Image of heart and circulatory system

Image of the heart and circulatory system

An Alnylam Pharmaceuticals drug that treats nerve pain caused by an inherited protein disorder now has results from a pivotal clinical trial showing that the drug also helps patients suffering from the disease’s potentially fatal effects on the heart. Preliminary data support expanding the drug’s use to more patients, which would introduce a competitive alternative to Pfizer’s blockbuster drug and put Alnylam in position to have its own blockbuster.

The main aim of the phase 3 study was to show an improvement over a placebo in a test that measures how far patients can walk within six minutes. Alnylam reported on Wednesday that those treated with its drug, Onpattro, showed a statistically significant improvement in this walking test, paving the way for the company to move forward with a regulatory filing later this year.

Shares of Cambridge, Mass.-based Alnylam opened Wednesday at $210 a share, up nearly 48% from Tuesday’s close.

Alnylam’s Onpattro was developed as a treatment for hereditary transthyretin amyloidosis (TTR), a disease caused by a genetic mutation that causes the liver to produce misfolded versions of the transthyretin protein. These abnormal proteins accumulate in tissues and organs throughout the body, causing a wide range of problems.

In the heart, protein deposits lead to enlargement of the heart walls and impairment of cardiac function. Cardiovascular effects of the disease include cardiomyopathy, irregular heartbeat, and heart failure. In people who do not have the genetic mutation underlying TTR, the disease can also develop as a normal part of aging. This form of the disease mostly affects the heart, leading to cardiomyopathy and heart failure.

Alnylam is developing drugs that work by a mechanism called RNA interference (RNAi). Its products deliver small interfering RNA that stops the gene from producing a disease-causing protein. This approach is sometimes called “gene silencing.”

In 2018, Onpattro became the first FDA-approved RNAi drug, a solution that covers the treatment of nerve pain experienced by patients with TTR. According to Alnylam, this manifestation of the disease affects about 50,000 people worldwide. TTR with cardiomyopathy affects more than 250,000 people worldwide, the company estimates. Sales of the drug were $474.7 million last year, according to Alnylam’s financial statements.

To help bring Onpattro to patients with cardiac manifestations of TTR, Alnylam is testing the drug in a phase 3 study involving 360 adults who have either a hereditary or a non-hereditary form of the disease. Patients were randomly assigned to receive either intravenously administered study drug or placebo for 12 months. After 12 months, all patients received Onpattro in an open-label extension study.

In addition to the six-minute walk test, the study had a secondary objective of measuring changes in quality of life according to a cardiomyopathy questionnaire. The study met this objective, but specific details of the results for the two endpoints were not released. Alnylam said the full study data will be presented at the International Symposium on Amyloidosis, which is being held on September 8 in Heidelberg, Germany.

“We couldn’t be happier with these results and what they mean for patients, doctors, families, caregivers – everyone in the ATTR amyloidosis community,” said Alnylam CEO Yvonne Greenstreet, speaking during conference call on Wednesday morning. “Furthermore, we believe these results demonstrate the true power of RNAi’s mechanism of action. By using a natural process to silence the production of the disease-causing TTR protein, we achieved a disease-modifying effect on the cardiac manifestation of ATTR amyloidosis.”

The study produced nonsignificant results for one of the secondary objectives, a composite endpoint measuring all-cause death, cardiovascular event rates, and change from baseline in the six-minute walk test compared with placebo. Efficacy analysis of deaths identified four in the Onpattro arm and 10 in the placebo arm. But the company did not perform formal statistical testing of the latter two endpoints because the small patient population and short duration of the study meant the study could not assess statistical significance.

The only treatment currently available for heart problems caused by TTR is Pfizer’s Vyndaqel, a small molecule that is designed to bind to the abnormal transthyretin, stabilizing that protein. According to Pfizer’s financial statements, the drug generated more than $2 billion in global sales last year.

With Onpattro’s latest results, Alnylam shows success where BridgeBio Pharma stumbled. BridgeBio’s approach is closer to Pfizer’s. The biotech’s drug, acoramidis, is a small molecule that is also designed to bind to and stabilize the problematic protein at the core of TTR. But last December, BridgeBio reported surprising interim data showing drug did not beat placebo in first part of phase 3 study. BridgeBio is continuing the study with the hope that following patients over a longer period of time will lead to better results.

An additional new drug application for Onpattro’s use in treating TTR-related heart problems should be ready by the end of this year, Greenstreet said. Along with the last ones FDA approval and the US launch of Amvuttra, a TTR drug whose tri-monthly dosing is less burdensome for patients than the tri-weekly dosing of Onpattro, Greenstreet said the latest Phase 3 results “provide further support for the expansion of the TTR franchise of Alnylam in what we believe could represent a multi-billion dollar opportunity for Alnylam over time.”

Magicmine, Getty Images

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