The Needle Issue #4
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Welcome to the latest issue of the Needle, a newsletter from Haystack Science on preclinical biotech. This week, we take a look at advances in lipid nanoparticles and gauge their promise as delivery vehicles for extra-hepatic organs. At the FDA, new Commissioner Martin Makary announced the June launch of AI toxicology models to streamline regulatory oversight and appointed Vinay Prasad, a vocal critic of the accelerated approval pathway, to succeed Peter Marks as CBER Director. The number of financings and deals for preclinical builds remains low, but last week Eli Lilly was busy making deals for antibodies and oligos. Meanwhile, valuations of public companies not yet in the clinic continue to be hammered in the markets.
Haystack chat Lipid nanoparticles (LNPs), like those used in the FDA-approved siRNA drug Onpattro, remain the delivery vehicle of choice for mRNAs, gene-editing and base-editing therapies. One drawback of intravenously administered LNPs is adsorption of apolipoprotein E triggers rapid liver uptake via low-density lipoprotein (LDL) and other receptors on hepatocytes. This results in a relatively short half-life and limit application of LNPs in other organs. Pieter Cullis, from the University of British Columbia, and his team report in Nature Communications a new LNP design that promises to enhance their lifetime in the blood. In previous work, the team had established that LNPs consisting of an oil droplet of ionizable lipid like MC3, surrounded by a monolayer of bilayer-forming lipids like egg sphingomyelin and cholesterol, further surrounded by a proper lipid bilayer lasted longer in the circulation. In their new study, they systematically modified the ratio of bilayer lipid to ionizable lipid (RB/I) and found that LNPs with RB/I=4 showed liposomal morphology, high mRNA encapsulation efficiency, and excellent transfection properties in vitro and in vivo. Moreover, these LNPs with high proportions of bilayer forming lipids lasted longer in the circulation and showed higher transfection efficacy in lymph nodes and pancreas than Onpattro-like LNPs. Cullis and his colleagues propose that the prolonged blood circulation lifetime is attributed to reduced plasma protein adsorption. The transfection competency of liposomal LNP systems is attributed to export of the solid core containing mRNA from the LNP as the endosomal pH is lowered. Their transfection potency, in turn, appears to depend on the cytoplasmic release of complexes that include mRNA and ionizable lipid, complexes that are generated as the endosome matures and its pH decreases. This work represents a promising strategy to increase the therapeutic index of drugs delivered by LNPs. The new LNPs are being developed by Nanovation Therapeutics, a preclinical startup co-founded by Cullis in 2021. In September, Nanovation clinched a $600 million deal with Novo Nordisk to license worldwide rights to its long-circulating LNPs for extra hepatic delivery of two base-editing therapies for rare genetic diseases, and up to five additional targets in cardiometabolic and rare diseases. Cullis is a serial entrepreneur who has founded several companies around lipid-based delivery systems for nucleic acid-based drugs, including Inex Therapeutics/Protiva Biotherapeutics/Tekmira/Arbutus Pharma and subsequently Acuitas Therapeutics, which developed the MC3 LNP for Onpattro in collaboration with Alnylam Pharmaceuticals. The group also collaborated with Drew Weissman of the University of Pennsylvania on LNPs for mRNA vaccines, which lead to their use in mRNA COVID-19 vaccines. To be a broad platform for the liver and beyond, LNPs must compete with several other delivery modalities, such as viral vectors and conjugates. In liver delivery, triantennary GalNAc-conjugated siRNAs, which target asialoglycoprotein receptors on hepatocytes, are now the delivery vehicle of choice for liver-targeted siRNAs. Apart from circulation lifetime, another issue that LNPs must contend with is organ accessibility due to fenestrations in blood vessels. In the case of the liver, pancreas, and bone marrow, pores are greater than 60 nm, allowing LNPs access to tissue. For mRNA vaccines, blood filtering lymph nodes also represent an excellent LNP target. However, tissues, such as brain (with its accompanying blood brain barrier), muscle and kidney have much tighter fenestrations (<15 nm), presenting an uphill delivery challenge for intravenous LNPs. Papers: Best of the rest New target biology: De novo DUOX2 expression in neutrophil subsets shapes the pathogenesis of intestinal disease | PNAS PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease | Nature Target-discovery platforms: Therapeutic discovery: Small-molecule targeting of SHOC2–RAS interaction in RAS-mutant cancers | Nature Inhaled DNAI1 mRNA therapy for treatment of primary ciliary dyskinesia | PNAS Review summarizing therapies in development for FUS-related ALS Advances in CAR-Ts: Disease mechanisms: Activation of lysosomal iron triggers ferroptosis in cancer | Nature Startup news 2021 IPO bubble hangover continues: Stiffel investment bank report analysis shows Wall Street continuing to punish public companies lacking clinical assets Simultaneous feast and famine: VC financing is down, but the few +100M mega rounds continue: VC financings drop 20% in Q1 but megarounds keep median deal size high RIP recent preclinical casualties: Following announcement from Roche of US investment last week, Eli Lilly is bolstering its investment in Purdue University: Lilly expands Purdue University collaboration with up to a $250 million investment Several announcements coming out of FDA. First relate to the use of AI to streamline FDA oversight Newly announced CBER Director Vinay Prasad is a vocal critic of the accelerated approval pathway: Low-value approvals and high prices might incentivize ineffective drug development Preclinical funding
Preclinical deals
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