Alnylam Pharmaceuticals been saying for a few years now that its lead RNA interference drug can reduce the levels of a protein responsible for a rare, crippling nerve condition known as familial amyoidotic neuropathy, or FAP.
But knocking down, or “silencing” genes that create harmful proteins isn’t enough to prove that a drug works. In the end, patients have to feel better. Today the Cambridge, MA-based company is saying that an RNAi drug it’s developing just might help them do that—at least based on the results of a small exploratory study.
At the American Academy of Neurology’s annual meeting in Washington, DC, Alnylam (NASDAQ: ALNY) is reporting the latest results of a Phase 2 extension study of patisiran, its most advanced RNAi drug. It’s important to note that this is a small study, of 27 patients, and it isn’t randomized or placebo-controlled—the type of trial Alnylam will ultimately have to succeed with to prove patisiran’s worth, and get it approved by the FDA.
But the trial is still noteworthy because it’s the most substantial evidence gathered to date showing patisiran’s ability to alter the course of patients’ disease—and a measure of validation for the scientific hypothesis behind RNAi drugs.
“These results really are great news for RNAi therapeutics in general,” says Alnylam president and chief operating officer Barry Greene. “They provide more evidence that bridges target knockdown to clinical benefit.”
Here are the numbers: Alnylam reports that the neurological function of the 20 patients in the study that have been on its drug for at least 12 months had improved, as measured by what’s 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 how patients respond to heat or touch—means patients are improving (and a higher score means they are suffering more nerve damage). The 20 patients on patisiran had a 2.5-point decrease, on average, on their mNIS+7 scores after 12 months. (The other seven patients have been on patisiran between six and 12 months, Greene says.)
Alnylam also presented six-month data from all 27 patients in the extension study; their mNIS+7 scores decreased by 1.4 points on average, a slight improvement from the 0.95 point average decrease in 19 patients Alnylam reported in October. The drug, administered intravenously once every three weeks, also continued to reduce about 80 percent of patients’ transthyretin—the disease-causing protein that clumps up in the body as a result of FAP—over about 16 months.
Since these results aren’t being compared to a placebo, Alnylam is comparing the mNIS+7 scores to a “natural history” study, or, a study of untreated FAP patients—basically combined data from other Phase 3 trials of patients with FAP, and scientific literature on the topic. It’s an indicator for how FAP patients would fare without treatment. Alnylam says untreated patients similar to the ones it enrolled typically have about an 18-point increase in mNIS+7 scores after 12 months.
Alnylam says there haven’t been any serious side effects in patients on patisiran; the most common were flushing (22.2 percent of patients) and “mild” infusion-related reactions (18.5 percent) that didn’t cause anyone to drop out of treatment. Diarrhea (7.5 percent) and peripheral edema (7.5 percent) were also reported in some patients. The side effects haven’t caused any patients to stop taking patisiran, Greene says.
The mNIS+7 scores are at the top end of the expectations of sell-side analysts. Before the data were released, for instance, Canaccord Genuity analyst Adam Walsh said an average decrease in mNIS+7 scores after 12 months would be a “grand slam” for Alnylam; Leerink Partners’ Michael Schmidt called it a “best case” scenario. Both were looking to good data as a key confidence booster for Alnylam’s ongoing Phase 3 study for patisiran.
“Even if the mean mNIS+7 score increases from 6 to 12 months, we think as long as the change from baseline remains more than 50 percent below the 18 points expected for untreated patients, we’d be highly confident in the probability of success of Phase 3,” Schmidt wrote.
In that study, a randomized, placebo-controlled trial called “Apollo,” the main goal is a statistically significant difference in mNIS+7 scores between placebo and treated patients over 18 months. Data are expected in 2017.
There’s a much larger sample size in that study, of course; Alnylam is enrolling up to 200 patients. But Greene is encouraged by what Alnylam has seen so far. He says given that untreated patients typically worsen by about 18 points on the mNIS+7 scale over a year, anything less than a 9-point increase for patisiran patients would have been a “pretty powerful” takeaway from the small Phase 2 extension study it’s reporting on today. Patisiran performed better than that.
“The fact that we saw a decrease really points to a halting of [disease] progression here,” he says. “It bodes incredibly well for the powering of Apollo [Alnylam’s Phase 3 trial].”
For example, Greene says, natural history data and other scientific literature suggests that placebo patients’ mNIS+7 scores would jump by 27 points in 18 months; if patisiran patients had even a 16 to 17 point increase over the course of treatment, Alnylam would hit statistical significance, though Greene adds—“obviously by looking at these data, we, the investigators—and, you can bet, the physicians—sure hope it’s better than that.”
FAP is a form of transthyretin amyloidosis, an inherited condition in which amyloid proteins build up in tissues of the body 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 (another form, affecting the heart, is more prevalent).
The only treatment options for FAP patients are a liver transplant, or Pfizer’s tafamidis (Vyndaqel), which is approved in Europe but not in the U.S. Alnylam is also in a race with another maker of RNA-based drugs, Isis Pharmaceuticals (NASDAQ: ISIS), which is co-developing a treatment with GlaxoSmithKline called ISIS-TTRrx that’s also in late-stage testing. Data from that trial are also expected in 2017. (Isis hasn’t disclosed any data from the therapy in actual FAP patients as of yet.)
Patisiran’s progress is a touchstone for the RNAi field, which now appears as close as it’s ever been to producing an approved drug. The concept is essentially to silence disease-causing genes before they make the proteins that trigger diseases by introducing short, synthetic strands of RNA into cells. RNAi’s history has been a roller coaster, largely due to solving the technical challenge of getting large RNAi molecules to their targets—and Alnylam knows that better than anyone. Its shares were worth just $6 apiece a few years ago, when several pharmaceutical companies backed out of the field. Now, indicative of the field’s resurgence, shares are worth more than $118.
Sanofi’s Genzyme unit has commercial rights to patisiran everywhere except North America and Western Europe.
Alnylam is hosting a conference call later this morning to discuss the data.