Anti-sotatercept antibodies don’t influence treatment safety, efficacy

About 25% of patients treated with therapy tested positive for antibodies

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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While about a quarter of pulmonary arterial hypertension (PAH) patients treated with the investigational therapy sotatercept tested positive for antibodies against it, the antibodies didn’t influence the therapy’s safety or effectiveness, according to a clinical trial analysis.

The study, “The impact of immunogenicity on the pharmacokinetics, efficacy, and safety of sotatercept in a phase 3 study of pulmonary arterial hypertension,” was published in Clinical Pharmacology & Therapeutics. It was funded by sotatercept’s developer Acceleron Pharma, now a subsidiary of Merck.

Sotatercept is designed to reduce the abnormal growth of blood vessel cells that contribute to blood vessel narrowing in PAH by normalizing the activity of certain growth factor proteins implicated in the process.

It consists of a fragment of a human receptor protein that binds the growth factors, fused to a human antibody fragment. Essentially, it binds to and traps the overactive growth factors to restore more normal signaling.

Therapies like sotatercept that contain human proteins run the risk of immunogenicity, or an immune response against the treatment. Developing anti-drug antibodies (ADAs) can affect a treatment’s safety, efficacy, or its pharmacological characteristics.

Researchers at Merck investigated the frequency of ADAs in patients treated with sotatercept, examining data from the Phase 3 STELLAR clinical trial (NCT04576988) that backed Merck’s regulatory application.

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In the trial, 323 adults with PAH were randomly assigned to receive under-the-skin injections of sotatercept or a placebo once every three weeks with background therapy for 24 weeks, or about six months. That was followed by an extension period where patients continued receiving their assigned treatment for up to week 72 (about 1.5 years).

The therapy boosted exercise capacity relative to the placebo, improved heart health and blood flow, and delayed clinical worsening.

Here, the scientists measured ADAs in blood samples from 162 people treated with sotatercept in the main trial.

At week 24, 42 patients (25.9%) showed evidence of sotatercept-targeted antibodies in their blood. All but two had tested negative for such antibodies before starting sotatercept. Antibodies were present in those two people before treatment, but increased by at least twofold after starting it.

Among the ADA-positive patients, 11 tested positive for neutralizing antibodies, ones expected to be able to diminish sotatercept’s activity.

Rates of antibody positivity were largely unchanged after 36 weeks, “suggesting that prolonged exposure to sotatercept did not increase ADA incidence,” the researchers said.

The median time to ADA onset was 3.3 weeks after the first sotatercept dose, and antibodies persisted in the bloodstream for a median of six weeks.

More than half of the ADA-positive patients (54.8%) had antibody responses that lasted less than four months, whereas 31% had persistent ADA responses of four months or more. Among the 11 people with neutralizing antibodies, eight had a persistent response.

Maximum antibody levels were similar between patients positive and negative for neutralizing antibodies.

No impact on effectiveness, pharmacology, safety

The presence of ADAs didn’t appear to influence sotatercept’s pharmacological properties or efficacy across the clinical trial outcomes, including its effects on exercise capacity and blood flow measurements.

While some differences were observed between groups regarding changes in levels of NT-proBNP — a marker of heart damage — the variability was high and the percent change over time was similar between groups.

There was also no effect of sotatercept on selected safety outcomes, namely hypersensitivity or allergic reactions, which have been linked to ADAs with other protein-based therapies. ADAs weren’t linked to increases in serious side effects or discontinuing treatment.

Overall, “immunogenicity analyses conducted in STELLAR indicate that the risk of clinical consequences related to antibody responses to sotatercept is low and that the detection of ADA is unlikely to change the sotatercept benefit/risk profile,” the researchers wrote.

Participants from the STELLAR trial were able to enroll in SOTERIA (NCT04796337), an ongoing long-term follow-up study. Data related to patients’ immune responses are being collected periodically and “should provide further insight,” the researchers said.

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