Evidence of the Covid-19 pandemic’s impact on US approval timelines is mounting, making those with pending regulatory decisions even more nervous than normal. Novartis is one such developer, awaiting news on whether its new lipid-lowering agent, inclisiran, will make it across the line before the end of the year.
During an investor event yesterday company executives said a paper-based inspection of a third-party manufacturing facility in Italy was still outstanding, but that they remained confident of inclisiran getting the nod by its Pdufa date "or shortly thereafter". After shelling out $9.7bn on The Medicines Company last year for the project, Novartis and its investors will be keen to see inclisiran getting to market as soon as possible.
|% of market cap||3%||8%|
|Event||US approval action|
Inclisiran, which is now branded Leqvio, targets PCSK9 via RNA interference. Impressive LDL cholesterol-lowering was achieved in phase III and, importantly, this looks to be in line with Amgen’s Repatha and Sanofi/Regeneron’s Praluent; both are monoclonal antibodies targeting PCSK9.
Safety also looked clean; however, the RNAi technology by which the agent works is very novel, which always raises the risks for approval. Still, in Europe the CHMP issued a positive opinion in October, which is an encouraging omen for the US decision.
Leqvio’s main advantage is convenience: it is given via twice-yearly subcutaneous injection, while Repatha and Praluent are subcutaneously injected every two weeks or monthly.
On the other hand both Repatha and Praluent are self-administered, while Leqvio needs to be given at the physician’s office. In light of the ongoing Covid-19 pandemic this could increase barriers to adoption.
A major remaining test of the project is a vast cardiovascular outcomes study, Orion-4, although that will not report until 2025.
|Inclisiran's phase III programme|
|Orion-5||56||Homozygous FH||H2 2021|
|Orion-8||2,991||ASCVD, hetero and homozygous FH||Primary completion Aug 2021|
|Orion-4||15,000||ASCVD (CV outcomes trial)||Primary completion Dec 2024|
|*Between-group difference (inclisiran vs placebo) at day 510. ASCVD=atherosclerotic cardiovascular disease. FH=familial hypercholesterolaemia. Source: clinicaltrials.gov & company releases.|
Approval is only the first hurdle for Leqvio, however. Repatha and Praluent have been huge commercial disappointments, largely because the price at which they were initially launched was too high.
Novartis will be highly motivated to avoid a similar misstep. The US pricing watchdog Icer released a draft report in November noting that Leqvio would need to come in at $5,481 to hit a standard cost-effectiveness threshold of $150,000 per quality-adjusted life year in patients with established atherosclerotic cardiovascular disease.
In specific patient subgroups, such as those with heterozygous familial hypercholesterolaemia, the threshold drug price could be higher. The average annual net cost of Praluent and Repatha is $5,644, according to Icer.
Sales of Leqvio are expected to hit $2bn by 2026, which would make the product as big as well-established Repatha that year, according to forecasts from EvaluatePharma. For this to happen Novartis needs to get the price and the launch right – and for US approval to come without delay.