Ahead of Alnylam's key heart disease readout, experts say Pfizer rival would be hard to displace

As a closely watched readout from Alnylam Pharmaceuticals' Amvuttra in the rare heart disease transthyretin amyloid cardiomyopathy (ATTR-CM) is expected in a few weeks, experts suggested the RNA silencer may have a hard time challenging a Pfizer med.

The incumbent Pfizer drug, tafamidis, is still expected to maintain the lion’s share of the ATTR-CM market even if Amvuttra’s HELIOS-B were to be positive, two cardiology experts at large academic medical centers said at a Leerink Partners event, according to a Friday note to clients.

Approved by the FDA in 2019 under the brand names Vyndaqel and Vyndamax, tafamidis will likely remain as the standard ATTR-CM therapy “given ease of use, pristine safety and accumulated real-world data,” the experts said, as summarized by Leerink’s analysts.

For Amvuttra, its key appeal lies in its potential as an add-on therapy. But that needs to be proven by clinical data from the HELIOS-B trial, and showing a statistically significant benefit on top of tafamidis is a very high bar, the experts said.

Tafamidis works by stabilizing transthyretin, whereas Amvuttra acts as an RNA silencer to reduce the production of the disease-causing protein. Although both experts acknowledged Amvuttra’s mechanism of action holds an advantage over stabilizers, they also emphasized that the cardiology field has moved away from over-interpreting the biological rationale but is instead focused on clinical data. There, Amvuttra faces a tough battle.

In the phase 3 ATTR-ACT trial, tafamidis slashed the risk of death by 30% compared with placebo. At the time of the mortality analysis, 29.5% of patients who took the Pfizer drug had died, compared with 42.9% in the control group.

Alnylam has argued that Amvuttra could compete directly with tafamidis. One expert agreed that Amvuttra could be a contender for first-line treatment if it shows similar death reduction as tafamidis did. However, showing a big survival benefit has become increasingly difficult as improved care has made patients less sick than they were when the ATTR-ACT trial was conducted.

To enhance the HELIOS-B trial to enable “the best demonstration” of Amvuttra, Alnylam in February tweaked the trial design and pushed back its expected readout to late June or early July. The extended follow-up is expected to give the trial more statistical power to show a significant benefit in lowering cardiovascular-related events. The last-minute adjustment was viewed as Alnylam acknowledging—and proactively trying to derisk—the data challenge facing Amvuttra.

The two key opinion leaders’ opinions matched the results from a Leerink survey of 57 ATTR-treating doctors last year. Doctors believed that tafamidis would largely be able to keep a 60%-plus share of the ATTR-CM market over the next few years, the survey found. About 68% of polled doctors said they would only try Onpattro—an older RNA silencer that was later rejected by the FDA in ATTR-CM out of efficacy concerns—after failure on tafamidis.

About two-thirds of ATTR-CM patients with NYHA class 2 disease could be stabilized by tafamidis, according to the two experts cited in Leerink’s Friday note. These patients are generally considered to have better prognosis and may make up the majority of clinical trials.

The two experts believe that Amvuttra, if eventually approved, will more likely be used in combination with tafamidis even if it doesn’t show a statistically significant survival benefit. A benefit in disease stabilization as reflected in hospitalization rate will be enough for this use, they argued. About 40% of patients in the HELIOS-B trial are on background tafamidis, according to Alnylam.

Still, a generally healthier patient population will make showing a large benefit difficult for Amvuttra. Besides, whether payers will support the combo approach remains to be seen.