Alnylam Pharmaceuticals, Inc. has spent the better part of two decades working to develop a new kind of drug, one that works by silencing genes rather that blocking proteins.
So-called RNA interference, or RNAi, has held out the promise of treating diseases at a genetic level since its discovery. But translating that scientific breakthrough into RNAi-based therapeutics has been a challenging quest.
Positive results from a late-stage study of Alnylam's lead drug patisiran, unveiled last week, bring RNAi to the brink of becoming a medical reality for patients with a rare, genetic disease. Success of the trial, called APOLLO, spurred a 50% jump in the biotech's stock price, and is the first successful Phase 3 study for an RNAi drug.
Reaching this point, however, has taken Alnylam 15 years and more than $1.6 billion in R&D investment.
"I feel that this is a scientific milestone and an example of the promise of molecular medicine," said Michael Polydefkis, a neurologist and director of the Cutaneous Nerve Lab at the Johns Hopkins University School of Medicine, who has worked with Alnylam.
"The ability to selectively knock down a specific protein and alter disease was scientific fiction not that long ago, and now it has been translated to the clinic."
With the positive Phase 3 results in hand, Alnylam is positioned to lead a field that big pharma — with the notable exception of French drugmaker Sanofi SA — abandoned one by one over the past decade. To complete the biotech success story though, Alnylam will have to transform itself from an R&D-focused pioneer into a commercial company.
At a high level, the logic behind RNAi-based therapeutics makes intuitive sense.
Problematic proteins are intertwined in the progression of many diseases, and finding ways to block their unwanted effects has underpinned drug development for decades.
RNAi, on the other hand, offers a way to interrupt the production of disease-causing proteins themselves —targeting the source rather than the downstream effect. First uncovered in 1998, RNAi can "silence" genes by destroying the messenger RNA that translates DNA instructions for protein synthesis.
The process occurs naturally, tapped by cells to eliminate proteins no longer needed for development. Channeling this mechanism to develop more powerful therapeutics tantalized the drug industry, spurring a wave of investment into the field.
"The potential promise here for RNA interference is you can go into cells, and you can eliminate unwanted proteins," said Mark Murray, CEO of Arbutus BioPharma Corp., in an interview. "This is something that historically we haven't really been able to do in pharmaceutical development because there was not real technology to do that."
Turning RNAi into a medicine, however, proved particularly challenging.
In order to silence a gene, Alnylam had to figure out how to deliver a strand of short interfering RNA to the relevant cells. Enzymes in the blood quickly destroy these siRNA strands, breaking down the molecules soon after they are injected into the bloodstream.
In a further hurdle, RNAi therapeutics are large molecules and don't easily pass through the cell membrane to trigger the desired gene silencing.
"The challenge has been — the singular challenge that stands out above all for this company — has been the delivery of our drug to a relevant target organ," explained Akshay Vaishnaw, head of R&D at Alnylam.
"We spent the longest time, ten years of the company almost, before we could figure that out."
Progress on that front, coupled with a 2012 licensing deal with Arbutus, finally gave Alnylam two delivery platforms from which to build its pipeline of clinical candidates around.
"The singular challenge that stands out above all for this company has been the delivery of our drug to a relevant target organ."
EVP of R&D, Alnylam
Lipid nanoparticle technology licensed from Arbutus, which Alnylam uses to deliver patisiran, protects the nucleic acid molecules from degradation and helps clear passage through the cell membrane.
It helps that patisiran's target, a disease known as hereditary ATTR amyloidosis, stems from a protein produced primarily in the liver. The organ, a common focus of drug development, has a large blood supply and a large proportion of anything injected into the bloodstream will end up there.
With lipid nanoparticles as a delivery vehicle, Alnylam was able to get patisiran to the liver, where it could work to halt production of a protein known as TTR. Stopping TTR synthesis seems to enable the body to clear deposits of TTR protein in peripheral tissues and help restore their function.
"In relation to hATTR, RNAi appears to be a 'molecular liver transplant' without the surgery," said Johns Hopkins' Polydefkis.
In APOLLO, treatment with patisiran reduced the progression of neuropathy and improved patient quality of life — in addition to hitting a clean sweep of five additional secondary endpoints.
Alnylam has also developed what it calls a GalNAc conjugate platform that allows for subcutaneous delivery, rather than patisiran’s intravenous infusion. Outside of patisiran, the remainder of Alnylam's pipeline relies on GalNAc.
Surge and retreat
During the decade Alnylam spent toiling on solving delivery, investment into the field — and into Alnylam — surged and, then almost as quickly, evaporated.
In 2006, four years after Alnylam’s founding, Merck & Co. bought Sirna Therapeutics for $1.1 billion to enter the RNAi field. That same year, Andrew Fire and Craig Mello were awarded the Nobel Prize in Medicine for their research into RNAi.
Alnylam rode the resulting wave of industry interest, securing $331 million upfront from Swiss pharma giant Roche AG in 2007 and inking collaborations with other pharma players.
Yet, the turn of the decade saw major drugmakers pull back, disenchanted with the vexing delivery problem. In 2010, Novartis AG, which had bought into Alnylam in the company’s early days, decided against expanding its partnership, triggering layoffs for the biotech.
Soon after that decision, Roche shut down its development work in RNAi, shocking the field. Further retreats from Merck and Novartis in subsequent years left Anylam as one of the few remaining players.
As the years ticked by, though, and the biotech continued to make progress, RNAi-based drug development slowly regained its luster.
Alnylam's position was buoyed substantially in 2014 by a $700 million investment from Sanofi Genzyme, which allowed the Alnylam to put more money behind clinical development, including APOLLO.
Preparing for a new chapter
Three years later, Alnylam’s persistence has begun to pay off.
Patisiran’s success in the APOLLO trial offers the strongest clinical validation of RNAi yet. It also helps shake safety concerns that emerged after a number of patients died in a study of another drug candidate called revusiran last fall.
Alnylam decided to shut down development of that drug, even though it found no clear explanation for the deaths. The setback temporarily dented confidence in Alnylam's platform, pushing shares in the company down by nearly half. More worries cropped up this month when Alnylam paused a trial of its hemophilia candidate after a patient died from a thrombotic event.
Reassuringly for Alnylam and RNAi's future as a platform, patisiran's safety profile in APOLLO looked clean. Only 7% of patients receiving patisiran discontinued treatment, compared to 38% of those on placebo — a sign that Vaishnaw says indicates patients saw a clear benefit from the drug.
If patisiran is approved, Alnylam will become the first company to commercialize an RNAi therapeutic.
For all of its scientific success, though, the company still needs to prove it can sell the fruit of its R&D efforts. And one of the first questions Alnylam needs to address is finding an appropriate price for patisiran.
Alnylam would be bringing the drug to market in a period where attention to drug pricing is particularly acute. Long-time CEO John Maraganore has previously indicated the company would probably price patisiran's annual cost in the six-figure range, which would put it on par with other orphan treatments.
Hereditary ATTR amyloidosis affects about 50,000 people worldwide. An approval for patisiran would probably clear it to treat about half of that population. Those patients have almost no other options, and from the looks of the APOLLO results released to date, patisiran would bring significant value to patients.
If Alnylam gets pricing right, patisiran could be set for eventual blockbuster sales. And it will need all the revenue it can earn to support further development of RNAi beyond patisiran.
Optimism from APOLLO has put RNAi firmly back on the map. But as the safety issues of this past year have shown, there are questions still left solve. If Alynlam is to remain the leader in RNAi, it will have to balance scaling commercial efforts with a laser focus on proving RNAi in other diseases.
At one point, industry watchers were predicting RNAi therapeutics would become the next monoclonal antibodies. That lofty ambition has been tempered by a decade of arduous R&D. After APOLLO, Alnylam has the rare chance in biotech to prove the viability of a new class of medicines.