By Ankit Mahadevia, CEO of Spero Therapeutics, as part of the From The Trenches feature of LifeSciVC
Earlier this fall, we prepared to report Phase III data for tebipenem HBr, our oral medication that, if approved, could help 2.7M patients with serious infections in the US alone go home and stay home from the hospital.
The data were in hand by Friday of Labor Day weekend; a small team sworn to secrecy parsed through the tables, listings, and figures summarizing the data. They knew the result, and now, after triple checking it into the late hours of the night, gathered our leadership team. Many of us were in person together for the first time since March in a (large, well ventilated, masks in tow) conference room to hear the readout.
Negative data meant that half of the team sitting together and many more of our teammates would be making their plans to leave the company if our lead clinical candidate could not advance to approval. Positive data meant we would set to work on the plans we had been making for months.
This was a moment like no other in Spero’s history, and one that’s unique in biotech as an industry just given the odds of drug discovery. The percentage of compounds that even get to Phase 3 is low, and those that make it past are fewer still. One of our Board members likened waiting for pivotal data to baking a (very expensive) cake for years when you can’t taste the batter or look in the oven door until it’s done. Despite a very strong scientific rationale for our dose, the degree to which chance and nature impact what we can deliver to patients makes a pivotal readout, as our CSO likes to say, “a character building event.”
So how does one plan for such an event, where all degrees of freedom for the enterprise (data positive, data negative, data mixed; market reacts well, market does not) are possible and largely hard to predict? We share some thoughts from our experience and the intensive scenario planning in the months prior that allowed us to move nimbly after we received our news.
Play to win: First, we trusted the extensive work that went into our trial design and dose selection and played to win. The broader market was quick to say how hard developing an oral agent for serious infections had been historically – 26 years had passed since the last approval of an oral for complicated urinary tract infections in this sector. Given this audacious task, taking a $75M+ investment meant some deep discussions about our level of conviction around tebipenem HBr before we started the trial and on the basis of interim data readouts within the trial. This meant that we took the long view in investing even ahead of the data to ensure we’d be on track from a commercial, manufacturing, and strategic perspective if the drug delivered in the study. We focused on long lead time activities that had the greatest impact on timeline to approval such as CMC and payor access. While the reason one does a clinical trial is to test a hypothesis, planning to fail means suboptimizing the path forward if the study is successful. This stance, of course, needs to be within limits; shorter lead time activities needed to optimize an NDA and launch needed to wait until the readout despite our team’s conviction.
Hold this mentality together with tactical downside planning (as hard as this may be): The ability to hold this mentality of playing to win, and being prudent about ensuring optionality if the drug fails, took a considerable about of mindfulness and mental agility for our team. Months before the data readout, we undertook the exercise of (as our team called it) planning for our wedding and our funeral at the same time. Planning for success is exhilarating – this plan was in place for some time. Planning for failure, was the opposite – I felt physically nauseous as we walked through the tactics of how we’d adjust the company’s footprint if we were pivoting to our earlier stage pipeline. The difficulty of scenario planning for our demise aside, the value of minding even the most tactical details of failing efficiently was the right thing to do – it would have enabled us to move fast to give our team clarity and ensure we had maximal resources for our remaining programs.
We also benefited from taking a long term perspective in this, as we planned the year before the readout around what we could control: ensuring that we have enough cash on the balance sheet and made enough clinical progress on our Phase II and Phase I pipeline programs for those programs to drive the company should tebipenem Hbr fail. Although we had conviction, holding that together with the possibility of failure enabled us to ensure a better universe of outcomes. There are limits to this as well; when playing to win and planning for another outcome were in conflict, tie typically went to playing to win as it related to capital strategy and investments in NDA readiness.
Help our teammates manage uncertainty: As a senior management team, we are best able to manage the whirlwind of anxiety and excitement ahead of a binary event, as we have some ability to invest resources to optimize the best and worst outcomes. More junior members of the team have less of an ability to invest , but they are no less impacted by the result. There was no magic bullet in our experience – just deep empathy and investment of time to have personal discussions. I credit each member of our executive team for taking the time to talk through this rollercoaster with their teammates and keeping them focused on the task at hand and mindful that we would do the right thing for employees regardless of the outcome. Equally important is investing the time to ensure that the team deeply understands the result after it is announced, despite the many external discussions that investors and clinicians were keen to have with us after the readout.
After ten minutes (which seemed like ten hours) of reviewing study design and protocol during this (now legendary) Friday meeting, our study physicians finally broke their poker faces on the video screen with a big smile, and announced the results – POSITIVE! We threw our “fail plans” in the trash, and popped more than one bottle of champagne for a Labor Day Friday evening unlike one we’ve ever had before. We’re thrilled to get to work on behalf of patients to get tebipenem Hbr to an NDA filing and ultimately to launch. Some very thoughtful planning in the years, months, and days ahead of our clinical readout ensured that we didn’t waste a single moment in getting started.