More details from two drug programs up for approval this year to treat a rare genetic disease emerged yesterday, published in side-by-side papers in the New England Journal of Medicine.
In one sense, the new papers hold no surprises, but they reinforce the similarities and differences between the closely watched drugs, one from Akcea Therapeutics (NASDAQ: [[ticker:AKCA]]), the other from Alnylam Pharmaceuticals [[NASDAQ: [[ticker:ALNY]]). An accompanying editorial in the journal praises the drugs for hitting their goals in the “landmark” trials. But the author, Joel Buxbaum of the Scripps Research Institute in San Diego, also underscores that as much as half of the patients in those trials did not respond to either drug, and to date there is no underlying biological key to know who might respond or not. This could have real-world ramifications in how the drugs are paid for.
“Although each of the trials unequivocally shows a therapeutic effect, there remain questions. Would a single patient have a response to each of the therapeutics to the same degree? If so, it is in the patient’s interest to use the least expensive therapy,” writes Buxbaum.
The disease in question is transthyretin amyloidosis, or ATTR. People who have inherited the disease produce a mutated version of the protein transthyretin, which normally helps ferry vitamin A around the body. The mutant version results in misfolded clumps of the protein that wreak havoc in the nervous system and other organs and result in pain, organ failure, and early death. The experimental drugs have been tested only in ATTR patients whose symptoms include neuropathy—about two-thirds of the 50,000 who are diagnosed worldwide each year. Some patients suffer heart damage but not nerve damage; they will not be covered if the drugs are approved this year.
Alnylam’s drug candidate patisiran has an FDA approval decision deadline of August 11. Akcea’s inotersen is due for an approval decision October 6, after the FDA pushed back the deadline by three months. Announced in May, the delay has arguably been the biggest stumble for either company so far; it knocked more than 20 percent off Akcea’s share price, which has since recovered.
Both Alnylam and Akcea’s parent company Ionis Pharmaceuticals (NASDAQ: [[ticker:IONS]]) released important Phase 3 data last year. (Ionis was in charge of inotersen until March of this year.)
Both noted that their drugs hit their main goals. Both alleviated the neuropathy that the buildup of misfolded proteins causes. Because trials have different designs and circumstances, comparing the size of the effect across trials is frowned upon by researchers and statisticians.
However, it’s clear that the drugs differ in two main ways: Where they are meant to be administered, and safety concerns. These issues will be important for patients and physicians if both experimental drugs gain FDA approval.
Patisiran is an infusion administered every three weeks in a clinic. Inotersen is a biweekly self-administered injection. Akcea is banking on the convenience of self-injection at home as a “benefit that allows [patients] to incorporate the drug into their lives,” says Akcea CEO and president Paula Soteropoulos.
At least one doctor who treats ATTR patients downplayed the difference between going to a clinic and injecting at home. “There will be workarounds for the logistical barriers,” says Morie Gertz of the Mayo Clinic in Rochester, MN.
A bigger issue for practicing physicians, he says, is knowing if a drug is working for a particular patient. “A key question is, ‘When do I stop one and try the other?'” says Gertz. “There’s no evidence to guide you.” Even in the two clinical trials, there was no trigger to stop an ineffective treatment, like there is in a cancer trial when a patient’s tumor starts to grow again.
Other than relying on patient feedback, there will be no way to regularly check a patient’s progress. The test (known as mNIS+7) both companies used in their trials to measure the main goal—a patient’s neuropathy improvement—is not widely available at all treatment centers, says Gertz, so patients taking one of the drugs will probably not get regular mNIS+7 check-ups. (Gertz took part in inotersen’s Phase 3 study and has been paid speaking fees by both Akcea and Alnylam.)
The question might be moot if insurers limit access to only one drug, a common practice when similar drugs are in competition. But strictly based on treatment effect, doctors at first will be feeling their way. “It will be a real challenge to know if a drug is working well or not,” says Gertz.
Another difference between inotersen and patisiran is safety. In inotersen’s big trial, some patients developed thrombocytopenia, or low platelet counts, which can lead to internal bleeding and deadly strokes. One subject in that trial died of a brain hemorrhage. In his NEJM editorial, Buxbaum underlined that no one has figured out why inotersen is acting like a blood thinner. His review of studies of other Ionis drugs that work like inotersen—that is, blocking a cell’s ability to make certain defective proteins—“suggests that the effect may be specific to inotersen.”
Soteropoulos says the low platelet counts were not behind the FDA’s decision to lengthen its review, which was originally meant to be a “priority” or sped-up six-month review. “It got to a point where they needed to make a decision and needed more time,” she says. “It was not any specific extra thing.”
Meanwhile, Akcea continues to monitor its trial participants with biweekly blood draws. Those would continue if inotersen is approved.
Trial participants taking Alnylam’s patisiran had no bump in side effects compared to those in the placebo arm of the trial, except for infusion-related reactions. Alnylam is giving patients analgesics and corticosteroids before each dose as a precaution.
As with any drug heading toward possible approval, pricing is a major question. Soteropoulos said “we all want to move
