BioWire Weekly - 005

Monday Morning Biotech News

DALL·E 3 depiction of weight loss.

Happy Monday, Readers! Let’s be relentless this week.

This edition of BioWire gives briefs on significant developments in the biotech industry, from revolutionary weight loss drugs continuing to show promise to unexpected hurdles in cancer immunotherapy trials, alongside strides in AI-powered drug discovery and pioneering organoid research. These stories reflect the dynamic nature of biotech and also give insight into how these advances and challenges could reshape treatments and research priorities. I invite you to share your thoughts and reactions in the comments below—what surprises you, what concerns you, and what excites you about these developments? Let’s start a conversation.

Battered Biotech: Gilead axes immunotherapy trials for Magrolimab, ending hope for the cancer drug.

Mechanism of Magrolimab as an immune checkpoint inhibitor (Chao et al, 2020).

Gilead Sciences has announced the termination of all remaining clinical trials of Magrolimab. Magrolimab is part of a class of drugs known as immunotherapeutics, which have become popular over the last decade for treating a variety of cancers. Immunotherapeutics function by targeting proteins on the surface of cancer cells that are involved in turning off the native immune system. In the case of Magrolimab, it targets the CD-47 protein, which some tumor cells use as a "don't kill me" signal to immune cells and thus evade detection. By blocking this signal, the drug aimed to make cancer cells more recognizable and destroyable by the body. However, these drugs have the risk of also affecting healthy cells, leading to the immune system attacking them.

The decision to halt the trials was not fully detailed but followed a stop in development for blood cancers and a pause in solid tumor trials due to a partial clinical hold requested by the FDA, typically concerning patient safety or trial design issues.

Originally acquired for $4.9 billion in 2020, Magrolimab had been a centerpiece of Gilead’s strategy to expand beyond its existing treatments, with the potential to treat a broad spectrum of cancers. Despite the high hopes, the drug faced critical challenges, including adverse reactions leading to a clinical hold and failed phase 3 trials, culminating in its discontinuation. This failure represents an enormous setback for Gilead's oncology ambitions and a severe blow to an already battered biotech industry.

GLP-1 and other weight loss drugs continue to be a focal point in 2024.

Bimagrumab Phase 2 data shows decrease body fat and maintained muscle mass (Heymsfield et al 2021).

Weight loss therapeutics have taken the biotech industry by storm, particularly GLP-1 agonists, which I highlighted in the article top 5 biotech breakthroughs of 2023. Continuing with this trend, they are projected to become the best-selling drug class in 2024. Despite their significant benefits for weight loss, these drugs often lead to a significant loss of muscle mass, which can have detrimental effects, particularly on older adults. To address this, there are ongoing efforts by companies such as Eli Lilly, Altimmune, and Biohaven to develop treatments that not only reduce fat but also preserve or even increase muscle mass. For instance, Eli Lilly's $2 Billion acquisition of Versanis aims to integrate Bimagrumab, a drug that reduces fat without affecting muscle, into their obesity treatment regime. It is believed that this new class utilizes a mechanism that blockades the activin type II (ActRII) receptor, which results in reduced fat mass while simultaneously driving muscle hypertrophy (Nunn et al., 2024). Additionally, Altimmune is developing pemvidutide, which targets both appetite and energy expenditure while preserving lean mass. The industry's goal is to create more sustainable weight loss solutions that can potentially allow periodic cessation of the drugs without regaining weight.

AI-Powered Breakthrough with Novel Macrocycles

Design and depiction of macrocycles from the Baker Lab (Bhardwaj et al, 2022).

Researchers at the University of Washington's Institute for Protein Design, using AI algorithms, have developed a new method for creating millions of novel, drug-like peptides, specifically focusing on macrocycles—ring-shaped peptides that can cross cell membranes to potentially disrupt pain signals, viral infections, and tumor growth (Salveson et al, 2024). These macrocycles, which are smaller than typical proteins yet highly effective, could be developed into oral medications. This innovation builds on previous work adapting DeepMind's AlphaFold for smaller peptide chains and has shown promising preclinical results, including the ability to inhibit proteins linked to COVID-19 and cancer. The successful development and licensing of this technology by UW spinout Vilya Therapeutics highlights its potential as a significant advancement in drug discovery.

Organoid Studies Illuminate New Pathways in Cancer and Neurological Disease Research

Time-lapse of a gut tissue organoid containing a tumor (Lorenzo-Martin et al, 2024).

Two recent studies published in Nature showcase the potential of organoids—3D clusters of cells resembling human organs—to advance biomedical research, particularly in understanding and treating diseases. One study focused on developing brain organoids to model Timothy syndrome, a rare neurological disorder, using stem cells from individuals with the syndrome (Chen et al, 2024). The organoids, injected into rats, provided a platform to test potential treatments, demonstrating promising results in replacing defective proteins and restoring neuron health. In another study, researchers created miniature colon organoids from mouse stem cells to model colorectal cancer, enabling the manipulation of tumor growth and investigation into the effects of calorie restriction (Lorenzo-Martin et al, 2024). While challenges remain in scaling up organoid production and complexity, these findings underscore the potential of organoids to complement animal models and enhance drug development and disease understanding.

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References:

https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-magrolimab-studies-in-solid-tumors

https://www.businesswire.com/news/home/20200302005443/en/Gilead-Acquire-Forty-4.9-Billion

https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-discontinuation-of-phase-3-enhance-3-study-in-aml

https://www.fiercepharma.com/marketing/glp-1s-track-take-drug-sales-crown-pd-1-inhibitors-2024-analyst#:~:text=According%20to%20a%20new%20report,%2Dand%2Dcomer%20last%20year.

https://davidkingsley.substack.com/p/top-five-biotech-breakthroughs-that

Bhardwaj, G., O’Connor, J., Rettie, S., Huang, Y.H., Ramelot, T.A., Mulligan, V.K., Alpkilic, G.G., Palmer, J., Bera, A.K., Bick, M.J. and Di Piazza, M., 2022. Accurate de novo design of membrane-traversing macrocycles. Cell, 185(19), pp.3520-3532.

Chao, M.P., Takimoto, C.H., Feng, D.D., McKenna, K., Gip, P., Liu, J., Volkmer, J.P., Weissman, I.L. and Majeti, R., 2020. Therapeutic targeting of the macrophage immune checkpoint CD47 in myeloid malignancies. Frontiers in oncology, 9, p.1380.

Chen, X., Birey, F., Li, M.Y., Revah, O., Levy, R., Thete, M.V., Reis, N., Kaganovsky, K., Onesto, M., Sakai, N. and Hudacova, Z., 2024. Antisense oligonucleotide therapeutic approach for Timothy syndrome. Nature, 628(8009), pp.818-825.

Heymsfield, S.B., Coleman, L.A., Miller, R., Rooks, D.S., Laurent, D., Petricoul, O., Praestgaard, J., Swan, T., Wade, T., Perry, R.G. and Goodpaster, B.H., 2021. Effect of bimagrumab vs placebo on body fat mass among adults with type 2 diabetes and obesity: a phase 2 randomized clinical trial. JAMA network open, 4(1), pp.e2033457-e2033457.

Lorenzo-Martín, L.F., Hübscher, T., Bowler, A.D., Broguiere, N., Langer, J., Tillard, L., Nikolaev, M., Radtke, F. and Lutolf, M.P., 2024. Spatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo. Nature, pp.1-8.

Nunn, E., Jaiswal, N., Gavin, M., Uehara, K., Stefkovich, M., Drareni, K., Calhoun, R., Lee, M., Holman, C.D., Baur, J.A. and Seale, P., 2024. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Molecular Metabolism, 80, p.101880.

Salveson, P.J., Moyer, A.P., Said, M.Y., Gӧkçe, G., Li, X., Kang, A., Nguyen, H., Bera, A.K., Levine, P.M., Bhardwaj, G. and Baker, D., 2024. Expansive discovery of chemically diverse structured macrocyclic oligoamides. Science, 384(6694), pp.420-428.