Readout for newly FDA-approved Amvuttra in a rare heart disease is on many Alnylam investors’ mind. But the company figures patience is a virtue.
Alnylam has decided not to perform an optional interim analysis of the closely watched Helios-B trial in transthyretin-mediated amyloidosis with cardiomyopathy (ATTR-CM), the company said in a press release Thursday. Instead, it will wait for a top-line readout that’s expected in early 2024.
Amvuttra got its FDA approval in hereditary ATTR polyneuropathy, a neurological form of ATTR, in June. But the ATTR-CM indication represents a much larger market.
The decision comes shortly after Alnylam’s first-generation RNA interference drug, Onpattro, hit its goal in a phase 3 ATTR-CM trial dubbed Apollo-B. And according to Alnylam president Akshay Vaishnaw, M.D., Ph.D., that trial success contributed to the Helios-B decision.
Alnylam feels “quite emboldened” after looking at detailed data from Onpattro’s Apollo-B trial, which “significantly increased” its confidence that Helios-B could have a positive readout, Vaishnaw said during the company’s third-quarter earnings call Thursday.
Helios-B is different from Apollo-B in multiple ways. While the Onpattro trial uses the six-minute walk test as the primary endpoint, the Amvuttra study uses a hard outcomes endpoint measuring patients’ cardiovascular health status. It’s worth noting that Onpattro didn’t meet its cardiovascular outcomes goal in Apollo-B, but Alnylam said it remains confident in Helios-B because the trial is about twice as big and follows patients nearly three times long, for up to three years.
Two other factors also affected Alnylam’s decision to skip the interim analysis. The study finished enrollment earlier than expected, which means that “any potential acceleration in an approval based on an interim analysis was minimal” compared with a full readout, Vaishnaw said.
Besides, Alnylam wants Helios-B to have the “strongest possible datasets” and doesn't want to mess with the statistics by taking an interim look at data, the R&D chief added.
In addition to the updated Helios-B plan, Alnylam also announced Thursday that it’s having second thoughts about developing RNA interference therapy for Stargardt disease, a rare genetic eye disease that can cause vision loss. Alnylam said it will not launch a phase 3 study of Amvuttra in Stargardt in late 2022 as previously announced.
Alnylam attributed the pause to Biden’s Inflation Reduction Act, which allows Medicare to directly negotiate prices of some high-expenditure drugs. Drugs with one single orphan drug designation is exempt from potential price negotiations, a term that may discourage companies from exploring approvals in additional indications, Alnylam CEO Yvonne Greenstreet noted on the call. Because Amvuttra and Onapttro already has an orphan status in ATTR, an additional orphan label could theoretically open it for potential pricing scrutiny.
The IRA only targets drugs that have high total expenditure on Medicare. Compared with drugs for more prevalent diseases in cancer, cardiovascular and inflammatory fields, it’s expected that a rare disease therapy would not cost equally as much to draw the U.S. government’s attention at least in the first waves of price talks. On the flip side though, it’s also worth noting that some researchers have suggested that the prevalence of ATTR-CM may be underestimated because of low diagnosis rate, and that the disease isn’t rare after all.
Alnylam is still digesting the legislation, but right now it wants to put the Stargardt disease plan on hold to “consider options for the best path forward,” Greenstreet said.
In the meantime, Amvuttra is enjoying quick uptake. In its first full quarter on the market, sales of the new ATTR drug reached $25 million. Amvuttra’s growth might be coming at the cost of Onpattro, as the older ATTR drug only racked up $145 million sales in the third quarter, down from $153 in the second quarter.
Alnylam acknowledged that Onpattro demand in the U.S. has dropped but added that Amvuttra’s strong launch uptake is more than offsetting the decrease, leading to a total ATTR franchise growth of 30% quarter over quarter in the U.S. Outside of the U.S., Alnyalm’s total ATTR sales dropped 5% quarter over quarter, thanks in part to a strong U.S. dollar.
At the end of September, 2,580 ATTR patients worldwide were on one of the two Alnylam products, up from 2,400 three months ago in June, according to Alnylam.