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2021-01-08| R&DTrials & Approvals

Alnylam Nears Fourth Approval with Successful Trial Data for RNAi Drug

by Ruchi Jhonsa
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In little more than two years, Alnylam Pharmaceuticals managed to secure the FDA approval for three of its RNA-interference drugs. Now it is eyeing for the fourth. On December 7th, Alnylam disclosed Phase 3 data of its transthyretin-mediated amyloidosis (ATTR) drug, Vutrisiran showing that it topped a placebo control in reducing the symptoms of the diseases after nine months of treatment.

ATTR is caused by the misfolding of TTR protein, which accumulates as amyloid deposits in multiple tissues including the heart, nerves, and GI tract. This leads to problems like polyneuropathy and cardiomyopathy. Alnylam is targeting this disease by silencing the production of mutant and wild-type TTR in the liver. This is expected to reduce the circulating TTR and prevent the accumulation of the protein.

 

Key Findings from Phase 3 Trial

In the HELIOS-A trial, 164 patients with hATTR amyloidosis showing signs of polyneuropathy were randomized to receive the test drug, vutrisiran or Alnylam’s previously FDA-approved drug, Onpattro. Even though Alnylam used Onpattro in the trial as a reference comparator, it did not derive primary endpoint by comparing the test drug to it. Instead, it derived primary and secondary endpoints by comparing the test drug data with historical placebo data obtained from Onpattro’s pivotal Phase III Apollo study.

To understand the improvement that the drugs brought about in ATTR patients, Alnylam used the mNIS +7 scale. This scale was developed to better capture the disease burden and progression of polyneuropathy in hATTR patients. The test drug outperformed the historical placebo control on the mNIS scale at nine months, causing the clinical trial to hit the primary endpoint. Interestingly, the majority of the patients showed improvements in neuropathy impairment. It also beat placebo in improving the secondary endpoints such as quality of life and gait speed. Besides improvements in neurological symptoms, the drug also brought improvements in cardiac health, a common problem found in hATTR patients. Significant improvement was found in cardiac health as measured by the changes in the NT-proBNP biomarker.

While Alnylam claims a stellar efficacy for the drug, the press release has only partial data, which makes it difficult to judge the efficacy of the drug. However, full details will be presented in an upcoming conference early this year, which will give more insights about the drug’s efficacy. As for safety, the test drug demonstrated an encouraging safety profile. All the patients continued in the trial despite some serious drug-related adverse events including dyslipidemia and urinary tract infection.

The drug is now ready for FDA submission and the company targets early 2021 to complete the process. Following the submission in the US, Alnylam will submit regulatory filings in other countries, including Brazil and Japan but not in the EU. In the European Union, the filing will be done only after an 18-month analysis is obtained at the end of this year.

 

Onpattro vs. Vutrisiran: Which Will Rule Them All?

Onpattro was the first one to bag the FDA approval for hATTR patients in 2018. As the only effective available treatment available, Onpattro sales skyrocketed and touched $300 million in 2020. Now, Alnylam is expecting the same for vutrisiran. But it might come at a cost of Onpattro’s sales. There are two possible reasons for that.

Patients treated with Onpattro undergo IV infusions for 80 minutes every three weeks. This is certainly a burden for patients. Vutrisiran, on the other hand, can be dosed subcutaneously once every three months using pre-filled injections. Topping that, Onpattro is currently available for treatment for Polyneuropathy whereas vutrisiran might cover the whole spectrum of patients experiencing neurological as well as cardiac symptoms.

Commenting on the market value of vutrisiran, Yvonne Greenstreet, MBA, President, and Chief Operating Officer at Alnylam, said, “We believe that vutrisiran could address an unmet need in the field. As a once quarterly subcutaneous injection, we expect to see strong uptake of the drug for polyneuropathy and mix phenotype patients. We believe that vutrisiran will significantly expand our opportunity beyond Onpattro, especially by achieving greater penetration in the mixed phenotype segment either as monotherapy or in combination with other drugs. Ultimately, assuming we achieve positive results in the ongoing Helios-B study with ATTR patients with cardiomyopathy, we expect that vutrisiran will potentially address the full spectrum addressing 300,00 thousand and more patients worldwide.”

By Ruchi Jhonsa, Ph.D.

Related Article: Alnylam Receives FDA Nod for its Third Rare Disease Drug

References

1. https://investors.alnylam.com/press-release?id=25366

 

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