Combining forces in metabolic disorders

Last week’s successful showing of Altimmune’s GLP-1/glucagon dual receptor agonist in an early-stage obesity trial has prompted the group to lay out further plans for the molecule in obesity and Nash. 

But there are nearly a dozen double or triple combo projects in development for these metabolic disorders. Lilly is the most prominent company here, with involvement in three programmes. The most advanced, tirzepatide, could soon be filed in diabetes with obesity not far behind. Altimmune has a long fight for market share ahead of it. 

A six-week interim cut of the phase 1 trial of Altimmune’s ALT-801, administered subcutaneously once a week, far surpassed the pre-established target of 2% weight loss at 1.8mg, the higher of two doses. All but one subject who received this dose achieved at least 3% weight loss by the sixth week. 

Nausea rates of 22% at the high dose might look alarming, but all cases were mild and crucially the dose was not titrated; compared with other GLP-1-based projects this might be acceptable. There was no report of vomiting, diarrhoea or constipation at either dose. 

The data are impressive, particularly as the patients did not undergo diet, exercise or behavioural modifications. That said, this was a small, single-centre trial, with 10 to 15 patients per cohort.

Final 12-week data from the trial, which will include higher doses, are expected in the third quarter. After that Altimmune will start a formal obesity programme for ’801. The same quarter it will start a separate 12-week phase 1b study of diabetic and non-diabetic subjects with non-alcoholic fatty liver disease (NAFLD), and a 52-week biopsy-driven Nash trial will begin in the first quarter of 2022.

Surmounting the competition

Altimmune has made a strong start, but the competitive landscape is daunting. The below analysis considers double or triple combinations that act on the GIP, GLP-1 or glucagon receptor pathways, and front and centre is Lilly. 

Tirzepatide, a GIP/GLP-1 combo, is to be filed this year in diabetes; the sellside’s consensus forecasts for this indication top $4.8bn for 2026, according to Evaluate Pharma. Topline data from Surpass-2, assessing the project in diabetes, showed 13% total weight loss at the highest dose. The specifically obesity-focused Surmount programme of five phase 3 trials is ongoing, but will not report before 2023. 

Lilly has three other combos in the clinic for metabolic disorders, including a triplet. Known simply as the GGG tri agonist research program, or triple G, this is in phase 1 in diabetes, with phase 2 trials in diabetes, Nash and obesity on the drawing board.

Conspicuous by its absence is one of biopharma’s most narrowly focused metabolic players. Over the past few years Novo Nordisk has shelved two doublets and a triplet, largely in favour of semaglutide. This single-action GLP-1 agonist achieved placebo-adjusted weight loss of 6-12% in its late-stage obesity trials.

It is sold as Ozempic for diabetes and Wegovy for obesity, and 2026 sales forecasts sit at $7.6bn and $2.5bn respectively for these indications. No wonder Novo feels it does not need combos. 

Few other pure GLP-1 agonists carry significant expectations, owing to the difficulty of competing with sema. The exception is Pfizer’s oral project PF-06882961, in phase 2 in both diabetes and obesity. In a small phase I trial presented last year ’2961 achieved average weight loss of around 8.5%. The sellside forecasts total 2026 sales of $134m.

Unique but unproven

Other big groups, finding themselves without a future metabolic blockbuster like sema, are pursuing the combo approach. Boehringer Ingelheim is developing BI 456906, in phase 2 in obesity and Nash, and Astrazeneca is trialling cotadutide in diabetes, diabetic kidney disease and obesity with Nash. Both are GLP-1/glucagon agonists. 

In a phase 2 study in obese or overweight diabetes patients, cotadutide achieved body weight reductions of 5% with the highest dose, 300µg. 

Amgen is doing something else. AMG 133 is a GLP-1 agonist combined with a GIP receptor antagonist. This mechanism, unique among clinical-stage assets, is backed by research, admittedly preclinical, to suggest that both boosting and inhibiting GIP can cause weight loss. It might take time to determine whether this occurs in humans. The phase 1 trial of ’133 should yield data next year, but weight loss is not one of its endpoints. 

Altimmune is at least ahead of Amgen in the metabolic combination race, but it is still behind several other much larger companies, and the fight for a share of the market will surely be fierce.