Povetacicept may be superior to current MG treatments: Early study

Povetacicept outperforms Vyvgart at reducing disease activity in mouse model

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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The experimental treatment povetacicept (ALPN-303) may be more effective than current available treatments for myasthenia gravis (MG), according to preclinical data from Alpine Immune Sciences, which is developing the therapy.

Specifically, povetacicept outperformed Vyvgart (efgartigimod) and off-label rituximab at reducing disease activity in a mouse model of the disease.

“Relatively few approved drugs appear to be directed at the underlying disease [mechanisms] of myasthenia gravis,” Stanford Peng, MD, PhD, Alpine’s president and head of research and development, said in a company press release. “These data indicate that povetacicept might deliver efficacy superior to some therapeutics currently in clinical use for myasthenia gravis and other [self-reactive-related] neurological diseases.”

The data were presented in a poster, “Povetacicept (ALPN-303), a Potent Dual BAFF/APRIL Antagonist, for the Treatment of Myasthenia Gravis (MG) and Other Antibody-Related Diseases,” at the annual meeting for the American Association of Neuromuscular & Electrodiagnostic Medicine, held Nov. 1-3 in Phoenix, Arizona.

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Povetacicept designed to reduce number, activity of antibody-producing B-cells

MG occurs when the immune system wrongly produces self-reactive antibodies that interfere with nerve-muscle communication, causing symptoms such as muscle weakness and fatigue. Most cases are driven by self-reactive antibodies against a protein called acetylcholine receptor or AChR.

Povetacicept is designed to reduce the number and activity of antibody-producing B-cells by blocking two signaling molecules involved in their activation, development, and/or survival: BAFF and APRIL.

A previous preclinical study showed treatment with povetacicept reduced the levels of several classes of antibodies (IgG, IgM, and IgA), including anti-AChR IgGs, in a mouse model of MG. The experimental therapy also significantly lowered scores of the experimental autoimmune myasthenia gravis (EAMG) clinical scale, suggesting less severe symptoms.

Now, researchers at Alpine used the same mouse model to compare povetacicept’s efficacy against other therapies used for MG. These included Vyvgart, an into-the-vein, or intravenous, medication approved for adults with generalized MG who test positive for anti-AChR antibodies, and an antibody that targets CD20, a protein present on the surface of B-cells.

These data indicate that povetacicept might deliver efficacy superior to some therapeutics currently in clinical use for myasthenia gravis and other [self-reactive-related] neurological diseases.

Rituximab — sold as Rituxan in the U.S., MabThera in Europe, and available as biosimilars — is an anti-CD20 antibody that promotes the death of B-cells and is used off-label for MG patients who fail to respond to standard treatments.

In the new study, the animals were given povetacicept, Vyvgart, or an anti-CD20 antibody for about three weeks. All treatments were administered directly into the abdominal cavity twice a week for three weeks, except for the anti-CD20 antibody, which was given once a week.

Disease activity was again evaluated using the EAMG scale, where higher scores indicate more severe symptoms. At the start of treatment, all groups of mice had similar clinical scores and antibody levels.

However, after treatment, the mean clinical scores were significantly lower in povetacicept-treated mice than in those given Vyvgart or an anti-CD20 antibody, suggesting povetacicept may be better at reducing disease activity.

Povetacicept was also associated with a significantly greater drop in average levels of IgG antibodies targeting the AChR protein, as well as total IgG, IgM, and IgA, relative to the other two treatments.

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Phase 1 RUBY-1 clinical trial found povetacicept to be well tolerated

In a first-in-human Phase 1 clinical trial, called RUBY-1 (NCT05034484), a single intravenous or subcutaneous (under-the-skin) dose of povetacicept up to 960 mg was found to be well tolerated relative to a placebo in 72 healthy adults.

The most common side effects reported at higher rates with the experimental therapy included headache (24% vs. 18% with a placebo) and dizziness (12% vs. 5%), none of which were deemed serious.

Both intravenous and subcutaneous povetacicept showed dose-dependent pharmacokinetics (movement into, through, and out of the body) and pharmacodynamics (effects on the body).

Compared with a placebo, povetacicept reduced the circulating levels of BAFF and APRIL as well as those of IgG, IgA, and IgM antibodies. It also reduced the number of antibody-producing B-cells.

Overall, the data supported the use of a subcutaneous dose of 80 to 240 mg, every four weeks, in future studies.

“We look forward to exploring other indications such as myasthenia gravis where povetacicept may be an active and convenient, yet potentially disease-modifying, treatment,” Peng said.

Alpine is also testing the therapy in early trials of people with other immune-related conditions.