Novo Nordisk Advances Semaglutide for NASH and Obesity with FDA Breakthrough Therapy Designation and Near 20% Weight Loss in Phase 3 Trials

On October 31, Novo Nordisk announced its financial results for the first three quarters of the year. During the quarterly earnings conference call, the company highlighted that its blockbuster glucagon-like peptide-1 (GLP-1) receptor agonist, semaglutide, not only continued to demonstrate strong performance in the treatment of type 2 diabetes but also achieved positive progress in the treatment of non-alcoholic steatohepatitis (NASH) and obesity. Semaglutide has been granted Breakthrough Therapy Designation by the U.S. FDA for the treatment of NASH. Furthermore, it met the primary endpoints in all four Phase 3 clinical trials for the treatment of obesity. Novo Nordisk plans to submit a regulatory application to the FDA for semaglutide in the treatment of obesity using a Priority Review Voucher.

In addition, the company’s investigational innovative obesity therapy AM833 and ziltivekimab, an investigational IL-6 antibody aimed at reducing the risk of major adverse cardiovascular events, have also yielded positive results in clinical trials. Below, we examine the latest performance of Novo Nordisk’s R&D pipeline.

Semaglutide Receives FDA Breakthrough Therapy Designation; Phase 2 Clinical Trial Results Are Positive

Novo Nordisk announced on a conference call that the U.S. FDA has granted breakthrough therapy designation to semaglutide for the treatment of patients with non-alcoholic steatohepatitis (NASH). This means that the FDA will work more closely with Novo Nordisk to advance the development and review process of semaglutide for NASH. As a monotherapy, semaglutide achieved positive results in Phase 2 clinical trials for NASH, significantly resolving histological features of NASH without worsening liver fibrosis compared to placebo. Among patients receiving the highest dose of semaglutide, 66.7% experienced resolution of NASH histological features, compared to 22.9% in the placebo group. This clinical endpoint is one of the two primary endpoints considered by the U.S. FDA and the European Medicines Agency (EMA) when reviewing NASH therapies.

▲Semaglutide significantly improves the resolution of NASH symptoms in patients, potentially helping to prevent disease progression (Image source: Novo Nordisk official website)

Moreover, semaglutide also demonstrated a trend toward providing clinical benefit in improving hepatic fibrosis in patients, with fewer NASH patients experiencing progression of liver fibrosis compared to placebo. Among patients receiving the highest dose of semaglutide, 5.8% experienced progression of hepatic fibrosis, compared to 21.4% in the placebo group.

▲ Semaglutide improves liver fibrosis in patients, with fewer patients experiencing fibrosis progression (Image source: Novo Nordisk official website)

Furthermore, semaglutide demonstrated significant positive effects on secondary endpoints such as liver stiffness, which are considered by regulatory authorities to be clinically relevant endpoints associated with NASH when reviewing NASH therapies. Novo Nordisk expects to initiate Phase 3 clinical trials in 2021 to evaluate the efficacy of semaglutide in treating NASH.

Obesity R&D Pipeline

Obesity is a chronic disease with an increasing prevalence worldwide. It is associated with an elevated risk of various conditions, including type 2 diabetes, cardiovascular disease, and chronic kidney disease. However, apart from surgical interventions, the efficacy of pharmacological weight-loss treatments remains suboptimal. Currently available weight-loss medications on the market typically achieve only approximately 5% reduction in body weight.

▲Semaglutide significantly reduced patient body weight in four Phase 3 clinical trials (Image source: Novo Nordisk official website)

Semaglutide met the primary endpoints in all four Phase 3 clinical trials for obesity treatment, with patients receiving a 2.4 mg dose of semaglutide achieving a weight reduction of 16.9%–18.2%. In the STEP 4 clinical trial, which investigated whether semaglutide could sustain long-term weight control, patients who continued treatment for 68 weeks experienced an 18.2% reduction in body weight, whereas those randomly switched to placebo at Week 20 regained weight over the subsequent 48 weeks.

▲Semaglutide Sustained Weight Loss in Patients in the STEP 4 Clinical Trial (Image source: Novo Nordisk official website)

Based on the excellent results demonstrated by semaglutide in Phase 3 clinical trials, Novo Nordisk plans to submit regulatory applications to the U.S. FDA and the European EMA in the fourth quarter of this year for the use of semaglutide (2.4 mg) in the treatment of patients with obesity. The company also intends to utilize a priority review voucher to file its application with the FDA, thereby further accelerating the review process.

In addition to semaglutide, AM833, an investigational therapy in Novo Nordisk’s obesity pipeline, is a subcutaneously injected amylin analog. Amylin is a peptide hormone co-secreted with insulin by pancreatic β-cells and plays a significant role in blood glucose control. AM833 and semaglutide suppress appetite by acting on different regions of the brain, suggesting that their combination may produce synergistic effects.

▲Semaglutide and AM833 control appetite through complementary mechanisms of action (Image source: Novo Nordisk official website)

In the Phase 1 clinical trial, the combination of AM833 at the highest dose with semaglutide achieved a 17.1% reduction in patient body weight within 20 weeks after treatment initiation, whereas semaglutide monotherapy resulted in only a 9.5% reduction at the same time point. Meanwhile, this combination therapy demonstrated safety and tolerability profiles similar to those of semaglutide monotherapy.

▲ The highest dose of AM833 as monotherapy (left panel) or in combination with semaglutide (right panel) reduced patient body weight by 10.8% and 17.1%, respectively (Image source: Novo Nordisk official website)

Novo Nordisk plans to initiate Phase III clinical trials next year to evaluate the efficacy of this combination therapy in treating patients with obesity. The company noted that while bariatric surgery currently offers the best outcomes for obesity treatment, it is generally reserved for patients who do not respond to dietary or exercise interventions, or for those who have developed severe health complications due to obesity. There remains a significant gap in efficacy between currently available weight-loss medications and bariatric surgery. However, drugs in Novo Nordisk’s obesity development pipeline hold promise for further enhancing weight reduction effects, thereby bridging the current therapeutic gap between pharmacological treatments and surgical interventions.

▲ Novo Nordisk’s obesity R&D pipeline is poised to fill the gap between weight-loss medications and bariatric surgery (Image source: Novo Nordisk official website)

Positive Results from Phase 2b Clinical Trial of IL-6 Antibody

In June this year, Novo Nordisk acquired Corvidia Therapeutics and its lead candidate drug, ziltivekimab, for $2.1 billion. Ziltivekimab is a fully humanized monoclonal antibody targeting interleukin-6 (IL-6). It is used to reduce the risk of major adverse cardiovascular events (MACE) in patients with chronic kidney disease (CKD) who also have atherosclerotic cardiovascular disease (ASCVD) and inflammation.

In the completed Phase 2b clinical trial, ziltivekimab as monotherapy significantly reduced levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) across all dose groups, while demonstrating favorable safety and tolerability. Based on these positive Phase 2b results, Novo Nordisk will initiate Phase 3 clinical trials in the second half of 2021 to evaluate the efficacy of ziltivekimab in reducing the risk of cardiovascular events in patients.

References:

[1] Financial report for the period 1 January 2020 to 30 September 2020. Retrieved October 30, 2020, from https://www.novonordisk.com/content/dam/nncorp/global/en/investors/irmaterial/quarterly_financial_reports/2020/20201030_Q3-CA.pdf

[2] Investor presentation First nine months of 2020. Retrieved October 30, 2020, from https://www.novonordisk.com/content/dam/nncorp/global/en/investors/irmaterial/investor_presentations/2020/20201030_Q3%202020-conference-call-presentation.pdf

[3] Semaglutide 2.4 mg shows superior weight loss versus placebo in the phase 3 trials STEP 2 and STEP 3, thereby successfully completing the programme. Retrieved October 30, 2020, from https://www.globenewswire.com/news-release/2020/06/12/2047467/0/en/Semaglutide-2-4-mg-shows-superior-weight-loss-versus-placebo-in-the-phase-3-trials-STEP-2-and-STEP-3-thereby-successfully-completing-the-programme.html

[4] Novo Nordisk reports weight loss of 14.9% (16.9% if taken as intended) in STEP 1 trial. Retrieved October 30, 2020, from https://www.globenewswire.com/news-release/2020/06/04/2043954/0/en/Novo-Nordisk-reports-weight-loss-of-14-9-16-9-if-taken-as-intended-in-STEP-1-trial.html

[5] Semaglutide 2.4 mg demonstrates superior and sustained weight loss versus placebo and in addition a 17.4% weight loss after 68 weeks in STEP 4 trial. Retrieved October 30, 2020, from https://www.globenewswire.com/news-release/2020/05/13/2032852/0/en/Semaglutide-2-4-mg-demonstrates-superior-and-sustained-weight-loss-versus-placebo-and-in-addition-a-17-4-weight-loss-after-68-weeks-in-STEP-4-trial.html

[6] Novo Nordisk successfully completes AM833 phase 2 trial and phase 1 combination trial with AM833 and semaglutide in obesity. Retrieved October 30, 2020, from https://www.globenewswire.com/news-release/2020/06/18/2050266/0/en/Novo-Nordisk-successfully-completes-AM833-phase-2-trial-and-phase-1-combination-trial-with-AM833-and-semaglutide-in-obesity.html

[7] R&D investor presentation. June 19, 2020 https://www.novonordisk.com/content/dam/Denmark/HQ/investors/irmaterial/investor_presentations/2020/RD_event_presentation_Final.pdf

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