- The Food and Drug Administration on Friday granted the first U.S. approval of a drug that works by 'silencing' genes to halt disease, completing a 16-year research journey for Alnylam Pharmaceuticals, the medicine's developer.
- Alnylam's drug, called Onpattro, stems from Nobel Prize-winning research into the therapeutic applications of a cellular process known as RNA interference, which can be used to interrupt the production of disease-causing proteins by degrading the signals that convey genetic instructions.
- Approval of Onpattro — OK'd to treat peripheral nerve disease caused by hereditary ATTR amyloidosis — delivers on the promise of RNAi first sketched out in 1998 by scientists Andrew Fire and Craig Mello. But it won't come cheap: Alnylam plans to sell the drug at an average annual list price of $450,000 per patient.
For the first time in 16 years of existence, Alnylam has a drug to sell.
Onpattro (patisiran)'s approval is the product of nearly two decades of research, during which Alnylam spent $2.3 billion on developing RNAi technology — and piled up nearly as much in accumulated losses.
In that span, drugmaker investment in RNAi first surged and then later dried up, as research roadblocks slowed the field's advancement. Novartis, Roche and Merck & Co. all pulled out after initial research, leaving Alnylam as one of the few remaining players.
RNAi's attractiveness as a research target stemmed from its powerful implications for treating disease. Most drugs work by counteracting the unwanted effects of problematic proteins. RNAi, on the other hand, acts by disrupting the messenger RNA cells used to produce the proteins in the first place. By interfering with mRNA, RNAi therapeutics can "silence" the target gene.
In the case of hereditary ATTR amyloidosis, mutations in the TTR gene lead to toxic buildup of the related protein, damaging tissue and organs, particularly peripheral nerves and the heart. Onpattro blocks production of TTR protein, preventing further accumulation of deposits.
A progressive disease, ATTR amyloidosis is generally fatal, with survival between two to 15 years from onset of symptoms.
Alnylam's pivotal study of Onpattro proved the drug effective in slowing progression of — and in some cases reversing — neuropathy compared to patients given placebo. Quality of life also appeared to improve and Onpattro led to relatively mild side effects. The latter point is particularly important, given both the relative newness of RNAi as a therapeutic tool, and because of serious adverse events Alnylam has seen elsewhere with its RNAi drug candidates.
The FDA approved Onpattro only for adult patients with polyneuropathy caused by ATTR amyloidosis, rather than the disease more broadly.
Like other first-in-class rare disease drugs, Onpattro will be expensive. Alnylam set a list price for Onpattro of $9,500 per vial, which — depending on dosing — averages out to $450,000 per year. After rebates and discounts, the effective net price is expected to be $345,000.
The biotech said it is pursuing outcomes-based arrangements that would link payment to Alnylam with the drug's real-world performance, and committed to not increase Onpattro's price beyond inflation unless "valuable new innovation has been achieved."
For now, Onpattro is the first drug OK'd in the U.S. for ATTR amyloidosis. But Alnylam may not be able to sit easy.
Rival Ionis Pharmaceuticals, and its majority-owned spinout Akcea, have successfully developed an anti-sense oligonucelotide that targets messenger RNA by another mechanism. Trial results showed the drug is also capable of slowing the progression of neuropathy in ATTR amyloidosis. A decision on approval was originally set by the FDA for July, but later delayed three months to early October.
While Alnylam's drug appears to have an edge in clinical efficacy, Ionis and Akcea's Tegsedi (inotersen) is given through a more convenient injection rather than intravenous infusion.
The role of spoiler could also go to Pfizer, which is set to present detailed data later this month from a Phase 3 study of its drug tafamidis. Earlier this year, the pharma said clinical results showed tafamidis reduced mortality and heart-related hospitalizations among patients with cardiomyopathy resulting from the condition.
Alnylam plans to quickly follow up on its RNAi success, having bet on the technology's potential as a broad platform for its experimental medicines.
Alnylam aims to launch a new RNAi therapeutic every 12-18 months
|Expected approval date
|Succeeded in Phase 3
|Acute hepatic porphyrias
|Interim Phase 3 results expected in Sept.
|Plans to begin pivotal Phase 3 by mid 2018
|Plans to begin pivotal Phase 3 by late 2018
SOURCE: Company presentations
"Assuming things go well, we're positioned to launch an important new medicine, an important new RNAi therapeutic every 12 to 18 months," said Barry Greene, president of Alnylam, in an interview. "It's profile rarely achieved in biopharmaceutical history."
Yet, after 16 years as a research company, Alnylam will now face the trials of living up to commercial expectations.