-101. How the therapy works is that a patient’s blood is collected, from which white blood cells are separated, and the T cells are altered to destroy B cells linked to the disease – which produce the autoantibodies that attack the acetylcholine receptors – like a typical CAR-T cell therapy.

The candidate, which is also being evaluated in the clinic to treat other autoimmune conditions such as, stiff person syndrome and lupus nephritis, will embark on a phase 3 study as phase 2 data is due to be released soon. 

Likewise, Philadelphia-based Cabaletta Bio’s CAR-T treatment CABA-201 is in the early stages in the clinic for myasthenia gravis as well as other autoimmune diseases like lupus erythematous, myositis, and systemic sclerosis. The biotech is currently recruiting patients for an ongoing phase 1/2 study.

NMD Pharma and Immunovant develop myasthenia gravis treatments; how far along are they?

Aside from monoclonal antibodies and CAR-T cell therapies being tested to treat the autoimmune condition, small molecule inhibitors like NMD670 are also racing to the finish line. Owned by Denmark-based NMD Pharma, its lead candidate NMD670 is designed to inhibit the skeletal muscle-specific chloride ion channel (CIC-1). Blocking this channel has been known to improve the connectivity between the nerves and muscles, which is lacking in the case of myasthenia gravis.

The first-in-class candidate received Investigational New Drug (IND) clearance from the FDA last year to initiate its ongoing phase 2 trial. It was also granted the orphan-drug designation from the FDA three years ago.

While most of these biopharmas are advancing their candidates in hopes of an FDA nod, there is one company that has shied away from seeking approval despite gaining positive clinical results. American biotech Immunovant put its monoclonal antibody batoclimab to the clinical test to target myasthenia gravis a few years ago. A recent phase 3 trial involving the therapy hit the primary endpoint. A 5.6-point improvement in the higher dose arm was achieved after 12 weeks in people who are AChR- positive compared to a 4.7-point recovery in the lower dose arm.

Although batoclimab was Immunovant’s long-standing candidate until last year, it switched focus to gear its anti-FcRn antibody IMVT-1402 towards the finish line instead, putting batoclimab on the back burner. And batoclimab’s recent success in the clinic doesn’t seem to have changed its mind either.  

Where does Imaavy stand in midst of Argenx and UCB contenders?

All of these recent advances could not only broaden treatment options for patients but also rock the boat for Danish drug developer Argenx. Its crowned jewel Vyvgart, or efgartigimod alfa, which is an FcRn inhibitor just like nipocalimab, has been around in the market for nearly four years now. But Argenx didn’t stop at its approval. It went on to develop Vyvgart’s similar subcutaneous version called Vyvgart Hytrulo, which is composed of efgartigimod alfa and the enzyme hyaluronidase, which keeps efgartigimod alfa in the body for longer so that the therapy can have a greater effect. 

Last month, a prefilled syringe version of Vyvgart Hytrulo nabbed FDA approval, allowing patients to finally be able to self-inject and receive treatment at home.

Another busy bee in the therapeutic space is Belgian pharma UCB. Its FcRn blocker Rystiggo snapped up approval two years ago, making it the first to treat people with myasthenia gravis who are AChR and MuSK antibody-positive. It also won approval for its complement inhibitor zilucoplan, dubbed Zilbrysq – which prevents the activation of the complement pathway – for patients who are AChR antibody-positive.

As Johnson & Johnson’s Imaavy is set to take on the “broadest population of people living with myasthenia gravis,” it will be sharing its spot with the likes of Argenx and UCB, which currently dominate the therapeutic field.

While Imaavy and these other drugs on the market can treat around 90% of patients with myasthenia gravis, there is a section of the patient population that is often missed. Patients who are antibody-negative may struggle with getting diagnosed in the first place. This is because of the absence of detectable AChR or MuSK antibodies that are typically used as markers to diagnose the disease. Doctors may also need to rule out other causes for muscle weakness before they arrive at myasthenia gravis, which makes the initial diagnosis challenging. 

New technologies related to myasthenia gravis treatments

• Therapeutic Vaccine for Myasthenia Gravis – University of Pennsylvania 
• MG-HI: The Myasthenia Gravis Health Index – University of Rochester 
• Novel Immunotherapies for Inflammatory Indications – QIMR Berghofer Medical Research Institute 

As for treatment options for this patient cohort, there aren’t many. Most biotechs and pharmas develop drugs for people who are antibody-positive, considering they make up most of the patient population. Immunosuppressants are often given and so are anticholinesterase inhibitors – which hinder acetylcholine from being broken down. But not all those who are antibody-negative respond well to the inhibitor drugs.

While there is a need for wider treatment options for people who are antibody-negative, Imaavy’s win is still a step up. And now, with the ease of being able to receive Vyvgart Hytrulo at home, the therapeutic field has come a long way, and it looks like there is more to come, as therapies climb the clinical pipeline.