[Updated, 8/28/18, 1:30pm ET. See end of story.]
Drug giant Pfizer (NYSE: [[ticker:PFE]]) could soon join a budding U.S. competition to treat the rare disease transthyretin amyloidosis, in which a common protein goes haywire and builds up into dangerous deposits in the heart and nerves.
Pfizer today presented results from a late-stage study of its drug tafamidis in patients who suffer deadly heart problems from two forms of the disease—one caused by inherited genes and another that occurs over time, predominantly in older men. The study was also published in the New England Journal of Medicine.
In the 30-month, 441-person study known as ATTR-ACT, tafamidis met its main goal, reducing risk of death by 30 percent and cardiac-related hospitalization—for heart failure and other conditions—by 32 percent compared to patients taking placebo.
“A 30 percent reduction in mortality is a big deal,” said Morie Gertz, who treats patients with transthyretin amyloidosis, or ATTR, at the Mayo Clinic in Rochester, MN, which was one of 54 sites that participated in the study. In historical studies of the disease, ATTR patients who don’t inherit the gene mutation but still develop heart disease often don’t live more than three or four years beyond their diagnosis, Gertz told Xconomy.
Pfizer’s data, however, had some noticeable gaps that left doctors and patients, not to mention investors eyeing the newly competitive space, wondering who exactly will benefit the most from tafamidis. The drug has had a hit-and-miss regulatory history for patients whose ATTR causes nerve damage.
Pfizer shares were down 2 percent to $41.55 in late trading Monday. Alnylam Pharmaceuticals (NASDAQ: [[ticker:ALNY]]), which saw its drug approved for hereditary ATTR earlier this month, saw its shares jump.
The courses of disease for those with hereditary and wild-type, which develops over time, are different; the reductions in deaths and hospitalizations were statistically significant when all patients were lumped together.
ATTR-ACT mainly studied patients with the wild type. More than three-quarters, or 76 percent, had the wild-type disease. They tend to be older and sicker, said John Berk, director of the Amyloidosis Center at Boston University, which also served as an ATTR-ACT study site. “I think we’re talking about people at the tipping point of their disease, on a downward trajectory,” he told Xconomy. Without treatment, the misfolded transthyretin accumulates in the heart tissue, thickening it and causing heart failure.
How many people with wild-type ATTR leading to heart disease could potentially be treated is a rough estimate—Pfizer puts the range at 400,000 to 500,000. On a conference call Monday, analyst Umer Raffat of Evercore ISI said he was “surprised” at Pfizer’s estimate and asked for corroboration. Brenda Cooperstone, chief development officer for rare disease at Pfizer, said the estimate was derived from “multiple sources.”
Whatever the true number of cases might be, it’s almost certainly higher than the estimated 50,000 worldwide who have hereditary ATTR. “We’re diagnosing the tip of the iceberg,” said Gertz, based on how many cases are confirmed only upon autopsy.
It remains unclear, however, how much benefit in ATTR-ACT accrued separately to the wild-type patients and the hereditary patients. “The trial wasn’t designed to look for statistical significance within each subgroup,” Cooperstone said. She said all subgroups of the study, including those taking different doses of tafamidis, 20 mg and 80 mg, showed a “consistent mortality benefit,” which is not necessarily as persuasive if it isn’t statistically significant—which is an indication that results are not likely to be skewed by random events or chance.
This is the first major study of a drug for ATTR patients specifically with heart damage. Berk commended Pfizer for its design. As with many rare diseases, there were little historical data to use as a guide to set the study’s goals. “They had nothing to go on and they decided to have primary endpoints that are real and understandable to FDA and to patients in general,” said Berk. “This is a precedent-setting study.”
Patients also showed a statistically significant improvement in function and quality of life, such as a test of walking for six minutes. These secondary goals of the study began to show results within six months, while survival improvements did not start to show up until the 18-month mark of the study.
Pfizer officials were clear they would push hard for approval based on the ATTR-ACT data and have started an early access program for patients. While the overall numbers were positive, it’s unclear if regulators will approve tamafidis for both sets of patients or just those who have the wild type. The lack of nuanced data is worth noting, given tafamidis’s mixed track record. It was approved by European regulators in 2011 as a treatment for ATTR that causes neuropathy, or nerve damage, then rejected by the FDA in 2012 for the same patient population.
The only drug approved for ATTR in the U.S. is patisiran (Onpattro) from Alnylam Pharmaceuticals. The FDA cleared patisiran August 10 to treat hereditary ATTR with neuropathy. Alnylam studied heart patients, too, but did not design its key study to make their outcomes a main goal. Nonetheless, it was a huge milestone for Alnylam and for the Nobel Prize-winning science that led to patisiran.
It’s important to note roughly two-thirds of all ATTR patients have both nerve and heart damage. There could be an overlapping group of U.S. patients eligible for both patisiran and tamafidis, if the latter is approved for hereditary ATTR. Tamafidis has the advantage of being a pill; patisiran requires an infusion, but there are a tangle of questions around prices, insurance coverage, and labeling to sort out.
Another injectable ATTR drug, inotersen (Tegsedi) from Akcea Therapeutics (NASDAQ: [[ticker:AKCA]]), was approved this summer in Europe for hereditary ATTR patients with neuropathy; the FDA could approve it by
