FDA seeks safety data for Lilly's oral GLP-1 Foundayo

The FDA may have approved Eli Lilly's oral weight-loss drug Foundayo in record time, but it still needs to see more safety data – including for liver and cardiovascular side effects.

Foundayo (orforglipron) is one of the first medicines to be approved after going through the FDA's super-rapid national priority review voucher programme, reducing the FDA's review timeline to a matter of weeks.

The recently released approval letter sent to Lilly for the oral GLP-1 drug gives some insights into how the FDA will regulate new medicines approved via this rapid review pathway in practice.

Specifically, the FDA is requiring Lilly to complete various post-marketing clinical trials of Foundayo to look at the potential risks for various side effects, including cardiovascular events, liver toxicity, and delayed gastric emptying (gastroparesis), as non-clinical or observational studies will not be sufficient.

That means Lilly must complete an ongoing clinical trial – ACHIEVE-4 – which is comparing Foundayo to insulin glargine in patients with type 2 diabetes and overweight or obese who are at elevated cardiovascular risk.

That study is due to generate results shortly, and Lilly is required to perform an analysis of major adverse cardiovascular events (MACE), i.e., cardiovascular death, non-fatal myocardial infarction, hospitalisation for unstable angina, and non-fatal stroke, as well as the potential for drug-induced liver injury (DILI).

The regulator is also asking the drugmaker to carry out a clinical pharmacology trial using ultrasound to measure the effects of both temporary withholding of Foundayo and fasting duration on retained gastric contents, to see if it can lead to gastroparesis – a potentially serious side effect that can lead to vomiting and entry of stomach contents into the airway.

Lilly must also carry out a milk-only lactation study in lactating women who have received a dose of Foundayo to assess concentrations of orforglipron in breast milk, according to the FDA.

Meanwhile, it also wants Lilly to conduct prospective, registry-based studies looking at safety in children and adolescents, pregnancy, and medullary thyroid cancer, as simply monitoring spontaneous postmarketing adverse events is not considered adequate for these purposes.

Lilly has also been asked for "enhanced pharmacovigilance" on Foundayo, with all serious unexpected domestic and foreign postmarketing cases of DILI attributable to the drug submitted within 15 days for a five-year period.

Lilly started selling Foundayo in the US earlier this month and is locked in a marketing battle with Novo Nordisk, whose oral formulation of GLP-1 drug Wegovy (semaglutide) was launched earlier this year.

The two companies have been trading blows over the relative merits of their two therapies, with Lilly emphasising that Foundayo can be taken any time of day, without food or water restrictions, while Wegovy has to be taken first thing in the morning on an empty stomach, half an hour before eating or drinking.

Novo Nordisk, meanwhile, has highlighted restrictions that appear in Foundayo's label, including that the drug should not be taken alongside oral birth control or the widely used cholesterol-lowering drug simvastatin, and is also claiming greater efficacy in achieving weight loss with oral Wegovy and approval of the injectable version of the drug for cardiovascular risk reduction.