An Alnylam Pharmaceuticals drug that treats nerve pain caused by an inherited protein disorder now has results from a pivotal clinical trial showing the drug also helps patients suffering the disease’s potentially fatal effects on the heart. The preliminary data support expanding the drug’s use to more patients, which would introduce a competitive alternative to a blockbuster Pfizer drug and put Alnylam in position to have a blockbuster of its own.
The main goal of the Phase 3 study was to show improvement, compared to a placebo, in a test that measured how far patients could walk in the span of six minutes. Alnylam reported Wednesday that that those treated with its drug, Onpattro, showed statistically significant improvement in this walk test, paving the way for the company to march forward with a regulatory submission later this year.
Shares of Cambridge, Massachusetts-based Alnylam opened Wednesday at $210 apiece, up nearly 48% from Tuesday’s closing price.
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, the protein deposits lead to enlarged cardiac walls and impairment of cardiac function. The disease’s cardiovascular effects include cardiomyopathy, abnormal heart rhythm, and heart failure. In people who do not have the genetic mutation at the root of 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.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
Alnylam develops drugs that work by a mechanism called RNA interference (RNAi). Its products deliver small interfering RNA that stop a gene from producing a disease-causing protein. This approach is sometimes referred to as “gene silencing.”
In 2018, Onpattro became the first FDA-approved RNAi drug, a decision that covered treatment of nerve pain experienced by TTR patients. 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. The drug accounted for $474.7 million in sales last year, according to Alnylam’s financial reports.
To support bringing Onpattro to patients with heart manifestations of TTR, Alnylam tested the drug in a Phase 3 study that enrolled 360 adults who have either the hereditary or non-hereditary form of the disease. Patients were randomly assigned to receive either the intravenously administered study drug or a 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 has a secondary goal of measuring quality of life changes according to a cardiomyopathy questionnaire. The study met this goal, but specific details about the results for either endpoint were not released. Alnylam said full data from the study will be presented at the International Symposium on Amyloidosis, which is convening on Sept. 8 in Heidelberg, Germany.
“We could not be happier with these results and what they mean for patients, physicians, families, caregivers—everyone in the ATTR amyloidosis community,” Alnylam CEO Yvonne Greenstreet said, speaking during a Wednesday morning conference call. “Moreover, we believe these results show the true power of the RNAi mechanism of action. By using a natural process to silence the production of the disease-causing TTR protein, we have achieved the disease modifying impacts on the cardiac manifestation of ATTR amyloidosis.”
The study led to non-significant results for one of the secondary goals, a composite endpoint measuring deaths from all causes, frequency of cardiovascular events, and the change from baseline in the six-minute walk test compared to a placebo. The efficacy analysis on deaths identified four in the Onpattro arm and 10 in the placebo arm. But the company did not perform formal statistical testing on the final two endpoints, because the small pool of patients and the short duration of the study meant that statistical significance could not be assessed.
The only treatment currently available for the heart problems caused by TTR is Pfizer’s Vyndaqel, a small molecule that’s designed to bind to the abnormal transthyretin, stabilizing this protein. The drug generated more than $2 billion in global sales last year, according to Pfizer’s financial reports. Potential gene-silencing competition is coming from AstraZeneca and partner Ionis Pharmaceuticals, which in June reported positive polyneuropathy results for their drug, eplontersen. A Phase 3 test of that drug in cardiomyopathy caused by TTR is ongoing.
With the latest Onpattro results, Alnylam is showing success where BridgeBio Pharma stumbled. BridgeBio’s approach tracks more closely with Pfizer’s. The biotech’s drug, acoramidis, is a small molecule that’s also designed to bind to and stabilize the problem protein at the root of TTR. But last December, BridgeBio reported surprising interim data showing the drug did not beat a placebo in the first part of a Phase 3 study. BridgeBio is continuing the study in the hope that following patients for a longer period of time will lead to better results.
A supplemental new drug application for the use of Onpattro in treating the heart problems associated with TTR should be ready by the end of this year, Greenstreet said. Along with the recent FDA approval and U.S. launch of Amvuttra, a TTR drug whose every three month dosing is less burdensome to patients than the every three weeks dosing of Onpattro, Greenstreet said that the latest Phase 3 results “provide further support for the expansion of Alnylam’s TTR franchise into what we believe could represent a multi-billion dollar opportunity for Alnylam over time.”
In a research note sent to investors Wednesday afternoon, William Blair analyst Myles Minter wrote that data from the six-minute walk test should be enough to support regulatory approval, based on prior FDA guidance. If the application is submitted by the end of the year and approved in a six-month time frame, Onpattro could launch commercially in TTR cardiomyopathy in the second half of 2023, he said. Alnylam aims to further expand its presence in TTR with a pivotal study of Amvuttra in TTR cardiomyopathy. Minter said that FDA approval of both drugs could expand the total addressable market for these drugs to more than 250,000 patients worldwide, helping Alnylam to potentially triple its revenue by 2025. [Paragraph added with analyst comment.]
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