Can Alnylam rise from the ASHes?

October was a bad month for Alnylam. Its shares plunged almost 50 percent after it abruptly scrapped its Phase 3 candidate revusiran, citing a disproportionate number of deaths in the active arm of the trial.

It was a major blow for the double-stranded RNAi company, which has weathered 14 years of R&D with no FDA approvals. With revusiran it lost of one of two late-stage candidates and the safety concerns quickly spread to the rest of its portfolio.

Now in San Diego, California, for the 58th American Society of Hematology (ASH) meeting, Alnylam desperately needs to change the conversation.

So what’s new? Pushkal Garg, Alnylam’s SVP of clinical development, met with MedCity News at ASH to discuss the latest data, the next best opportunity, and the fallout from revusiran.  

A Phase 3 replacement

Alnylam has updates on three different RNAi candidates, delivered throughout the four-day conference.

On Dec. 3, the company reported positive results for givosiran (ALN-AS1), an investigational treatment for acute hepatic porphyrias, currently in Phase 1 trials.

Come Monday, Alnylam will also give updates on its Phase 1/2 study of ALN-CC5 in paroxysmal nocturnal hemoglobinuria (PNH).

Right now, the news is really about fitusiran, Alnylam’s inventive approach to treating hemophilia A and B.

The company shared new data from two ongoing studies; an open-label extended Phase 2 trial and a Phase 1 trial of the drug in hard-to-treat patients. A Phase 3 program for both patient cohorts is now scheduled for early 2017.

Fitusiran was generally well tolerated, the company reported, and checked the two most important boxes: It increased thrombin production and subsequently decreased the median annualized bleeding rate, the standard endpoint for Phase 3 trials in hemophilia.

“We’ve brought that down to a very low level, basically to zero,” Garg said. 

While there are still many unknowns, the therapy has the potential to treat all forms of hemophilia, which affect an estimated 400,000 people worldwide.

The disease is caused by genetic mutations that lead to a deficiency in one of two blood clotting factors; factor VIII (type A) or factor IX (type B).

Factor replacement therapy is the obvious solution, but it is incredibly expensive and burdensome. Due to the short half-life of the drugs, patients with severe forms of the disease need IV treatments 2-3 times per week. Even with regular dosing, blood levels can be unstable.

Around 30 percent of patients with severe hemophilia A will also develop inhibitors — antibodies to the synthetic factor, which can rule-out that therapy.

Alnylam’s once-monthly subcutaneous injection could overcome these challenges, but it takes giant leaps into the unknown.

“What we’re doing is actually a very counterintuitive approach,” Garg said.

Instead of increasing levels of the pro-clotting factor thrombin, fitusiran suppresses another protein called antithrombin III, which inhibits coagulation. It’s an idea borrowed from rare case studies of patients that coinherited both deficiencies. Combined, they balance each other out.

The approach could treat both forms of hemophilia, along with the subset of patients that have developed a resistance to factor replacement therapies.

According to Garg, the Phase 1 results were “similar to what we saw in patients without inhibitors; good, reproducible, stable reductions in antithrombin.”

Other companies are of course zeroing in on hemophilia A and B, a population that spends around $10 billion per year on factor replacement therapies. Many take a gene therapy approach, which has its own intrigue and hazards.

Spark Therapeutics and Pfizer have already shared positive results at ASH, reporting on their joint gene therapy program. According to the news release, all nine patients in a Phase 1/2 trial in hemophilia B reduced their factor infusions by 99 percent.

It’s all good news for the field.

“I really applaud the fact that over time there are going to be a few different therapies for these patients,” Garg said.

Can the company break its 14-year dry spell?

Fitusiran is progressing, but Alnylam urgently needs to prove it can take a product to market.

After the failure of revusiran, the late-stage focus has turned to patisiran, which targets neuropathy complications in hereditary ATTR (hATTR) amyloidosis. The drug is currently being tested in a fully-enrolled 225-person trial, dubbed APOLLO.

Results from the trial are expected in Sept. 2017. But Garg sees a lot of cause for optimism in the meantime. The company has been monitoring a subset of 25 patients taking patisiran for over 2 years.

“We’re seeing some pretty amazing results,” Garg said. “Over two years the neuropathy appears to be stable in more than 70 percent of patients — or even improved. If you look at the average neuropathy score it actually declines by about 6.75 points. You would have expected a 30-point increase in neuropathy.”

All going well, the company will have filed with the FDA by the end of 2017. What concerns investors, however, is the many overlaps the drug has with the ill-fated revusiran.

Revusiran – will it happen again? 

The revusiran trial involved 206 patients with hereditary ATTR cardiomyopathy. That’s the same pathway and disease that patisiran targets, but instead of nerves, it addressed cardiac complications.

Patients in the study were randomized two-to-one into the active and placebo arms.

“What they found was that there were 16 deaths in the active arm and two in the placebo arm, instead of 12 and six,” Garg said, of the data monitoring committees’ findings.

It could have been bad luck or it could have been due to a baseline imbalance. The trial was randomized, but it was also very small and involved extremely sick patients. The median lifespan of individual’s with hATTR cardiomyopathy is around 2.5 years, Garg noted.

A third theory is that reducing levels of the protein target, TTR, has some negative cardiac consequences. But patisiran targets the same pathway and, after close scrutiny, the data monitoring committee found no evidence of the same side effects in that study.

What seems more likely, is that the therapeutic technology imposed too much stress on a very sick patient population.

Patisiran is a first-generation Alnylam drug, which is delivered intravenously. All other candidates, including fitusiran, are given through a subcutaneous injection. Revusiran was a second-generation drug but it had a much shorter therapeutic effect and required far greater doses. It was a beta option of the new technology, so to speak.

“The exposures from that drug are much higher,” Garg explained. “We have to give 26 or 28 grams of that medicine in a year. Whereas, opposed to something like the hemophilia product where we give anywhere from 600 to 1000 milligrams.“

Revusiran was a major setback, but the company still has plenty of promise in its pipeline.

Photo: virusowy, Getty Images