After falling flat with Tresiba, Novo Nordisk desperately needs semaglutide, billed as its biggest growth driver, to live up to expectations. By the end of the year the Danish group could have US and EU approval for its once-weekly GLP-1 agonist, which will be vital for clawing back market share from Eli Lilly.
Novo’s chief science officer, Mads Krogsgaard Thomsen, is confident that the Danish group has the best-in-class agent, but there are reasons to be cautious about the product’s sales potential. One is pricing, with Mr Krogsgaard Thomsen admitting that Novo will only be able to charge a small premium if sema is approved. “We’re not talking about trying to get a 20%, 30% or 40% premium,” he tells EP Vantage.
Another is the fact that, despite a win in the 3,000-patient Sustain 6 cardiovascular outcomes trial, sema is unlikely to get a cardiovascular risk-reduction indication on its label straightaway. “The study was too small,” Mr Krogsgaard Thomsen says. “But we hope to get data in there – which will mean we can go out and tell physicians about it.”
He says Sustain 6 was designed prospectively only to assess non-inferiority and safety, not superiority – nevertheless, it showed a 26% reduction versus placebo in the time to first occurrence of cardiovascular death, non-fatal myocardial infarction or stroke, driven by a 39% decrease in stroke.
“We underestimated the efficacy of sema,” says Mr Krogsgaard Thomsen. “We expected to be in the 10-15% range, but the event rate was higher than we expected, and the difference was bigger than we expected.”
To support a label expansion, Novo plans to start a bigger CV outcomes trial next year in up to 14,000 patients, which should take around a year and a half to enrol. The group had always expected to carry out this study, he adds, but it is a prime example of the size of the investment Novo is making in sema as it seeks to stay ahead of Lilly, which is taking the market by storm with its rival once-weekly GLP-1, Trulicity.
That investment in sema includes a slew of other studies, including the 10-trial Pioneer programme for a once-daily oral version, due to read out next year. This programme features a head-to-head study against Lilly and Boehringer’s SGLT2 inhibitor Jardiance.
|Oral semaglutide phase III trials|
|Study||Setting||Data due||Trial ID|
|Pioneer 1||Vs placebo in type 2 diabetes||Q1 2018||NCT02906930|
|Pioneer 2||Vs Jardiance in type 2 diabetes||Q2 2018||NCT02863328|
|Pioneer 3||Vs Januvia in type 2 diabetes||Q2 2018||NCT02607865|
|Pioneer 4||Vs Victoza in type 2 diabetes||Q2 2018||NCT02863419|
|Pioneer 5||Vs placebo in type 2 diabetes and moderate renal impairment||Q2 2018||NCT02827708|
|Pioneer 6||CV outcomes study in type 2 diabetes||2018||NCT02692716|
|Pioneer 7||Flexible dose adjustment vs Januvia in type 2 diabetes||2018||NCT02849080|
|Pioneer 8||Vs placebo in insulin-treated type 2 diabetes||2018||NCT03021187|
|Pioneer 9||Vs placebo or Victoza in Japanese type 2 diabetes patients||2018||NCT03018028|
|Pioneer 10||Vs Trulicity both in combination with one oral antidiabetic drug in Japanese type 2 diabetes||2018||NCT03015220|
SGLT2 inhibitors, being oral, tend to be used ahead of injectable products like GLP-1s, but oral sema could change this, Mr Krogsgaard Thomsen believes. “Jardiance by no means matches our GLP-1s, but until we have oral sema they have the benefit of a tablet.”
He is confident of getting a result, stating: “When that reads out I would expect superiority on weight and glucose.” If all goes well oral sema should be launched by 2020, he says.
The injectable version still has around 14 years' patent life remaining, he estimates, while the oral version has slightly longer. This helps explain why Novo is going all in on sema – it is also studying the injectable form in obesity and Nash. In the former the drug works by decreasing appetite, Mr Krogsgaard Thomsen believes: “It’s a specific effect on the brain.”
Obesity is becoming ever more important to Novo as pricing pressure continues to hit the diabetes market, with Mr Krogsgaard Thomsen questioning the wisdom of investing in slightly better diabetes drugs that will not command a premium. “It’s difficult to argue that we should spend billions creating a somewhat better version of Tresiba. It won’t fly,” he says.
A phase II study in obesity recently found nearly 14% weight loss with sema, versus 2% with diet and exercise alone – phase III development is slated to start next year.
|How sema stacks up: top diabetes products in 2022|
|Annual WW sales ($m)|
|1||Trulicity||Eli Lilly||GLP 1 agonist||Marketed||926||3,872||27%|
|2||Victoza||Novo Nordisk||GLP 1 agonist||Marketed||2,979||3,295||2%|
|3||Tresiba||Novo Nordisk||Insulin analogue||Marketed||603||2,708||28%|
|4||Januvia||Merck & Co||DPP IV inhibitor||Marketed||3,908||2,672||-6%|
|5||NovoRapid||Novo Nordisk||Insulin analogue||Marketed||2,964||2,509||-3%|
|6||Semaglutide||Novo Nordisk||GLP 1 agonist||Filed||-||2,422||n/a|
|8||Humalog||Eli Lilly||Insulin analogue||Marketed||2,769||2,020||-5%|
|10||Janumet||Merck & Co||DPP IV inhibitor & biguanide||Marketed||2,201||1,777||-4%|
|25||Semaglutide Oral||Novo Nordisk||GLP 1 agonist||Phase III||-||707||n/a|
|DPP: Dipeptidyl peptidase; GLP: Glucagon-like peptide. Source: EvaluatePharma.|
Sema’s molecular structure means that it can cross the blood-brain barrier more easily than Novo’s older GLP-1 agonist Victoza, according to Mr Krogsgaard Thomsen. As well as potentially improving its efficacy in obesity, this might also make sema useful in Alzheimer’s or Parkinson’s diseases. "If academics can help us show an effect, we would embrace it.”
Meanwhile Trulicity is a “huge molecule” so cannot get into the brain, he says. “This is why sema showed twice the weight loss versus Trulicity in Sustain 7.”
However, Lilly is a formidable opponent, and Trulicity is still forecast to be the biggest diabetes therapy in 2022, according to EvaluatePharma sellside consensus, despite being beaten by sema in Sustain 7 (Novo and Lilly head for diabetes pricing battle, August 18, 2017).
“In my view it’s us and Lilly competing. We are stronger on the GLP-1 and insulin side; they are strong because of the breadth of their portfolio,” says Mr Krogsgaard Thomsen.
“Lilly is overtaking Sanofi as the world’s number-two diabetes company – but they’re not going to overtake us.” Novo needs sema to deliver if it wants to keep it this way.
|Top-three diabetes players|
|Company||Sales ($bn)||Market share||Market rank|