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IN THIS EDITION
- Of vaccines and vaccinology, in COVID-19 and beyond: How to build a vaccine, and fast
- Healthcare’s great unlock: The new healthcare landscape and the opportunities for startups
- The first healthtech giant: A major merger aims to create the first end-to-end digital health platform, at scale.
- Pharma picks their PROTAC horses: A new drug modality moves to the big leagues
- Upgrading cell and gene therapy “software” for safety: Cracking the (engineering) code and fine-tuning living medicines
Of vaccines and vaccinology, in COVID-19 and beyond
When are we going to have a COVID-19 vaccine, and how are we compressing a development process that usually takes 10-15 years years into 12-18 months? What will and won’t be compromised here, and where do new technologies – like plug-and-play manufacturing and mRNA (messenger RNA) vaccines – come in? Rajeev Venkayya, president of the Global Vaccine Business Unit at Takeda Pharmaceutical Company and former White House Special Assistant to the President for Biodefense (where, among other things, he was the principal author of the National Strategy for Pandemic Influenza) joins this episode of the a16z Podcast, in conversation with general partner Jorge Conde to talk all things vaccines and beyond. We may actually see the emergence of a “neo” anti-vaxxer due to the pandemic… but we are also entering a “renaissance for vaccinology” (much of it thanks to our ability to engineer biology).
Healthcare’s great unlock
Very rarely, maybe once a generation, an event comes along that completely transforms a stagnant industry. We are experiencing that moment right now in healthcare – leading to a mass acceleration of opportunities for company creation across the space. In the video and article Healthcare: The Great Unlock, general partner Julie Yoo shares how the entire topography of healthcare is changing – from a rewiring of the value chain, to new gravitational centers for data, to category-creating regulation – and what happens when we finally have the ability to integrate technology into aspects of the healthcare system that historically have been intractable.
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The first healthtech giant
Telemedicine provider Teladoc and diabetes coaching company Livongo recently announced they are merging (whether this should be referred to as Teledongo or Televongo has been the subject of a heated debate in our Slack channels; we like the latter!). On our news show 16 Minutes, general partners Vijay Pande and Julie Yoo discuss with Sonal Chokshi how this merger creates the first virtual-native care delivery platform at scale, but the commensurate challenges with integrating two vastly different care models; what this deal means for the broader virtual care category; implications for incumbents and startups; and more.
Pharma picks their PROTAC horses
A new drug modality is moving into the big leagues by targeting disease-related proteins in an entirely new way: programmed protein degradation. The core breakthrough is the creation of PROTACs (proteolysis targeting chimeras), a type of bifunctional ligand. PROTACs work by binding a disease-causing protein and an ubiquitin ligase – labeling the target protein for degradation, then essentially “trashing” it using the cell’s own protein degradation machinery. Unlike most drugs, which inhibit proteins with distinct ligand-binding pockets (enzymes, receptors, etc), PROTACs can drive the degradation of a wide range of proteins, many previously deemed to be ‘undruggable’ – meaning a whole new category of therapeutics could be on the horizon.
Major pharma companies are now looking to pick their PROTAC horse in the race. This summer has seen a flurry of activity, fundraising, and partnership deals as initial clinical data come to light. In May, Arvinas showed promising data for their prostate cancer program with the first-in-human data for any PROTAC drug, allaying some concerns about off-target effects and toxicity issues for this new modality. The same week, Vividion announced a partnership with Roche leveraging Vividion’s proteomics screening platform and proprietary small molecule library to target several key oncological and immunological disease-related proteins. In July, Kymera also signed a deal with Sanofi in the first of the major PROTAC partnership deals to disclose the drug target: IRAK4. This choice was particularly notable since IRAK4 may be druggable without PROTAC technology (several drug companies, including Pfizer and Curis, are actively in trials with small molecule IRAK4 inhibitors). If PROTACs outperform small molecule inhibitors in this head-to-head comparison, it could be a huge boost for the modality.
This is yet another example of how new modalities are unlocking the potential to target previously intractable proteins in important indications. Watch this space: we’re going to see more opportunities for bifunctional ligands within and beyond PROTACs.
-Judy Savitskya, a16z bio deal team partner
Upgrading the cell and gene therapy “software” for safety
More “living medicines”, such as cell and gene therapies, are entering clinical trials than ever before – many of which have the promise to treat previously incurable diseases. But figuring out how to increase efficacy, make them safe, and ultimately deliver them to patients remains some of the most challenging (and potentially rewarding) open problems for these new therapeutics. The field received a sobering reminder of the challenges still facing these medicines after the recent deaths of four patients participating in clinical trials. Many signs indicate the high dosing of the therapies as the root cause of the fatal immune responses, which points to the importance of further refining cell/tissue specificity, immune evasion, and potency in these medicines.
One of the primary areas of focus to do this has been on improving the systems by which these medicines are delivered. This is the “hardware” component that encapsulates the gene-based medicine, usually a domesticated virus (AAV). There are new approaches that involve using ML-driven design to engineer variants of the gold-standard AAVs to make them more organ-specific; others are exploring new non-viral systems that are naturally less immunogenic.
But is just improving the “hardware” enough? So far, much less attention has been devoted to re-thinking the other essential component of gene therapies, notably the “expression cassette” and its various components that encode the therapeutic DNA of interest (i.e. the “software” that encodes the “drug”). By redesigning the genetic program itself, it may be possible to achieve a new level of specificity for these therapies. For example, new synthetic promoter designs have unprecedented cellular-level specificity, novel engineered regulatory elements can drive significantly higher protein expression, and engineered switches allow for easy on- or off- regulation of activity (with miRNA or even light). Implementing these strategies will allow precise regulation of where, when, and how much therapy is delivered, ultimately lowering the required dose and improving both efficacy and safety.
These medicines have the real possibility of one day being true “cures” to patients who badly need them. Refining them is key to getting them to those patients faster. Our very ability to iteratively design and engineer biology to develop these new features is a fundamentally new step in the process. By figuring out which dials to turn and levers to pull, the R&D process for living medicines can now begin to mirror that of small molecules drugs, with extensive screening and lead optimization, leading to better and safer medicines for all. Those who are able to crack the code of engineering better ways to adjust and fine-tune the dials of these medicines will be solving some of the biggest open challenges in the field today.
-Andy Tran, a16z bio deal team partner
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