Big pharma’s new year catalysts

If 2022 was about progress in Alzheimer’s, the new year looks to start with a battle in metabolic disorders, namely type 2 diabetes and obesity. Novo Nordisk is hoping to maximise efficacy of the oral formulation of its GLP-1 agonist semaglutide, by ramping up the dose, to help fend off threats from Lilly’s Mounjaro. 

Elsewhere, Astrazeneca and its partner Daiichi will see data from two antibody-drug conjugates. Enhertu will try its chances in ultra-low Her2 breast cancer while datopotamab deruxtecan is in immunotherapy-failed lung cancer patients. Pfizer and Roche, meanwhile, are gunning for haemophilia B with the gene therapy fidanacogene elaparvovec, although CSL and Uniqure have got there first. 

Round one

Lilly’s Mounjaro might be the new kid on the metabolic block but Novo is not standing still. In diabetes, oral semaglutide is branded Rybelsus and is approved at a 14mg dose. A study called Pioneer Plus is testing 25mg and 50mg, compared with 14mg, over 52 weeks. Rybelsus achieved a placebo-adjusted blood sugar reduction of 1.1 percentage points in its 26-week Pioneer 1 study.

Perhaps more important are obesity data, from a study called Oasis 1, which tests 50mg oral semaglutide versus 14mg.  

Oasis 1 is a 660-participant, 68-week study. The 50mg dose is achieved by dose escalating across 16 weeks and the primary endpoints are the relative change in body weight, and an achievement of body weight reduction greater than or equal to 5%. 

The aim is to achieve Wegovy-type weight loss; Wegovy is the brand name of injected semaglutide approved in obesity. The drug has shown a placebo-adjusted -12.4 percentage point change in body weight at week 68. The most common adverse events were gastrointestinal, which will be watched closely in Oasis 1.   

Lilly’s Mounjaro is already approved in type 2 diabetes and a filing in obesity is expected before the end of 2023. At the same time, oral projects are in development from Lilly, Pfizer and Amgen, so Novo needs to keep up the pace. 

More ADCs on their way

Daiichi Sankyo and Astrazeneca’s antibody-drug conjugate heavy weight Enhertu already has three breast cancer settings on its label, including Her2 low, and the developers are striving to add more. Next up are data in Her2-low patients who are also hormone receptor (ER) positive; the study also includes a Her2 ultra-low cohort, and any signal here could open up an even wider pool of patients.  

The Destiny-Breast06 study pits Enhertu against chemotherapy in ER-positive patients whose disease has progressed on endocrine therapy in the metastatic setting. The primary measure is PFS.  

Her2-low patients are defined as having an immunohistochemistry (IHC) score of 1+, or IHC2+ with a negative in-situ hybridisation score (ISH-). Those with an expression of Her2 greater than zero but less than 1 are known as ultra-low. 

Another antibody-drug conjugate from Daiichi and Astra has key data due in lung cancer. Datopotamab deruxtecan is a Trop 2-directed conjugate that uses the same toxic payload as Enhertu. 

The pivotal Tropion-Lung01 study is in a broad second-line NSCLC setting and includes patients who have previously been treated with a PD-(L)1 MAb. Datopotamab is up against docetaxel and the primary endpoints are PFS and overall survival. 

While Keytruda has reshaped the first-line lung setting, the I-O failure space remains wide open. 

Next in line

Pivotal data are expected soon from Pfizer and Roche’s haemophilia B gene therapy, fidanacogene elaparvovec. The partners are completing the Benegene-2 trial in 45 male patients. The primary measure is the annualised bleeding rate from week 12 to month 15.  

Uniqure and CSL recently gained FDA approval for their gene therapy, Hemgenix, which has set a high efficacy precedent. Its approval was based on the Hope-B study where Hemgenix showed an estimated mean annualised bleeding rate of 1.9 bleeds/year during months 7 to 18, which was assessed as non-inferior to the rate in the lead-in period.

The project also looks durable, with mean factor IX activity at 24 months similar to 3-month values. 

The table below contains a list of upcoming catalysts with consensus forecasts from Evaluate Pharma.