GLP-1 agonists have already enjoyed huge success in type 2 diabetes, and developers hope that these agents will soon prove their worth in related conditions. Novo Nordisk has much riding on two sideways steps for this mechanism – obesity and Nash – and data in both settings are due in the coming months.
In the liver disease Nash the proven cardiovascular benefits of GLP-1s, as well as certain other beneficial effects they are thought to bestow, could make these drugs ideal candidates. Novo is running a handful of mid-stage studies with semaglutide, its once-weekly agent, to test the theory; given that Nash is a huge focus for many in biopharma, these results will be of wide interest.
Partly this is because GLP-1s are thought likely to form the backbone of future Nash combinations. The failure of several novel mechanisms – and underwhelming results in those deemed to have succeeded – have shown that to have a real impact more than one mechanism will be required.
Speaking at a media roundtable in December Novo’s chief executive, Lars Fruergaard Jørgensen, echoed this opinion, adding that as various competitor approaches fell by the wayside interest in the Danish company’s work grew.
“We sense there is a big appetite for collaborating with us. Because of the weight-lowering profile of sema and some of the anti-inflammatory properties it has a role to play in Nash,” he told journalists. “From an in-house and business development focus there could be additional mechanisms for us to have that are complimentary to sema, so we can have broader presence. We are actively scouring and researching to see what they might be.”
|Novo's Nash pipeline|
|Stage||Project||Mechanism of action||Notes|
|Phase II||Ozempic||GLP-1 receptor agonist|
|Phase I||NN9500||FGF-21 stimulant|
|Preclinical||UD-014||SSAO inhibitor||Licensed from Ube Industries in Nov 2019|
|Research project||DCR-NOVO1||RNAi therapeutic||Licensed from Dicerna in Nov 2019 for $175m up front|
The Danish company has struck a couple of deals here; however, it seems that earlier-stage transactions, rather than moves that might help Novo get to market more quickly, are more likely to emerge in the future.
Mr Jørgensen said Novo had looked at whether it should collaborate on or take out a more advanced project. “We decided not to because we believe we have a longer-term play, and a better play, [in semaglutide],” he said.
This might disappoint shareholders in companies with advanced Nash assets – Genfit and Madrigal in particular – though surprisingly positive phase III results could change everything. First of all, though, semaglutide needs to show its worth.
The once-weekly injected drug, sold as Ozempic in diabetes, is in three trials, one under a Gilead collaboration testing various combination regimens. The first dataset and arguably the most important will emerge from the large three-dose study Novo is running versus placebo, due in the second quarter.
This has enrolled 320 patients with biopsy-confirmed Nash and stage 1-3 fibrosis, and tests Nash resolution without worsening of fibrosis as primary endpoint.
|The semaglutide Nash programme|
|NCT02970942||320||Three doses vs placebo; primary measure Nash resolution w/o worsening of fibrosis||Q2 2020|
|NCT03987074||109||Semaglutide, firsocostat, cilofexor combo study; Gilead collaboration||Mid-2020|
|NCT03987451||69||Semaglutide vs placebo; Nash with cirrhosis; primary measure fibrosis improvement w/o Nash worsening||2021|
|Source: clinicaltrials.gov, company statements.|
GLP-1s are thought more likely to be useful in Nash resolution than improving fibrosis. Various studies have shown that these agents can improve markers of liver function and have beneficial effects on liver inflammation and steatosis, all of which are tracked in clinical studies to assess Nash resolution.
A phase II study of liraglutide – Novo’s once-daily GLP-1, Victoza – points at what semaglutide should be capable of, albeit in a very small number of patients. Nine of 23 patients had resolution of Nash versus two of 22 in the placebo group, while only two in the active arm registered progression of fibrosis, against eight in the control.
Showing a benefit on fibrosis would be a huge win for Novo. Analysts at Stifel commented recently that if semaglutide achieved this it could be perceived as a negative for most standalone Nash companies, given that the drug has already demonstrated a positive benefit on diabetes and cardiovascular outcomes.
Of course the Nash has space has reliably disappointed over the past couple of years, and the disease has proven itself much tougher than expected. But, with a well-known mechanism, Novo has a better chance than many others to make a mark.