Patients Have “Fingers Crossed” As Alnylam Awaits Historic FDA Decision

Xconomy Boston — 

[Updated, 8/6/18, see below] By next weekend, the FDA could for the first time approve a medicine that uses a biological trick that was only discovered two decades ago: RNA interference, which silences a gene before it can make a harmful protein. That medicine is patisiran (Onpattro), from Alnylam Pharmaceuticals (NASDAQ: ALNY).

An approval wouldn’t just be a scientific milestone. It’s a medical one, too, for patients with a rare, progressive, and deadly disease called hereditary transthyretin amyloidosis (hATTR).

“We’ve been waiting many, many, many years for a treatment,” says Mary O’Donnell, the president of the nonprofit Amyloidosis Foundation. “We have our fingers crossed.”

Doctors in the U.S. try to manage peoples’ symptoms or slow the progression of hATTR with a generic drug meant for other diseases, but nothing has yet been specifically approved for hATTR, which causes nerve damage, heart problems, and ultimately an early death. In a study that included 225 patients, patisiran—an infusion given at a clinic once every three weeks—has shown that it might not just halt the destructive biological process that underlies the disease, but in some cases, improve nerve function. Its approval would follow a nod in Europe in July for a similar drug, inotersen from Akcea Therapeutics (NASDAQ: AKCA). The FDA should decide on an inotersen approval by early October.

“The conversation is changed by these two drugs,” says John Berk, the assistant director of the Amyloidosis Center at Boston University School of Medicine, and an investigator in trials for both patisiran and inotersen. (Berk co-authored two papers on the two drugs that the New England Journal of Medicine published in July.)

Though its exact prevalence is unknown, hATTR is estimated to affect 50,000 people worldwide. People who have the disease make a mutated version of the protein transthyretin, which builds up in misfolded clumps, causing damage to a variety of tissues around the body. Some patients suffer just the nerve damage, an insidious process that 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.

If the disease affects the heart, people might live just a few years past diagnosis, says Berk. The prognosis is better for those with just nerve damage—up to a 15-year life expectancy—but the effects are still debilitating. The disease can rob mobility and put people in wheelchairs and eventually on bedrest; they can die from infected sores and sepsis. Most patients have both nerve and heart problems, Berk says.

Much is unknown about hATTR. It is often mistaken for other medical issues involving either nerve or heart damage. It can take years to get the proper diagnosis after a battery of tests. There are no approved blood tests, for example, that look for misfolding TTR. (Alnylam and Akcea are offering free genetic testing to help find patients.)

hATTR is also caused by more than 120 different mutations, and each might lead to a different disease trajectory—it could start in someone’s early 30s, or late 50s. O’Donnell knows of a musician whose mother and aunt died from hATTR in their 30s, for example. Now their age, he has no bowel control. “Somehow or other, he’s just bulldogging through,” she says.

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. The aunt and mother O’Donnell spoke of bothdied from their disease despite transplants. And diflunisal, which can cause stomach or kidney problems, isn’t for everyone, Berk says.

The drug tafamidis (Vyndaqel), which is similar to diflunisal, is approved in Europe but not in the U.S. Its owner Pfizer (NYSE: PFE) could soon file for approval for hATTR patients with heart problems. Detailed results from a Phase 3 study are expected later this month.

Amidst the optimism, there are important caveats. It’s unclear how long patisiran and inotersen’s benefits will hold up, or who will respond. Some 25 to 30 percent of patients didn’t benefit from treatment in Phase 3 trials for the two drugs, says Berk. It’s also unknown how much transthyretin—the protein these drugs stop the liver from making—the body needs, or whether it may do harm to keep levels of the protein low over time. Both patisiran and inotersen would be taken for life.

It’s also unclear if the Phase 3 results for patisiran will be predictive for U.S. patients, says Dan Ollendorf, chief scientific officer of the Institute for Clinical and Economic Review, a nonprofit drug-pricing watchdog that recently published a draft report on both treatments. Most patients in patisiran’s Phase 3 trial were European, with a different genetic mutation than typically seen in U.S. patients and thus a different disease trajectory, Ollendorf says. [Updated to clarify that Ollendorf’s point applies to patisiran, but not inotersen. Only 30 percent of the patients in Akcea’s Phase 3 trial were from Europe.]

Ollendorf also cautions that the benefits shown in the key studies were indirect: numerical improvements on tests of neurological function that measure things like muscle weakness and reflexes. Ollendorf says the overall numbers were “impressive,” but there are limited data on how those improvements translate to a higher-quality life, like walking with less use of a cane or walker. 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, Ollendorf says.

(Alnylam’s patisiran showed a cardiac benefit, but the study was not designed to lead to strong evidence that the drug could be approved for cardiac symptoms. The company won’t comment on matters related to the drug’s label given how soon it expects an FDA decision, said spokesperson Christine Lindenboom.)

“We firmly believe that ICER’s review is premature” since the data for patisiran and inotersen, and the field’s understanding of the disease itself, are evolving, Lindenbloom says. The report “must be viewed in balance with the urgent need and the potential benefits that new treatments for hATTR amyloidosis may offer to patients and their families.”

The FDA has been willing to approve drugs for rare, deadly diseases, including some cancers, based on indirect, or “surrogate” measures, well before the drugs have built a track record of actually improving patients’ lives. In the most extreme recent case, the agency in 2016 approved the Duchenne muscular dystrophy drug eteplirsen (Exondys 51) because it was “reasonably likely to predict clinical benefit” based on a study of just 12 patients.

The data for patisiran and inotersen are much more thorough, however. Unlike the decisive eteplirsen trial, both hATTR drugs were studied in conclusive, placebo-controlled trials.

But the lack of knowledge about hATTR has investigators like Berk cautious. Is the disease caused by more than just misfolding TTR? Is there a certain point at which it gets too late to benefit from treatment? The non-responders in the inotersen and patisiran trials are “a really important group to study,” Berk says.

If approved, how will the two drugs be integrated into practice? Ollendorf expects all identified patients to be given a trial of one drug or the other. Economically speaking, that’s important. Both drugs are likely to command very high prices, in line with the cost of many rare disease drugs. Analyst estimates have come in at $200,000 to $400,000 per patient, per year. And as ICER wrote in its report, an FDA approval will increase awareness, leading to more people getting diagnosed. And that could drive up the cost and impact on the healthcare system.

“The questions are how to do this in a fiscally responsible and medically responsible fashion?” Berk says. At BU, patients with early-stage hATTR who might be able to handle slight progression will start on a stabilizer like diflunisal, while those with more advanced disease will immediately get patisiran or inotersen. BU patients who progress on stabilizers will then get patisiran or inotersen either on top of, or instead of, their existing treatments, he says.

It’s historically been a “name-your-own-price situation” for rare disease drugs, Ollendorf says. “At some point some manufacturer of an orphan drug will say ‘We’re going to do things differently.’”

Alnylam has said exactly that. “If someone has the extreme kind of benefit, and disease reversal, we should get paid full price,” Alnylam president Barry Greene told Xconomy in January. “And if they derive less benefit, then they should pay less.” Last month, spokeswoman Lindenboom said the company was working to finalize the price for patisiran and expects it to be “within the range” of similar drugs. She says now that Alnylam has been working with commercial insurers to develop “value-based agreements” for patisiran.

Ollendorf says Alnylam has been having conversations with ICER for a long time. The two aren’t working together the way ICER recently did with Regeneron Pharmaceuticals (NASDAQ: REGN)—in that case, ICER named a price range for a cholesterol drug and Regeneron stuck to it. But “they’ve definitely been engaged” with ICER, he says.

With patisiran and inotersen on the verge of coming to market, access and affordability are major worries for the Amyloidosis Foundation’s O’Donnell (Lindenbloom says Alnylam is working on “strategies and support programs” to help patients quickly access patisiran, but didn’t provide specifics.). A family she knows in California recently did everything possible to get tafamidis from Europe. They procured it from the pharmacy at the Vatican, of all places. (A relative in Italy mailed it to them.) The out of pocket costs will approach $100,000 per year, she says.

“It’s fine that we’ve got a drug that’s going to do some wonderful things, but will the patients be able to afford it?” O’Donnell says. “There’s no answer to that yet here in the U.S.”

Photo courtesy of the Amyloidosis Foundation.