Axial partners with great inventors creating unique business models. Profiling exciting life sciences companies at the earliest stages is important. Rather than talk about their work specifically conveying the opportunity set is more important where the company and others in the field will bring to market currently confidential inventions to more people.

Undruggable genome

Pursuing 10%-20% of the accessible targets has had a tremendous impact on human health. Antibodies have become commoditized after 2-3 decades of development and are good tools to get to extracellular targets. Small molecules have been very useful but are limited in the intracellular targets that are available to them. As a result, many new modalities (i.e. stapled peptides, PROTACs, molecular glues) are being developed to successfully pursue the other 80% of targets, which are mainly intracellular. These new modalities are often reliant on endocytosis and vesicle trafficking. New companies solving this problem are Arvinas, Hexagon Bio, Unnatural Products, LifeMine, FogPharma, and C4 Therapeutics. Each company is exciting for different reasons building different types of moats around IP, experiments, data, and chemistry.

For intracellular targets, the drug development industry has focused on orally bioavailable small molecules limiting opportunity to targets with accessible binding sites. Between 10%-14% of human genes produce proteins that could bind small molecules. Moreover, only 20% of these genes are likely to be associated with disease. Druggability is a multidimensional problem many large companies have not pursued including:

Binding affinity

Oral bioavailability

Cell permeability

Serum stability

Pharmacodynamics/Pharmacokinetics (PD/PK)

Toxicology

Targeting undrugged proteins has unique challenges - non-enzymes, such as scaffolding, regulatory or structural proteins, and their activities are often dependent on protein-protein interactions. It is difficult to predict how drug binding to non-enzymes might affect changes in protein function. But with super-exponential decrease in the cost of sequencing, undrugged targets can be classified and linked to disease indications.

Three great reviews on the topic are from Craig Crews- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925121/ and Kevan Shokat- https://www.nature.com/articles/nrc.2017.36 Other great labs solving the problem are Nomuraand Verdine.

Overall, why are previously undruggable targets are now druggable?:

Cheaper computational power to simulate molecular targets Improved NMR and crystal structure data Proliferation of new therapeutic modalities More diverse chemical libraries Improved drug delivery systems Improved high-throughput screening methods Clearer understanding of signaling pathways Accessibility of cell-based assays that are more physiologically relevant

Probably the most important undrugged target is KRAS, which is mutated in 20%-30% of cancers including 3 severe forms: lung, colon, & pancreatic. Despite over 30 years of research, an approved RAS inhibitor has not been identified making it conventional wisdom that the protein class is undruggable. Despite the lack of success so far, it is still a global priority to drug KRAS and meet this unmet clinical need. With technical advances and an improved understanding of cell signaling, targeting RAS proteins is possible. In 2013, the NCI established the National RAS Initiative and a set of companies have stepped up to the challenge. Other important targets are c-MYC (Myc pathway), PP2A (Raf/MEK/AKT), SHP2 (multiple pathway node), HDM2/p53 (multiple pathway node), MDM2/p53 (multiple pathway node), Nrf2 (multiple pathway node), NFE2L2 (multiple pathway node), KLA4 (multiple pathway node), E2F1 (multiple pathway node), CBP/β-catenin (Wnt).

Conventional wisdom would suggest that improved modality design and chemistry are the most important pieces to solve this problem. These two parts are important but delivery is becoming increasingly important. Companies like Suono Bioand GenEditare doing great work here. For new drug modalities coming online and through the clinic, developing new ways to bring them to specific tissues and into cells is probably going to become the most important part to solve the undruggable genome. Delivery requires a better understanding of cellular cargo transport and is dependent on an increasing understanding of endocytosis:

Source: https://biologydictionary.net/active-transport/

To enable a shift in the field and improve the odds of success, a better understanding of the mechanisms driving internalization, trafficking, and also the intracellular fate of therapeutics is required. Depending on the receptor or protein targeted, a drug may be transported via the early or late endosome and potentially then after to the lysosome. The ability for the drug to escape the endosome is to date poorly understood, both from a physicochemical properties and conformational perspective.

Ultimately for the undruggable genome, there are a few companies to be built:

Therapeutic delivery that goes beyond blood Software and screening to match combinations of modalities (conjugates) with undrugged targets Uniform delivery of cargo to a site (i.e. solid tumor) Delivery with complete control of cellular uptake and endosomal release

For any company in the field and in general, designing a durable business model is important for all stakeholders (i.e. founders, investors, employees, partners). A conventional model is to commercialize a set of molecules and bring them to the clinic either selling them after a major value-creating event or rarely using it to build a large company (i.e. the last $100B biopharma company created has been Gilead, which started off founder-driven led by Michael Riordan). This will always be an important approach. Designing new modalities is incredibly important too, but take a long time to gestate. PROTACs have taken ~20 years of world-class work to get into the clinic. New inventions can enable a new type of business to emerge. Other pathways are just generating large-set of molecules and making them valuable - this requires scale and high-amounts of automation/capital. Discovery services are increasingly viable for commoditized molecules. Companies centered around delivery can build different types of moats focused on tissues/cell types and becoming modality-agnostic. Even using diagnostics to create a full-stack business is becoming increasingly important due to the overall shift to fee-for-value and the need to increase pricing-power of drugs. Overall, any company pursuing the undruggable genome needs a sterling team along with the proper alignment between technology and business model. Like any good castle, the business model needs to be prepared to adapt to multiple situations (i.e. new regulation, a new invention).

Undrugged targets are accessible due to collective improvements in drug development and software analysis. Targeting 10% to 20% of the available targets has had a tremendous impact on human health and ~80% of targets are still undrugged. New modalities are making important undrugged targets (i.e. c-MYC and KRAS) targetable. With new modalities, delivery and endocytosis become important fields of study. Technology along with new regulations and incentives ought to improve our ability to pursue currently intractable targets.

Have a nice day.