Novo Nordisk’s disappointing fourth quarter highlighted just how tough the diabetes segment has become. While the Danish company believes that it can keep growing in diabetes by developing differentiated medicines, expanding into new areas would give it a much needed boost.
Novo’s next big bet is obesity, where it already markets liraglutide as Saxenda and will soon begin a phase III trial of its once-weekly injectable form of semaglutide. The company also has six projects in phase I that could eventually pave the way for a combination approach (see tables below).
GLP-1 agonists like liraglutide and semaglutide are thought to work in obesity by reducing appetite, “but there are also mechanisms that increase how you burn energy – if you can combine those there is the potential to do even better than GLP-1 monotherapy,” Novo’s chief executive, Lars Fruergaard Jørgensen, tells EP Vantage.
|Novo's obesity pipeline|
|Project||Mechanism||Obesity impact||Status||2018 expected status|
|Semaglutide||GLP-1 agonist||Appetite reduction||Phase II||Phase III|
|G530L*||Glucagon analogue||Appetite reduction + energy expenditure||Phase Ib||Phase II|
|AM833||Amylin analogue||Appetite reduction||Phase Ib||Phase II ready|
|PNY1562/NN9747**||Peptide YY analogue||Appetite reduction||Phase Ib||Phase Ib|
|NN9499||FGF 21 analogue||Energy expenditure||Phase Ia||Phase Ib|
|NN9277||Glucagon and GLP-1 co-agonist||Appetite reduction + energy expenditure||Phase Ia||Phase Ib|
|NN9423||Glucagon, GLP-1 and GIP tri-agonist||Appetite reduction + energy expenditure||Phase Ia||Phase Ib|
|*Phase I in combo with liraglutide and phase II planned in combo with semaglutide.|
|**Phase Ib completed with monotherapy, phase Ib in combo with semaglutide planned.|
|Source: Company 2017 annual report; capital markets day presentation 2017.|
One approach that Novo is testing has been tried before without success: AM833 is an amylin analogue, as is Amylin Pharmaceuticals’ pramlintide, whose development was discontinued in obesity in 2011. Pramlintide is approved for diabetes as Symlin.
As for the other mechanisms that Novo is evaluating, the competition appears to be limited but there are a handful of potential challengers. The most advanced is Sanofi’s glucagon and GLP-1 co-agonist SAR425899, which this year is due to move into phase III in obesity and start proof-of-concept trials in Nash.
Sanofi also has a glucagon, GLP-1 and gastric inhibitory polypeptide (GIP) tri-agonist, SAR441255, but this is in preclinical development.
Meanwhile, in the fibroblast growth factor (FGF) 21 class Bristol-Myers Squibb’s BMS-986036 – licensed from Ambrx and also known as ARX618 – posted a phase II win in Nash last April.
If Novo can crack the obesity problem it could reap the rewards. Around 650 million people worldwide are affected but only 2% are currently receiving treatment, according to the company.
Commercial potential of oral drugs has been limited by fears about their potential to be abused, which has resulted in them having to be dosed at levels that leave virtually no therapeutic window. The lack of options is illustrated by the fact that Glaxosmithkline’s over-the-counter drug Alli still features in the top five in spite of its gastrointestinal side effects.
|Top five obesity drugs in 2022|
|Product||Company||Mechanism||Approval||2022e obesity sales ($m)||Placebo-adjusted weight loss in pivotal trial|
|Saxenda||Novo Nordisk||GLP-1 agonist||2014||927||3.7-5.2% at 56 weeks|
|Contrave||Orexigen||Norepinephrine, dopamine reuptake inhibitor & opioid antagonist||2014||258||2.0-4.1% at 56 weeks|
|Alli||Glaxosmithkline||Lipase inhibitor||2007||182||3% at 1 year|
|Qsymia||Vivus||Adrenoceptor agonist & anti-convulsant||2012||87||3.5-9.4% at 1 year|
|Belviq||Eisai||Serotonin agonist||2012||68||3.3% at 1 year|
|Source: EvaluatePharma; product labels.|
Mr Fruergaard Jørgensen points to the “more acceptable safety profile” of GLP-1 agonists versus older obesity medications, which is no doubt helping drive uptake of Saxenda – Novo’s product is the biggest obesity drug, and by 2022 will have extended its lead by some distance, according to EvaluatePharma sellside consensus.
Semaglutide could raise the bar further in terms of efficacy, the chief exec believes. “In phase II [sema] showed a weight-lowering profile double that of Saxenda. There are different types of surgical interventions – some are more dramatic than others – but we believe we could do as well as some of the bariatric surgeries.”
Any medicines that come close to the efficacy of surgery could expand the sector by providing a cheaper and less invasive alternative. Interestingly, Mr Fruergaard Jørgensen notes that bariatric surgery is currently reimbursed by Medicare while obesity drugs are not. “We’d like to create the case that a less invasive medical intervention should be reimbursed.”
A 4,500-patient pivotal trial of semaglutide in obesity, called Step, is due to start this year and complete in 2020; Novo also plans to begin a 12,500-patient trial of cardiovascular outcomes in obesity, Select.
Further into the future, Novo could “potentially” look at oral semaglutide in obesity, Mr Fruergaard Jørgensen says. But for now the focus for the oral project is diabetes, where Novo recently reported positive data from its first pivotal trial (Novo Nordisk prepares to swallow its rivals for breakfast, February 22, 2018).
Novo is also evaluating injectable semaglutide in Nash, but is further behind here, with a phase II trial recruiting. Enrolling patients has been problematic, Mr Fruergaard Jørgensen admits, partly owing to the need to carry out invasive liver biopsies. “All companies struggle in getting patients recruited – it’s going a bit slower than we would’ve liked. But we’ll get it done.”
Semaglutide’s promise in Nash is linked to its impact on weight, Mr Fruergaard Jørgensen believes. “The first weight and fat you lose is around the organs, which helps in the case of Nash,” he says, adding that the product’s anti-inflammatory effect might also be important here.
For a long time the mainstay of obesity treatments has been diet and exercise. Mr Fruergaard Jørgensen thinks that technology, combined with medication, could have a role to play here, and says that Novo is open to working with developers of apps that support patients with lifestyle changes.
Still, lifestyle interventions rarely work over the long term, and pills have had little impact. If Novo can develop injectable therapies that are better tolerated and more efficacious than current options, drugs could finally have a role to play.
|Injectable semaglutide studies in obesity and Nash|
|Obesity & CV disease||Select||N/A||?|
|Nash||Phase II trial||NCT02970942||Nov 2019|