Alvea’s Story, Wins, and Challenges [Unofficial]

Intro

A few months ago, the other (former) Alvea executives and I made the difficult decision to wind Alvea down and return our remaining funding to investors. In this post, I’ll share an overview of Alvea’s story and highlight a few of our wins and challenges from my perspective as an Alvea Co-Founder and former CTO, in hopes that our experiences might be useful to others who are working on (or considering) ambitious projects to solve the biggest problems in the world. I’m sharing everything below in a personal capacity and as a window into my current thinking—this is not the definitive or official word on Alvea and it doesn’t necessarily represent the views of any other Alvea team members*. I expect my reflections to continue evolving as I further process the journey and outcomes of this project, and hope to share more along the way. 

*Note (added 11/1): Cate Hall, another Alvea Co-Founder and executive, also endorses these reflections.

Alvea’s Story

First vaccine sprint and decision to continue Alvea (December 2021 through April 2022)

We launched Alvea in response to the Omicron wave of COVID-19 (the most transmissible and immune-evasive variant then to have arisen) as a short-term, high-risk project with the goal of developing an easily-deployable, room temperature-stable DNA vaccine against Omicron as quickly as humanly possible, without compromising on safety and quality. We ultimately carried this vaccine candidate into Phase I clinical trials in less than 6 months, becoming the fastest startup ever to take a new drug candidate from company launch to a human clinical trial. Our success in this initial sprint caused us to expand our ambitions for Alvea and explore ways of building on the track record and momentum we’d built up. 

One of our initial strategies was to deploy our first vaccine (which was optimized for the Omicron BA.2 variant), and then leverage our development platform to roll out updated versions in response to the emergence of new variants. However, a few key updates convinced us that this was not a promising path. First, the time between waves of new variants continued to drop, making it more difficult to keep up with viral evolution. Second, the FDA and other regulators began an expedited approval process for updated versions of the mRNA vaccines that had already been authorized, making it more difficult for new vaccines to break into the commercial market (a great pandemic regulatory move, though!). Additionally, early efficacy results for our vaccine were underwhelming and suggested that it was unlikely to provide sufficient protection to justify continued investment, particularly against the newest variants in low- and middle-income countries. In light of these updates we decided to stop development of our candidate and consider other paths forward.

Product pursuits (May 2022 through July 2022)

Despite discontinuing our first vaccine program, we believed we’d landed on a compelling model for general-purpose acceleration of promising drugs and vaccines into the clinic, so we set out to find other high-impact products we could accelerate with this approach. We specifically targeted products and technologies with early published preclinical data that were nearing readiness for clinical testing, with the idea that we could pick them up and dramatically speed up their development and deployment. We ran multiple “product pursuits” in parallel to explore possible technologies, with particular focus on nucleic acid vaccines that could be formulated as dry powders for inhaled administration and on therapeutic interfering particles, a class of RNA therapeutics/prophylactics that are expected to be highly resistant to viral evolution. Neither of these efforts uncovered product opportunities that were clearly good bets under this model—all those identified were either insufficiently promising from an efficacy standpoint, or too far from the clinic for us to make a high-confidence bet. However, the process did yield a set of more speculative technology ideas that involved greater technical risk, but had a strong enough case for impact to potentially be of high expected value.

Second vaccine sprint (August 2022-December 2023)

We ultimately took the highest-upside technologies identified in the product pursuits and combined them to create a new COVID vaccine candidate designed to be broad-spectrum/variant-resistant, shelf-stable at room temperature, and self-administrable by inhalation. This involved betting on much more speculative technologies than we used for our first candidate, but we thought this bet was justified given the potential upside, which included not only the next generation COVID-vaccine itself, but also the validation of platform technologies that could help enable rapid design and efficient distribution of effective countermeasures against future worst-case pathogens.

We set ourselves an ambitious goal of submitting a clinical trial application for the new product in ~4 months from the start of development (compared to multiple years for typical new product development of this kind). While the experiments we ran in this sprint showed initial promise for two of the three core technologies we used in the design, the results were not sufficiently compelling to warrant a rapid push into clinical trials, as it was clear that the underlying technologies required further development prior to being deployed. So, we decided to hold off on the application submission, despite having laid the groundwork for another rapid Phase I trial. 

Funding environment change and pivot (Dec 2022 - May 2023) 

As we neared the end of our second sprint, the funding environment for projects like Alvea changed dramatically—the philanthropic funding available for cash-intensive, impact-motivated projects plummeted around the same time that the venture capital market for early stage biotech companies plunged to historic lows. Together, these changes seriously limited Alvea’s funding options.

In response, we cut our burn rate, and proceeded with two parallel efforts:

1. We ran a series of smaller-scale, lower-cost follow-up experiments to further develop the technologies that underpinned our second vaccine design, and began pursuing government grants and other non-dilutive funding sources to allow us to continue pushing these technologies toward the clinic. Although we collected some promising data from early experiments, we did not secure sufficient funding to make a major commitment to this program in the time we allotted, and were further dissuaded from pursuing it further at Alvea as it did not offer a clear path to financial self-sustainability for the company.
2. We mapped alternative commercial strategies for Alvea that would incur less technical risk and be a better fit for the new funding environment. After many rounds of iteration we crafted a partnerships-focused business model, where we’d offer our rapid translation and early clinical development capabilities as a service to other biotech companies. The central idea was that we would use the internal systems and infrastructure we’d built to accelerate drug and vaccine candidates from other companies into the clinic, and capture a portion of the commercial value created as a result. This strategy offered a commercial path for Alvea that was more robust to the funding environment (as other companies would be footing most of the bill for development), and was also a means of efficiently expanding our general-purpose rapid response capabilities by working on a diverse set of 3rd party molecules. We built a sales pipeline, pitched versions of this offering to 50+ biotech companies, completed two pilot projects, and lined up an initial customer for an end-to-end development program, at which point we decided to pivot the company completely to this new business model.

Wind down and PanLabs spin out (June-Present)

As we gained traction with the new partnership strategy following our pivot, we continued digging deeper into commercial forecasting for this new strategy, evaluation of the potential paths to impact on worst-case biorisks and global health, and reflection on the global context in which we were operating. This analysis ultimately led us to conclude that despite the promise of the strategy, the path to impact was too long and uncertain, and the commercial potential insufficiently large, for us to feel confident in committing the necessary time and financial resources to its pursuit. 

There was no definitive set of outputs from this analysis that sealed the wind down decision, which unfortunately limits the level of detail I can provide here. There were considerable differences of perspective amongst the departing executives about the conclusions on different points of analysis and the weights they should be assigned—for example, I was optimistic about our commercial prospects but concerned about lock-in effects of the new strategy and counterfactual uses of my and the rest of the team’s time, while others were more skeptical of the viability of the path to realizing Alvea’s upside potential. However, despite these differences, we were ultimately unanimous in concluding that the balance of factors pointed toward winding down and returning our remaining runway to investors. 

As part of the wind down, we helped launch a new non-profit, PanLabs, an impact-focused research and development organization. PanLabs is led by Brian Wang, formerly Alvea’s head of R&D, and he’s joined by a large part of Alvea’s Science team.

Wins

Record time to safe clinical development

Our most concrete win was the development of our original vaccine candidate into the clinic in record time without compromising on safety. To our knowledge, we became the fastest biotech company ever to go from company founding and design of a novel drug candidate to the start of a clinical trial. This achievement required solving a huge number of technical, operational, regulatory, and logistical challenges, which our team consistently knocked out of the park. When we consulted with expert advisors and industry veterans on our overall project and many of the individual problems therein, they often told us that what we were trying to do was likely impossible. We proved them wrong at nearly every turn. While the efficacy of this vaccine was not what we hoped, we believe this success is a testament to what’s achievable when a talented, altruistic group of people come together to tackle a seemingly impossible task. We hope to see many more such projects in the future. 

General-purpose rapid drug development capacity

In the process of developing our lead vaccine candidates and exploring many others, we built general-purpose systems and infrastructure that could be used to accelerate development of diverse drugs and vaccines, for biosecurity and beyond. We honed approaches for quickly in-housing new tools and technologies, squeezing extraordinary work out of external vendors, and leveraging strategic parallelization and vertical integration to radically collapse conventional drug development timelines (e.g. under our oversight, multiple external industry partners reported hitting their own clinical and manufacturing milestones more quickly than they’d previously thought possible). We hope that our success in this area can serve as general inspiration and proof of concept for more efficient drug development, and that others may be in a position to apply the specific strategies we developed. We’re exploring the best ways to share these, but for now please get in touch if you or anyone you know would be interested in learning more!

Team Development

One of Alvea’s biggest indirect achievements, and the piece of our story which I expect may have the greatest long-term impact, is the growth and development that our projects catalyzed for the people who worked there. Many of our team members played central roles in the end-to-end design and development of a vaccine into the clinic. Nearly every person who worked at Alvea took on and solved problems that were thought by many others (both within and outside the company) to be completely intractable, and developed a general attitude of embracing such challenges. In just a little over a year, multiple team members went from being early-career individual contributors, to exceptional managers and directors, helping position them to launch and lead ambitious high-impact projects in the future, in biosecurity and beyond. I believe the central factor in enabling this extraordinary growth and development was the simple fact of continuously putting people in situations where it was required of them.

Medical countermeasure knowledge

Due to the experiences of Alvea’s alumni, there is now far more expertise and experience with pandemic-relevant medical countermeasure development represented in the effective altruism and biosecurity communities. This positions us much better to collectively evaluate whether new medical countermeasure projects are promising and likely to be cost-effective, either as general preparedness measures or in response to specific threats, and to pursue such projects if warranted. We are also excited about opportunities for this knowledge and experience to be applied to biosecurity interventions beyond medical countermeasures, and to other cause areas entirely—Alvea alumni are already working at PanLabs on ambitious countermeasures for worst-case scenario pandemics, on technology roadmapping for Far-UVC, on applying lessons from pharmaceutical regulation to AI governance, and more.

Challenges

Note: The challenges below are selected for high confidence and I’m sharing them here in hopes that they provide useful data points on the kinds of issues that other organizations like Alvea might encounter. Importantly, they are not intended as an explanation or justification for the decision to wind Alvea down.  

Challenges of rapid growth

In early 2022, we rapidly expanded the Alvea team as well as our spending, growing to about 35 people within the first few months of our existence and making big investments in projects, equipment, and people. This growth and early spending was essential for us to hit our initial goals, but once the first sprint was over we failed to quickly recognize where our organizational capacity, head count, and financial and operational overhead required adjustment in service of sustainability. We didn’t confront this issue head-on until the start of 2023, when funding constraints forced us to look more clearly at our overall traction and burn rate and decisively address the discrepancy between the two. We conducted two rounds of layoffs, implemented more rigorous financial tracking and budget controls, and did substantial operational streamlining in the following months which helped address this issue, but our delay had already consumed substantial time and money. 

Costs of complex non-standard corporate set up

A series of our early choices about Alvea’s corporate structure caused lasting issues that negatively affected our prospects. In the process of spinning Alvea up under intense time constraints, we made quick and unusual decisions about corporate governance and the distribution of Alvea’s equity. These decisions created thorny issues and hindered Alvea’s progress by consuming substantial ongoing time and energy from the executive team, and by making fundraising more difficult. Defaulting to standard startup legal structures and norms wherever possible would likely have avoided most of these challenges. 

Navigating the transition from short- to long-term goals

Alvea started as a time-limited project pursuing a specific near-term objective (taking our DNA vaccine candidate into clinical trials as quickly as possible) to have a large impact in a public health emergency. We maintained a laser-like focus on that objective for the entirety of our first sprint. After our initial success, we decided to continue building Alvea and only then began spending significant time thinking about longer-term strategy. This resulted in a form of strategic “debt” which, despite our strategy work from then on, was challenging to overcome. On reflection, I see missed opportunities for more thorough ideation, analysis, and red-teaming of early strategic roadmaps, and for more explicit recognition of our changed needs following the end of the first sprint. Taking advantage of these opportunities would have come with painful near-term costs, but the setbacks would have been a worthwhile price to pay. The additional investment could have put us on a stronger trajectory by more quickly revealing high-leverage issues and productive strategy alternatives (e.g. experimenting with a partnerships-focused business model months sooner than we did). 

Conclusion

Alvea’s journey and ultimate dissolution have taught me an enormous amount about the challenges of building companies/organizations, of solving big problems, and of aiming for a massive positive impact in the world. The experience has not, however, changed my perspective on the importance or the potential of such pursuits, which I continue to believe in deeply. I hope Alvea’s story may prove useful to those considering other projects in a similar vein. I also recognize that what I’ve written here is incomplete, and that specific people would probably benefit from more detailed explanations or discussion of some of the things I’ve shared (or not shared) above. If that’s you, please don’t hesitate to reach out to me directly.

To conclude, I want to echo the gratitudes shared in the official Alvea announcement—I am enormously thankful to the entire Alvea team, our investors, and our other supporters and collaborators for making it possible for us to take this shot. The people I worked with at Alvea, both within and outside the company, stand out as the most talented, most caring, most fun, and most ambitious team I’ve ever been a part of.