With Pfizer's 'pipeline surprise,' there's a new kid on the ATTR block

Tafamidis has been approved in the EU for TTR familial amyloid polyneuropathy since 2011, but the FDA rejected its application in 2012. (Michal Jarmoluk)

Pfizer reported positive results from a phase 3 trial of tafamidis in transthyretin cardiomyopathy, a form of the rare disease transthyretin amyloidosis (ATTR). The news drove down stocks for Alnylam and Ionis, both of which are developing drugs for hereditary forms of ATTR: patisiran and inotersen. 

The ATTR-ACT trial compared an oral daily dose of 20 mg or 80 mg of tafamidis to placebo. It involved 441 patients with hereditary transthyretin cardiomyopathy or the wild-type form of the disease. Topline data show that tafamidis met its primary endpoint, demonstrating a statistically significant decrease over placebo in all-cause mortality and frequency of cardiovascular-related hospitalizations at the 30-month mark, Pfizer said.

Evercore analyst Umer Raffat called the data "a very rare late stage pipeline surprise" that even for a company the size of Pfizer, "may be at least ~4% accretive to EPS ($0.11/share for ~$1B in sales)." Raffat went on to clarify that his $1 billion estimate is for tafamidis as a cardiomyopathy drug, without considering its potential as a broader TTR drug.

ATTR is caused by a mutation in the TTR gene, resulting in abnormal TTR proteins that fold incorrectly. Symptoms usually include neuropathy as well as cardiomyopathy. There is no approved treatment yet for TTR cardiomyopathy.

“These topline results are important for people with transthyretin cardiomyopathy and bring us one step closer to realizing the potential for a new treatment for those in desperate need,” said Brenda Cooperstone, M.D., senior vice president and chief development officer of rare disease at Pfizer Global Product Development. "We look forward to sharing the detailed results of the study with the cardiovascular community and discussing these data with health authorities to determine an appropriate regulatory path forward.” 

It hasn't been all smooth sailing for Pfizer, which acquired tafamidis in 2010. It filed for approval based on data from a single study in TTR familial amyloid polyneuropathy (TTR-FAP), which resulted in a rejection from the FDA in 2012. The drug is marketed as Vyndaquel in the European Union, where it is approved to delay peripheral neurologic impairment in patients with stage 1 TTR-FAP.

The news is a double-edged sword for other companies working on TTR. Just yesterday, Alnylam unveiled late-phase data showing patisiran improved cardiomyopathy. And last September, a phase 3 readout showed that the treatment beat out placebo in improving neuropathy impairment.

So, "on the one hand," wrote Evercore's Steven Breazzano, the tafamidis data is "validating for patisiran," suggesting a study in the cardiomyopathy indication "will also succeed (given the robust benefit in the FAP population,) but also enables a competitor as tafamidis is now potentially positioned for approval with an outcomes label."

Alnylam and Ionis both presented phase 3 data in November, with patisiran's 34-point improvement against placebo edging out inotersen's 20-point difference. 

Having rejigged its deal with Sanofi to to take full control of patisiran, Alnylam expects to commercialize the treatment for hereditary ATTR this year, while Ionis recently teamed up with its spinoff, Akcea, to bring inotersen to market. The collaboration came seven months after its previous partner, GlaxoSmithKline ditched Ionis as the pair were closing in on a regulatory filing for inotersen.

Editor's note: This story has been updated to include analyst comments.