John Evans, CEO of Beam Therapeutics, on the Business of Biotech

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John Evans, CEO of Beam Therapeutics

In our final season 1 episode, we spoke with John Evans, CEO of Beam Therapeutics. Beam Therapeutics is a leader in the nascent gene editing space, pioneering proprietary base editing (i.e., single nucleotide swaps in the genetic code) to develop precision genetic medicines.

John has led Beam Therapeutics since 2017, most recently leading their $300M+ research collaboration with Pfizer. He was previously SVP of Portfolio Leadership at Agios Pharmaceuticals , commercializing the first-in-class IDH inhibitor IDHIFA. Prior to Agios, John worked in Infinity Pharmaceuticals and McKinsey. John earned his bachelors in English from Yale, his MBA from Wharton, and Masters in Biotechnology from UPenn.

In our conversation, John and I covered:

• Navigating a career in biopharma, including starting out in Big Pharma vs. biotech
• Lessons in commercializing therapies from preclinical stages to approval
• The programmability of Beam’s gene editing platform
• Evaluating partnerships with Big Pharma, including equity dilution vs. product value dilution
• Future trends in gene therapy accessibility, in terms of both disease areas and healthcare costs

1:16 to 5:29: Navigating a career in biopharma

• On a “linear” trend in biotech: Following his English degree from Yale, John found his passion in pharmaceutical business, moving from consulting to bigger biotechs to progressively earlier-stage, smaller, more “science-y” organizations.
• On going first to Big Pharma vs. moving to earlier-stage biotechs directly: Smaller stage biotechs, John admits, have fewer guardrails, with a focus on speed of execution without too much on-the-job training, which you could alternatively pick up at bigger organizations. However, ‘big picture’ learnings surface more readily at smaller organizations: how science generates data, how data translates to value, and value drives investments dollars which in turn fuel further science.

“Either you should do what I did, which is steadily get smaller — don’t spend too long in the bigger phases, but learn what it should look like…or jump more quickly in the smaller end but make sure you have incredible mentors already in place, who know what to do and can teach you. That’s the trade. One of the two needs to be true”

5:30 to 11:45: Learnings from commercializing therapies across the development life cycle

• On the criticality of having a genetic driver of disease: At Infinity Pharmaceuticals, John led their lead oncology program, which failed without genetic validation. Using his learnings, John moved to Agios, leading IDH inhibitor commercialization (Ph1 — approval). The key difference from Infinity was a clear genetic driver of disease: with IDH inhibition, there was a distinct gain-of-function mutation to target, an evident biomarker readout upon activity, and straightforward translation of pathophysiology to patient outcomes. Genetic validation of a disease target, as he explains, can give a clear path to development: who to treat, which signals to read early, and whether a relatively rapid path to approval exists. This approach underlies the new class of precision medicines.
• On evaluating ‘risk’ in developing medicines: John explains that therapeutic development will inherently involve risk, but it can depend on where you take it. For traditional therapies, target/biology risk remains key: whether intervening in the pathophysiology will translate to therapeutic outcomes, which becomes evident in later stages of clinical trials. John prefers technology risk, which resides early in executing the required genetic edits; however, if completed successfully, there are fewer questions whether such a change will correct for disease phenotype.

11:46 to 16:38: Beam’s ‘programmable’ gene editing platform

• On Beam’s best-in-class editing strategy: Traditional approaches, like CRISPR, remain programmable in its “search and replace” approach, yet cause double-stranded DNA breaks and have limited control. In contrast, Beam leverages CRISPR but avoids DSBs by making a single nucleotide (base) change, yielding greater control/precision and fewer off-target changes.
• On scalability challenges around precision medicine: While going after certain mutations can yield smaller subsets of patient populations, John reminds us that Beam’s platform accelerates the development of new medicines after the initial development (e.g., proving a safe, efficient genetic edit in a specific tissue expedites similar genetic editing, derisking future therapies), so subsequent patient subsets should be easier to go after. Furthermore, John expects regulatory innovation to accelerate as greater precision medicines enter the commercial fold: proving the safety of the technology for the initial genetic edit should then expedite testing of that technology for other edits and diseases. Beyond point mutation correction, Beam’s base editors seek to silence, activate, and change the function genes, all of which can go after larger patient populations.

16:39 to 21:54: On leading and evaluating Big Pharma collaborations

• On the value of pharma partnerships: In biotech, John explains that the key is to de-risk your programs, generate value, yet own enough of your products to capture the enterprise value you are generating. The two main paths for this, as he explains, remain equity financing and pharma partnerships.
• On ‘dilution’ in pharma partnerships: John’s Agios/Celgene deal shared development costs but largely ceded commercialization rights. The key dilution trade-off, here, was product value dilution (instead of traditional equity dilution). By contrast, Beam has retained more control over its pipeline; Beam’s recent collaborations either focus on novel targets outside of Beam’s focus (e.g., Pfizer) and require the expertise of external organizations (e.g., Verve’s cardiology expertise).

“[The Celgene deal] was fairly dilutive — not on equity, but on product value. We [had] given away most of the control and value of that portfolio… [At Beam] we made the decision that we didn’t want to do a big deal early — we didn’t want to give away too much control too early. We’ve kept all [our] assets wholly owned; now, we can do that because equity markets have been much better.”

21:55 to 33:30: Future trends in gene editing

• On the variety of gene editors today, and which will ‘win’: John favors permanent edits to the genome that avoid double stranded breaks. But beyond that, John does not envision a ‘winner takes all’ outcome. High-efficiency, cell-type agnostic, precise edits favor base editing, for example, though gene insertion requires an alternative, complementary approach. Yet beyond editors, John predicts the next wave of innovation will center around the delivery mechanism of payload (e.g., ex-vivo editing, in-vivo lipid nanoparticles, viral vectors). As such, John views three components to the future of precision genetic medicines: complete the right kind of edit for payload, deliver it to the right tissue, and manufacture it in a scalable manner.
• On expanding gene therapies beyond rare diseases: John reframes gene therapies today as targeting not necessarily rare diseases, but ‘serious’ diseases. In balancing severity of unmet need with as-of-yet uncharacterized risk (with these new modalities), he points out that therapies today must “go after the areas with the highest urgency to treat” — which could be rare, but may well include larger populations as comfort with the technology grows.
• On improving patient access to cell and gene therapies in the future: While John admits several current gene therapies have yet to be proven as truly one-time cures, he believes future gene editing medicines should be permanent, which would justify the higher prices to displace other chronic medical costs.

Nota bene: Even Peter Marks, Director of CBER at FDA, has recently remarked about the financial viability of the cell and gene therapy space going after small patient populations.

“These will be expensive therapies, but the value to the healthcare system overall will be a net savings, because you are preventing medical costs and displacing expensive chronic therapies and removing a lifetime of hospitalizations…That’s different from saying it’s easy to pay for them. There’s a payment issue, around that one-time lumpy check that a payer has to write…We still need to work on making [these therapies] cheaper over time. As technology advances, there will be ways to democratize this to bring [prices] down… But because we are transforming serious diseases and displacing other expensive care, [these therapies] will still be attractive”

33:31 to End: Advice to those seeking a career in biotech

• Follow your curiosity, and find your mentors: Rather than stress over your first job out of school, John stresses the importance of following your passion across multiple jobs, collecting data around what you like. Furthermore, he recommends finding mentors: seeing great leaders in action and living that journey with them to understand what works and what doesn’t for your own adventure, gradually building up experience over time before running an enterprise directly given the complexity of the industry.