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Alnylam Gets Landmark FDA OK For First-Ever RNAi Drug

Xconomy Boston — 

[Updated at 4:08 pm ET, see below] Alnylam Pharmaceuticals made history this afternoon.

The FDA has just approved Alnylam’s patisiran (Onpattro), making it the first medicine specifically cleared to treat a rare and deadly disease called hereditary transthyretin amyloidosis (hATTR). The decision is a scientific milestone too: it marks the first-ever approval for a medicine that uses RNA interference (RNAi), a method cells can use to silence a gene before it makes a harmful protein.

[Updated here and below with details on pricing, patient population size, and the value-based pricing scheme.] The FDA’s approval is specifically for the treatment of the peripheral nerve damage suffered by hATTR patients. On a conference call Friday afternoon, Alnylam said it will discuss with the FDA how to expand the drug’s label to include other hATTR patients with other kinds of symptoms, such as heart problems, which might require additional study. Company officials estimated there are 20,000 to 30,000 patients worldwide with hATTR and the nerve damage, including fewer than 3,000 adults diagnosed in the US.

Alnylam also said the drug’s average list price–which doesn’t include rebates to insurers—is $450,000 per patient, per year. The average net price, taking rebates into account, is $345,000 per year, Alnylam said.

Alnylam executives have been vocal for years about plans to tie their drug’s price to the benefit it provides patients. And today the company made good on that promise, though it didn’t disclose specifics. In a statement on Friday, Alnylam said it has agreed in principle to the structure and key terms of “value-based agreements” with “major health insurers” including Harvard Pilgrim Health Care. Through these deals, Alnylam would be paid based on patisiran’s ability “to deliver outcomes in the real world setting comparable to those demonstrated in clinical trials,” the company said.

In the conference call, Alnylam leaders said that under these agreements, treated patients would be evaluated annually by their doctors using clinical measures. If the patient improves and nerve damage is reversed, Alnylam said it would be paid in full. But if the disease gets worse, the company would provide discounts of varying levels, but officials didn’t give any further detail on the discounts.

Alnylam’s (NASDAQ: ALNY) triumph, however, doesn’t guarantee a big revenue surge from sales of the company’s first product. There may be many patients who remain undiagnosed or misdiagnosed, and a competing company’s similar drug could be approved in the U.S. soon.

Nonetheless, patisiran’s approval is a noteworthy scientific achievement. It is the culmination of nearly two decades of scientific work that began when scientists Andrew Fire and Craig Mello discovered RNAi 20 years ago. They won a Nobel Prize for their discovery in 2006.

Since 2002, Alnylam, the RNAi field’s biggest company, has tried to use the method to make drugs, undergoing a series of ups and downs, clinical setbacks, and more before getting patisiran to the finish line.

It took years to figure out how to deliver large RNA molecules safely and effectively into cells, and pharmaceutical companies fell in and out of love with RNAi along the way. But Alnylam has survived, in large part, because of early partnerships that left it with enough cash to weather the storm.

After burning through almost $2.4 billion, SEC filings show, the company is now a commercial business with a product soon to be on the market. Three other Alnylam RNAi medicines for hemophilia, high cholesterol, and acute hepatic porphyria (a rare liver disease) are in late-stage testing.

“After 16 years, tireless perseverance through near-death moments, billions of dollars in investment, we’ve finally succeeded in advancing RNAi therapeutics as a whole new class of innovative medicines,” said CEO John Maraganore (pictured) in an e-mail to Xconomy. “What matters most? The difference we can now make in the lives of patients with hATTR amyloidosis.”

hATTR is estimated to affect 50,000 people worldwide. People who have the disease make a mutated version of the protein transthyretin (TTR), which builds up in misfolded clumps, causing damage to a variety of tissues around the body. Some patients suffer just the nerve damage, which starts with numbness in the toes, then feet, and moves upwards. Others suffer a corrosion of the heart’s wiring that can lead to heart failure and death. Most patients have elements of both issues.

The only treatments to date in the U.S. are liver transplants or diflunisal, a generic anti-inflammatory drug used off-label to “stabilize” the TTR protein and slow the progressive nerve damage. But liver transplants are risky, tough to get, and don’t always work. And diflunisal can cause stomach or kidney problems, so it isn’t for everyone.

The treatment paradigm for hATTR is now being upended, however. Alnylam’s drug is a small RNA molecule, delivered to the liver by a lipid nanoparticle, that works by interfering with the RNA for the abnormal form of the protein transthyretin (TTR) to block the production of the protein.

With the arrival of patisiran and a rival, similar-type drug, inotersen (Tegsedi), from Akcea Therapeutics (NASDAQ: AKCA), new drugs are emerging that could give patients the chance to halt the progression of their nerve damage—and in some cases, improve nerve function. European regulators approved inotersen in July and the FDA could approve it by Oct. 6. Patisiran is currently under review in Europe.

Then there’s tafamidis (Vyndaqel), a Pfizer drug which is similar to diflunisal and is approved in Europe but not in the U.S. Pfizer (NYSE: PFE) could soon file for approval for hATTR patients with heart problems, and detailed results from a Phase 3 study are expected later this month. Those results, and whether the FDA ultimately approves tafamidis—it rejected the drug several years ago—could affect the commercial potential of both patisiran and inotersen.

Last week, Xconomy delved into the impact patisiran’s approval could have on patients, clinicians, and payers, and the questions and challenges ahead. It’s unclear how long patisiran and inotersen’s benefits will hold up, who will respond, or whether any safety problems will crop up over time. There is also little information about the impact the drugs have on cardiac symptoms—like thickening of the heart tissue—that can kill patients more quickly. All of which could play into how insurers cover the drugs, how physicians prescribe them, and who might be able to access them.

Clinical trials have different designs and circumstances, so comparing one drug to the other is fraught with caveats. But the biggest differences between the two drugs is how they are administered, and their side effects. Alnylam’s drug is given via infusion at a clinic once every three weeks and patients are given precautionary analgesics and corticosteroids before each dose. Inotersen is a once-weekly self-administered subcutaneous injection. Alnylam has touted patisiran’s safety profile (the most common side effects are upper respiratory infection, and those related to the infusion, including back pain, nausea and abdominal pain). However, worrisome kidney problems and dangerously low platelet counts have cropped up in clinical studies of inotersen—meaning patients will likely require frequent monitoring.

Here’s more on Alnylam, RNAi, and the coming commercial battle between patisiran and inotersen.

Corie Lok contributed to this report.