The Needle. Issue #1
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Welcome to the Needle, a newsletter from Haystack Science on preclinical biotech. If you are interested in science commercialization and how to take early-stage discovery therapeutic assets to market, this newsletter is for you. We aim to provide quick and insightful updates on preclinical research and the business around it every week. If you find the content helpful, please forward it to your friends and colleagues.
Introducing ‘The Needle’ The Needle is written by Haystack Science’s Juan Carlos Lopez and Andy Marshall. We spent several decades leading Nature Medicine and Nature Biotechnology, two of the world’s leading translational research journals. Our careers have since taken us into pharma, philanthropy, venture capital and company building to learn the challenges of translating academic science into clinically transformative medicines. There are many blogs and newsletters for biotechnology and biobusiness, but few resources that go deeply into the challenges of preclinical research that leads to new medicines and how initial drug target discovery efforts can be developed into an investable package for first-in-human studies. This newsletter is aimed at founders, entrepreneurs, technology transfer personnel and investors interested in understanding fast-moving developments in biomedical research and the commercial context around them. Each week we'll provide a brief take on one piece of preclinical research (Haystack chat), together with noteworthy papers, startup news, financings and deals. Haystack chat Incretin agonists like GLP-1 have transformed the treatment of obesity. Writing in Nature, Katrin Svensson, from Stanford University, and her collaborators report the identification of a new peptide with similar appetite-suppressing activity, but with a different mechanism of action. The authors developed a computational approach to systematically map peptides potentially generated by the proteolytic action of PCSK1 across the human genome. Out of the thousands of peptides that they identified, the team pinpointed BRP, a 12-residue peptide derived from BRINP2, and showed that it reduces food intake in mice and minipigs with a potency similar to GLP-1, without inducing nausea or aversion. And like GLP-1, BRP reversed obesity in mice, but its action was independent of GLP-1 receptors and of other central appetite-regulating pathways, such as leptin and MC4R. In fact, the appetite-suppressing effects of BRP and GLP-1 were additive. BRP is present in human cerebrospinal fluid and in mouse brain, where it seems to activate several hypothalamic nuclei. Although the effect of BRP seems to involve a Gαs-coupled GPCR, its receptor remains unknown, and its identification would be an important step towards exploring the therapeutic potential of the BRP pathway. Similarly, the half-life of BRP in plasma is less than 10 minutes. Chemical optimization of BRP to address bioavailability, pharmacokinetics, pharmacodynamics and immunogenicity will be necessary steps to test its potential as anti-obesity agent. Looking beyond metabolic disease, the computational approach of Svensson and her team will likely lead to the identification of many more biologically active peptides. This program represents a promising starting point for drug development. Synthetic analogs of peptide hormones have an established track record of success. Of the 60 or so NME peptide drugs approved by the FDA to date, >65% are peptide-hormone analogs that act as receptor agonists. In contrast, only 8% of FDA-approved peptide NMEs are antagonists. The commercial peptide-hormone space is crowded, including big players like Lilly, Novo Nordisk, Merck, Amgen, AstraZeneca, Takeda and Sanofi. Several well established biotechs like Zealand Pharma, Ferring Pharmaceuticals, Ironwood Pharmaceuticals and Innovent Biologics are also active in this area, as well as newcomers like Ambrosia Health, Antag Therapeutics, CinFina, Deep Apple, i2O, Kallera, Metsera, MindRank, Pep2Tango, Remedium, Rivus, Six Peaks and Viking Pharmaceuticals. With >65 clinical programs for incretin drugs already in progress, competition in metabolic disease is cutthroat; recently, Pfizer announced that it was discontinuing development of its oral GLP-1 agonist danuglipron due to unfavorable liver toxicity. Just last week, phase 3 results of Lily’s oral drug orforglipron in people with diabetes and obesity demonstrated similar safety and efficacy to peptide GLP-1s. In related news on peptide startups, Johnson & Johnson’s JLabs recently recruited TwoStep Therapeutics to its Mission Bay campus in San Francisco. TwoStep is developing multi-specific targeted peptide conjugate therapies for solid tumors and was spun out of Stanford University last year by Carolyn Bertozzi, Jennifer Cochran, Ron Levy, and Caitlyn Miller, with a seed investment of $8.7 million led by NFX. Janssen/JLabs has a track record in incubating peptide startups: Protagonist Therapeutics received both a $14 million investment from JJDC in 2013 and a JLabs residency, ultimately leading to a licensing deal with Janssen in 2017, which led to Icotrokinra (an IL‑23R macrocycle peptide) now in late-stage trials for moderate-to-severe plaque psoriasis. Papers: Best of the rest Small molecules restore mutant mitochondrial DNA polymerase activity | Nature RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa | PNAS Therapeutic potential of allosteric HECT E3 ligase inhibition | Cell Startup news University of Oxford spinout Orfonyx Bio comes out of stealth Syncona’s new accelerator Slingshot announces first seed investment in Apini BioInnovation Institute in Denmark announces three new startups Protolea Bio winner of Cancer Tech Acclerator at UK’s Discovery Park Gastrobody Therapeutics announced as part of University of Cambridge’s START Accelerator 2.0 cohort BioMed X launches program to support biomedical researchers impacted by NIH funding gaps Proposal for US Innovation Accelerator to help companies bridge valley of death Funding
Deals
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If you’re interested in commercializing your science, get in touch. We can help you figure out the next steps for your startup’s translational research program and connect you with the right investors and company builders. Please send feedback; we’d love to hear from you (info@haystacksci.com). Until next week, Juan Carlos and Andy |