Pfizer’s tafamidis for the rare disease transthyretin amyloidosis (ATTR) has hit the mark in a phase 3 trial, setting up regulatory filings and a challenge to rival ATTR drug developers Alnylam and Ionis.

The big pharma company unveiled results from the ATTR-ACT trial at the European Society of Cardiology (ESC) meeting in Munich, Germany, this week, which showed tafamidis significantly reduced all-cause mortality by 30% and cardiovascular-related hospitalizations by 32% compared to placebo over a 30-month period. The study has also been published in the New England Journal of Medicine.

On the face of it that looks like a big win for Pfizer, as analysts at Credit Suisse indicated ahead of the ESC that even a 10-15% reduction in mortality would be "practice-changing" and investigators were "looking for 20-25%."

Professor Perry Elliot, ATTR-ACT study investigator and chair of cardiovascular medicine at University College London, commented that "any study which shows a 30% reduction in mortality, as demonstrated in ATTR-ACT, is remarkable. Tafamidis therefore has the potential to help people with this condition live longer and live better."

Pfizer says it is in discussions with regulatory authorities about filing tafamidis for approval in ATTR cardiomyopathy based on the study, just a couple of weeks after Alnylam started rolling out its new ATTR polyneuropathy product Onpattro (patisiran), and according to Barclays analysts the drug could get approval in 2019. Meanwhile, Ionis and Akcea are hoping for a green light from the FDA in October for their candidate Tegsedi (inotersen), which has just been approved for ATTR polyneuropathy in Europe.

The size of the mortality improvement in ATTR-ACT means that tafamidis is looking like a potent contender in the rare disease, which is caused when the protein transthyretin becomes unstable and misfolds, leading to the formation of amyloid which is deposited in the heart. This causes the heart muscle to become stiff and results in heart failure.

Pfizer has set up an expanded access program to make its drug available to patients with cardiomyopathy caused by ATTR (ATTR-CM) before regulatory approval. Patients with myopathy survive an average of three to five years after diagnosis, and there are no approved drugs to improve survival with therapy limited to managing symptoms.

While on the face of it tafamidis and Onpattro are addressing different manifestations of the disease, patients often have both symptoms and so could be in line to receive either drug, say the Credit Suisse analysts. And tafamidis is already approved for polyneuropathy in Europe (as Vyndaqel), although it was rejected for that indication by the FDA in 2012.

"If approved, tafamidis would be the first disease-modifying therapy to have a specific indication for treating TTR-CM and the only therapy to have clinical outcome data, which in addition to being an oral therapy should set it apart from Alnylam’s Onpattro."

They add however that some physicians they have spoken to view Alnylam’s drug as safer and may use it for will "use patisiran to treat cardiomyopathy while getting reimbursement for polyneuropathy," which may go some way to explain why Pfizer's shares were down 2% in early trading, while Alnylam shot up 14%. They are predicting $600 million in peak sales for tafamidis in ATTR-CM in 2026.

Meanwhile, Umer Raffat of EvercoreISI said ahead of the ESC that investors were looking for around a 25%  improvement in outcomes, evidence that the benefit was not driven by hospitalizations and an effect on patients with a TTR gene mutation as well as those with so-called ‘wild-type’ disease, where the protein becomes unstable with age.

Judging by the ESC presentation, tafamidis seems to have met all three of those expectations with principle investigator Professor Claudio Rapezzi, of the University of Bologna, Italy noting that "the extent of the tafamidis benefit was independent of etiology (wild type vs hereditary) and drug dose (80 vs 20 mg)."

It’s worth mentioning that ATTR is chronically under-diagnosed—capturing perhaps as low as 1% of the population—and the availability of multiple products being pushed by their developers will drive awareness and could make it a growth market, with plenty of commercial potential for all players. And there may be the potential for combination use down the line.

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