[Updated with comments at 9:49 am ET, see below] For the first time ever, a medicine using RNA interference, a method of muting a gene before it can make a harmful protein, is headed for an FDA review. If the agency grants a commercial license, it would be a major victory not just for the drug’s developer, Alnylam Pharmaceuticals, but for a field of science that has been on a roller coaster ride for nearly 20 years.
Alnylam (NASDAQ: ALNY) said this morning that patisiran, a drug being developed for the rare nerve disease familial amyloid polyneuropathy, succeeded in a 225-patient Phase 3 trial called Apollo. It helped slow the decline in patients’ neurological function, a progression that is a hallmark of FAP, better than a placebo after 18 months of treatment. It also succeeded on a variety of additional study goals testing the drug against a placebo, including measures evaluating patients’ muscle strength and walking ability.
Alnylam, however, only provided the top-line results of the study. It will disclose the actual magnitude of the drug’s benefit when it presents the full data at a medical meeting in November.
The Cambridge, MA, firm will now file for approval of patisiran in the U.S. in late 2017 and in Europe in 2018, which might soon make the Alnylam therapy the first RNAi drug to ever reach the market.
“We are very proud to report the first ever positive Phase 3 results for an RNAi therapeutic, marking the potential arrival of an entirely new class of medicines,” said CEO John Maraganore (pictured), in a statement. “This moment is the culmination of a 15-year journey of tireless work by countless contributors who have overcome enormous scientific and business challenges to make RNAi therapeutics a reality.”
Shares of Alnylam soared more than 51 percent and closed at $113.84 apiece on Wednesday.
The main goal of the study was a statistically significant difference on a test of neurological function known as the “modified neuropathy impairment score,” or mNIS+7. Essentially, a decreased score on mNIS+7—which measures things like muscle weakness, reflexes, and response to heat or touch—means patients are improving. A higher score means they are suffering more nerve damage.
Alnylam said today, without providing specifics, that the mean and median mNIS+7 score of patients on patisiran in the study had “negative” values, meaning the condition of a “majority of patients” improved. The average change in the mNIS+7 score was significantly lower in the patisiran group than the placebo group, the company said.
The drug also led to a statistically significant difference in patients’ quality of life based on the results on a survey called the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy. Furthermore, it led to a difference, compared to placebo, in patients’ muscle strength and walking ability, Alnylam said.
The most common side effects patients experienced were peripheral edema (29.7 percent of patients on patisiran, compared to 22.1 percent on placebo) and infusion-related reactions (18.9 percent on patisiran, 9.1 percent on placebo). Alnylam said these side effects were “mild to moderate” in severity. Fewer patients on the Alnylam drug (4.7 percent) dropped out of the study because of side effects than those on placebo (37.7 percent). Additionally, more patients on placebo died (7.8 percent) than on patisiran (4.7 percent).
[Updated with comments from Maraganore] On a conference call Wednesday morning, Maraganore said the data suggest patisiran may “halt or even improve” patients’ disease and “transform their quality of life.”
“These data exceed all of our hopes and expectations,” Maraganore said on the call. “Frankly, we could not have dreamed for a better outcome here.”
FAP is a form of transthyretin amyloidosis, an inherited condition in which proteins don’t fold into their normal shapes correctly. The misfolding makes them build up and cause damage to the nerves, heart, and other organs. About 10,000 people have the nerve-damaging form, FAP, and they tend to live another 5 to 15 years after symptoms crop up. A different form of transthyretin amyloidosis, which affects the heart, is more prevalent.
The only treatments for FAP are a liver transplant or Pfizer’s tafamidis (Vyndaqel), which is approved in Europe but not in the U.S.
Alnylam is heading towards a commercial battle with Ionis Pharmaceuticals (NASDAQ: IONS), which will file for approval of a rival FAP drug, inotersen, by the end of 2017.
The Ionis drug is more convenient because it can be injected just under the skin, while the Alnylam drug has to be infused intravenously. But worrisome kidney problems and dangerously low platelet counts cropped up in clinical studies of inotersen. If it is approved, patients will likely require frequent monitoring. Ionis executives have downplayed those issues, calling them manageable and reversible, and countered that patients have to be prepped for Alnylam’s drug with analgesics and steroids, which might lead to complications after long-term use.
Alnylam, meanwhile, is highlighting patisiran’s safety profile. Without the need to monitor patients, patisiran might “erase any of the advantages” of inotersen’s convenience, Maraganore said at a conference this month in New York. Alnylam also plans to do “home infusions” for patients in markets where it is possible, Maraganore said.
If approved, patisiran won’t be cheap. At the conference this month, Maraganore said patisiran—meant to be administered once every three weeks, for life—will have a “six-figure price per year” if approved, which would be in line with the going rate for so-called orphan drugs for rare diseases with no other treatments. The first treatment for spinal muscular atrophy, Biogen’s (NASDAQ: BIIB) nusinersen (Spinraza), for instance, costs $750,000 for the first year and $375,000 each year thereafter. Sarepta Therapeutics’s (NASDAQ: SRPT) Duchenne muscular dystrophy drug eteplirsen (Exondys 51) costs an average of $300,000 per year.
Alnylam spent $382.4 million on R&D in 2016 and $276.5 million in 2015. The company declined to disclose how much it spent over the years developing patisiran specifically, however.
[Updated with comments from Greene] Pending approval, Alnylam expects to begin selling the drug in mid-2018, president Barry Greene said on the conference call. Alnylam believes the drug can help the estimated 20,000 to 30,000 patients around the world with TTR amyloidosis—including those with some degree of heart problems.
Rare disease drug developers have had varying levels of success convincing payers to cover the increasingly high prices of orphan drugs. Greene said the company has been talking with payers and expects “real receptivity to patisiran,” given the data Alnylam has accrued.
“We are working with the payer community to design programs so that when we have an approved therapy, we can help patients achieve rapid and affordable access,” Greene said.
The looming commercial battle aside, today’s patisiran data are a scientific victory for a field that has been waiting for years to deliver on its initial promise.
RNAi is a method cells use to mute a gene with strands of RNA before it can produce a protein. It was first discovered in 1998 by a team led by scientists Andrew Fire and Craig Mello. As Mello, who has no ties to Alnylam, explained to Xconomy recently, the two weren’t directly studying gene silencing, just trying to use it as a tool when they “noticed there were really surprising things going on.” Eight years later Fire and Mello won a Nobel Prize for their work.
Drug makers found RNAi particularly intriguing because it offered the potential to create synthetic versions of the protein-blocking RNA: a new class of drugs to aim at diseases that other drug making methods—like monoclonal antibodies or small molecule drugs—couldn’t touch.
Firms like Alnylam, Sirna Therapeutics, RXi Pharmaceuticals and more formed in the early 2000s to try to harness the technology. But as is often the case with new science, it has taken years of ups and downs to get RNAi even this close to market.
Significant hype was followed by the hard smack of biological reality. Delivering relatively large RNA molecules into the right cells, without causing unintended problems, proved a daunting task that even Mello recently said the field “underestimated.”
Across the first decade of the 2000s, clinical studies ended in failure. Large pharmaceutical firms like Roche, Abbott Laboratories, Pfizer, and Novartis fell in and out of love with RNAi. Other drug development methods and tools, such as gene therapy and CRISPR-Cas9 gene editing, have since garnered more headlines and hype.
Alnylam survived through dark days and became the RNAi field’s largest company, thanks to several early partnerships that raked in a pile of cash. It tailored its ambitions exclusively to diseases it could target by delivering the molecules to the liver. It focused largely on rare diseases with no available treatments, hoping for quicker development paths.
There have been recent bumps along the way for Alnylam. Last year, it dumped one drug in Phase 3, revusiran, and another in early-stage testing, ALN-AAT. Both moves were due to safety problems, as was the company’s recent decision to suspend all trials of an experimental hemophilia drug, fitusiran. But Alnylam was bullish enough to open a commercial hub in the U.K. in September 2016 while the Apollo trial was ongoing.
Patisiran’s success today makes that bet a good one and marks a turning point both for Alnylam and, at long last, RNAi.
As Mello said earlier this month, before the data were released: “It’s a whole new ballgame now. The hard work has been done, or a lot of it. It’s time to start making drugs.”
Alnylam splits rights to patisiran with Sanofi, part of a wide-ranging alliance. Alnylam has rights in the U.S. and Western Europe, Sanofi everywhere else.