There is a furious pace of innovation, deal flow and drug approvals for the new class of glucagon-like peptide 1 (GLP-1) receptor agonists and the emerging next gen Dual Agonists for the treatment of obesity and weight loss.
Among mature pharmaceutics companies, the bandwagon took off when the sleepy backwater of GLP-1s for diabetes treatment revealed a much more exciting potential: weight loss. Dose escalation ensued, allowing an enormous TAM to be grafted onto the GLP-1s as weight loss therapies.
For Q3 2023, Novo’s Wegovy (semaglutide) made $1.38 billion, while Lilly’s Mounjaro (tirzepatide) earned $1.4 billion. Mounjaro is formally indicated for type 2 diabetes, but its active ingredient last month won the FDA’s approval for weight management, for which it is being sold as Zepbound.
For Q4 2023, worldwide Mounjaro revenue was $2.21 billion compared with $279.2 million in Q4 2022. U.S. revenue was $2.11 billion compared with $256.7 million in Q4 2022, or about 700% growth.
The GLP-1 bandwagon has created a variety of winners and losers in financial markets including companies in the medtech sector, weight loss companies and other biotechs caught in the blast zone of impact.
And the bandwagon is changing business models among some pharmaceutical companies. Eli Lilly recently launched a new margin- and funnel- and moat-building online service, LillyDirect, offering telehealth prescriptions and direct home delivery of its new Zepbound weight-loss drug. Perhaps this is the first step towards an even higher trapeze of a recurring revenue for weight-loss-as-a-service business model?
In December 2023, Roche agreed to acquire Carmot Therapeutics for $2.7 billion upfront and the potential for $400 million in milestone payments. Carmot’s clinical pipeline includes subcutaneous and oral incretins with best-in-class potential to treat obesity in patients with and without diabetes. CT-388 is a weekly injectable, Phase 2 ready, dual GLP-1/GIP receptor agonist for the treatment of obesity in patients with and without type 2 diabetes. CT-996, currently in Phase 1, is a once-daily oral, small molecule GLP-1 receptor agonist intended to treat patients with obesity and type 2 diabetes. CT-868 is a Phase 2, once-daily subcutaneous injectable, dual GLP-1/GIP receptor agonist intended for the treatment of type 1 diabetes patients with overweight or obesity. Carmot also has preclinical programs in development for the treatment of metabolic diseases.
Today, there are a small number of biotechs in clinical stage development of GLP-1s and the next generation of GLP-1 dual dgonosts that have the potential to improve outcomes with fewer side-effects through titration of GLP-1.
Here are three with varying degrees of clinical development and market caps:
Altimmmune (ALT) Stock price$9.5; market cap: $500 million
ALT recently released its Phase II Momentum trial results, showing its GLP-1/glucagon agonist pemvidutide significantly reduced weight in overweight or obese adults. After 48 weeks, the 1.2-mg pemvidutide dose led to an average 10.3% weight loss, increasing to 11.2% and 15.6% with the 1.8-mg and 2.4-mg doses, respectively, versus a 2.2% loss with placebo. Over 30% of patients on the highest dose lost over 20% of their weight. Pemvidutide, a dual-agonist peptide, activates GLP-1 and glucagon receptors, potentially treating obesity and related liver issues by mimicking diet and exercise effects—reducing appetite and boosting energy use. In the double-blind, placebo-controlled Momentum trial with 391 participants, pemvidutide also improved metabolic markers like serum lipids and blood pressure, showing good safety and retention rates. Most side effects were mild, with nausea and vomiting being most common, and treatment-related dropouts increased at higher doses, mainly in the first 16 weeks.
Here is a recent interview with ALT’s CEO.
Viking Therapeatics (VKTX) Stock price: $24; market cap: $2.4 billion
Summary
I am optimistic about VKTX’s VK2809, a thyroid hormone receptor-β agonist taken orally and aimed at NASH/MASH treatment. This area, expected to expand rapidly due to significant unmet needs, is ripe for treatment adoption. In a Phase 2a trial, VK2809 significantly reduced liver fat by 54-60% and achieved an 88% response rate (≥30% relative liver fat reduction), linking to NAS and fibrosis reduction—a connection further confirmed by resmetirom (Madrigal Pharmaceuticals ) in its Phase 3 trial. No serious safety incidents have been noted, dispelling former concerns about THRβ agonists and their potential cardiovascular and thyroid risks. VK2809 is now under investigation in the VOYAGE Phase 2b trial for patients with confirmed NASH, where it has already met its primary goal by showing a statistically significant decrease in liver fat content at 12 weeks, alongside promising safety and tolerability outcomes. The trial is expected to conclude in the first half of 2024 with more histological data. Although VK2809 might not reach the market first, the vast patient base within MASH, most of whom have comorbidities that could benefit from varied mechanisms of action, presents minimal competition overlap and the chance for combination treatments. VKTX is also advancing VK2735 (GLP-1/GIP) for obesity treatment in the ongoing Phase 2 VENTURE study, started in the third quarter of 2023, with Phase 1 oral formulation’s topline results anticipated in the first quarter of 2024. This will shed light on the potential for next-generation injections and oral versions.
Detailed Picture
VKTX is focused on therapies for the treatment of metabolic and endocrine disorders, with three compounds currently in clinical trials. The company’s clinical programs include VK2809, an orally available, small molecule selective thyroid hormone receptor beta agonist for the treatment of lipid and metabolic disorders, which is currently being evaluated in a Phase 2b study for the treatment of biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis. In a Phase 2a trial for the treatment of non-alcoholic fatty liver disease (NAFLD) and elevated LDL-C, patients who received VK2809 demonstrated statistically significant reductions in LDL-C and liver fat content compared with patients who received placebo.
The company is also developing VK2735, a novel dual agonist of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors for the potential treatment of various metabolic disorders. Data from a Phase 1 trial evaluating VK2735 (dosed subcutaneously) for metabolic disorders demonstrated an encouraging safety and tolerability profile as well as positive signs of clinical benefit. The company also recently initiated a Phase 1 study to evaluate an oral formulation of VK2735. The company’s Phase 2 VENTURE trial has accelerated, narrowing the timing of data release from
1H24 to 1Q24.
In the rare disease space, the company is developing VK0214, a novel, orally available, small molecule selective thyroid hormone receptor beta agonist for the potential treatment of X-linked adrenoleukodystrophy (X-ALD). VK0214 is currently being evaluated in a Phase 1b clinical trial in patients with the adrenomyeloneuropathy (AMN) form of X-ALD. The company holds exclusive worldwide rights to a portfolio of five therapeutic programs, including VK2809 and VK0214, which are based on small molecules licensed from Ligand Pharmaceuticals.
NeuroBo Pharmaceuticals (NRBO) Stock price: $4.8; market cap: $25 million
NRBO is a clinical stage drug development company with a focus on obesity and weight loss.
Its most advanced drug candidate, A-1726, is a novel oxyntomodulin analogue functioning as a GLP1R/GCGR dual agonist for the treatment of obesity. The FDA approved the company’s IND on February 1, 2024, and Phase 1 trials will commence shortly. Its other therapy is DA-124, a novel G-Protein-Coupled Receptor 119 (GPR119) agonist with development optionality as a standalone and/or combination therapy for both MASH and T2DM. Its Phase 2a first patient was dosed September 15, 2023 with interim data due in 1H 2024. Full results due in 2H 2024. The company is backed by strategic partner and major shareholder, Dong-A ST. DA-1726 outperformed Semaglutide (WEGOVY), a GLP-1 agonist, in mouse models of obesity. The company has a negative EV.
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