Alnylam Pharmaceuticals has had to abandon its plans to pursue a label expansion of Onpattro (patisiran) after the US Food and Drug Administration (FDA) issued a complete response letter (CRL).

The CRL was issued regarding the New Drug Application (sNDA) for Onpattro for the treatment of the cardiomyopathy of transthyretin mediated (ATTR) amyloidosis. The letter cited that there was insufficient evidence to demonstrate Onpattro’s clinical efficacy in treating cardiomyopathy caused by the wild-type or hereditary ATTR amyloidosis, therefore, the drug “could not be approved in its present form”.

Alnylam was quick to add that the CRL did not identify any issues with the clinical trial or drug quality and manufacturing.

The CRL is a complete turnaround from the positive recommendation Onpattro received from an FDA Advisory Committee (AdCom) panel in September regarding the label expansion. The panel voted nine to three in favour of approving the therapy for the cardiomyopathy condition.

Onpattro is an RNA interference (RNAi) therapy that was first approved by the FDA for the treatment of hereditary ATTR amyloidosis polyneuropathy in 2018. Onpattro reduces the amount of mutant or wild-type transthyretin (TTR), a transport protein present in the liver, by silencing the mutant TTR mRNA in hereditary ATTR amyloidosis.

ATTR amyloidosis is a rare condition caused by the build-up of TTR, characterised by clumps in the body’s organs and peripheral nerves. In the case of polyneuropathy, TTR build-up takes place in the peripheral nerves, thereby causing symptoms like tingling, numbness, or pain in the hands and feet, whereas in the case of cardiomyopathy, these TTR clumps are deposited in the cardiac tissue leading to heart failure.

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Following the CRL, the company stated that it will “no longer pursue an expanded indication for Onpattro in the US”.

Alnylam is also investigating another RNAi therapy, vutrisiran, for treating cardiomyopathy of ATTR amyloidosis in a Phase III trial (NCT04153149). The top-line results from the trial are expected in early 2024.

Onpattro’s sNDA application was supported by data from the placebo-controlled Phase III trial (NCT03997383). The study met its primary endpoint by showing a significant difference in functional capacity, as measured using the 6-Minute Walk Test (6-MWT), compared with the placebo.

In July, Roche licensed Alnylam’s hypertension RNAi therapy, zilebesiran, for an upfront payment of $310m (SFr281.99m). The latter is also entitled to milestone and royalty payments for this deal. Both companies will share the marketing costs and profits from the drug in the US, whilst Roche will be solely responsible for these outside the US.