Upcoming events – FDA decisions loom for Alnylam and Pfizer

The companies hope that the US regulator approves patisiran and lorlatinib.

Welcome to your weekly digest of approaching regulatory and clinical readouts. The PDUFA date for Alnylam’s transthyretin amyloidosis candidate patisiran is two weeks away, and Alnylam is sitting pretty. If approved, as seems likely, the product will be first to market after the FDA extended the review period for Tegsedi, a rival from Ionis.

Pfizer’s next-generation Alk inhibitor lorlatinib is also due an FDA decision some time in August. The project, a follow-on to the group's Xalkori, is expected to bring in 2024 sales of $263m, according to EvaluatePharma's sellside consensus, and approval, sought for NSCLC patients who have not responded to other Alk inhibitors, seems probable.


Hereditary transthyretin amyloidosis is caused by mutations in the TTR gene, causing abnormal amyloid proteins to accumulate and damage organs and tissues. Patisiran is an RNA interference project intended to block the production of malformed transthyretin.

In May the FDA delayed the approval date for Ionis’s rival RNAi amyloidosis project Tegsedi (inotersen) from July to October, saying it needed more time to evaluate the company’s responses to questions about the submission. First-mover advantage thus passed to Alnylam, since patisiran is scheduled for an approval decision by August 11.

This decision will almost certainly be positive given the spectacular results in patisiran’s phase III trial, Apollo. Patisiran did not slow patients’ decline on the modified Neuropathy Impairment Score +7 but actually reversed it, prompting Alnylam to claim that the therapy might improve neurological function in most patients (Alnylam celebrates a successful Apollo mission, September 20, 2017).

Thus the only question is the label. Apollo recruited patients whose amyloidosis had caused polyneuropathy, but the trial’s results showed signs of improvement on cardiac endpoints, possibly giving the FDA scope to grant a label covering patients with cardiac symptoms too.

Alnylam vs Akcea/Ionis in amyloidosis
    Global sales ($m)
Product Company 2018 2020 2022 2024
Patisiran Alnylam 27 374 796 1,092
ALN-TTRsc02 Alnylam - 17 330 793
Tegsedi Akcea (Ionis) 4 147 344 736
Source: EvaluatePharma.

Alnylam today got a boost with a positive opinion from Europe’s CHMP, but this only came in patients with polyneuropathy. The product will be marketed there under the brand name Onpattro if approval follows – usually a given following a CHMP thumbs up.

Analysts see patisiran beating Tegsedi from the off, and even reckon that Alnylam’s follow-up ALN-TTRsc02 will outsell Tegsedi in 2024. Doubtless Ionis will do what it can to compete on price, but 2024 consensus forecasts from EvaluatePharma suggest that only one of the rival projects will be a blockbuster in six years’ time.

Study Trial ID
Apollo NCT01960348

Follow-on Alk

Back in 2011 Pfizer seized first-mover advantage when Xalkori became the first drug approved for the 3-7% of lung cancer patients who harbour an Alk genetic rearrangement.

This niche has since become competitive, with Roche’s Alecensa and Novartis’s Zykadia also now available first-line. Lorlatinib represents Pfizer’s own next-generation strategy, and its regulatory filing was accepted by US, EU and Japan authorities in February, with the FDA setting an action date in August.

The filing seeks use in Alk-positive NSCLC patients who have failed one or more other Alk inhibitors. This rationale is driven by the view that lorlatinib covers the broadest range of Alk resistance mutations, including G1202R, the most common resistance mechanism to second-generation Alk inhibitors.

At the AACR conference Pfizer presented lorlatinib data showing a 69% overall remission rate among 59 Xalkori progressors. In the same trial, in patients who had progressed on an Alk inhibitor other than Xalkori and subjects who had failed two or more Alk inhibitors, the remission rates were 33% and 39% respectively.

The Alk setting has become crowded, so follow-on projects must differentiate themselves. Xalkori has one major drawback in its lack of CNS penetration, meaning that it cannot tackle brain metastases; lorlatinib, along with the other second-generation Alk inhibitors, does not have this problem. 

More second-generation drugs could soon join the others in first-line use: just this week Takeda’s Alunbrig, approved in the US in Xalkori failures in April, hit its primary progression-free survival endpoint in Alta-1L, a first-line head to head study against Xalkori.

Pfizer is taking a similar approach with the first-line Crown study, which could give its Xalkori franchise a handy lifecycle extension. 

Lorlatinib trials in Alk-mutated NSCLC
Study Detail Trial ID
B7461001 Phase II, pts who have failed 1 or more Alk inhibitors NCT01970865
Crown Phase III, first-line pts, lorlatinib vs Xalkori NCT03052608

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