SPR994:  A Long Shot, With Lots Of Twists And Turns To Phase III

Posted May 23rd, 2019 by Ankit Mahadevia, in From The Trenches, Portfolio news

This blog was written by Ankit Mahadevia, CEO and founder of Spero Therapeutics, as part of the From The Trenches feature of LifeSciVC. 

At Spero we are privileged to be enrolling our pivotal study for SPR994, our oral antibiotic with the bacteria-killing power of an IV to treat patients with serious urinary tract infections.  A frightening sign of our deteriorating antibiotic arsenal is the three million patients in the US alone whose infections do not respond to oral antibiotics used in past decades; if these patients are hospitalized they can cost an average of $4,000 more to treat than if an effective oral agent were available.  In this era of a value conscious health care system, there are few interventions that are more cost-effective than getting patients out of the hospital or keeping them out. SPR994 could provide the tool to make this happen.

We tell the story of why patients need SPR994 often (here) ;  how we found SPR994 is a story worth telling as well. SPR994 has been an important driver of Spero’s growth and a lesson on how long shots built on a shoestring budget have the potential to pay big dividends.

Starting out: $200k budget and looking for a needle in a haystack

Since inception, Spero’s mission has been to build a complementary portfolio treating serious infections. Clinician colleagues consistently highlighted the need for a broad spectrum oral agent as the missing piece in their toolkits. Based on this need, our Board supported investing time and potentially up to $200k over four months to explore the landscape further.  This was not a trivial decision as we already had our hands full with the rest of our pipeline, but the end game of expanding our portfolio with a drug to help millions of patients was tantalizing.

Our first comprehensive search for such an agent yielded little. On the cusp of moving on to other projects, we tried a last-ditch effort of employing a colleague, a fluent Japanese speaker, to look within the non-English medical literature for a hidden gem. He ultimately found tebipenem pivoxil, marketed by Meiji Seika in Japan, which we reformulated to become SPR994.  The Japanese literature highlighted tebipenem pivoxil’s great credentials as a molecule, including the potency to treat resistant pathogens, best in class oral bioavailability, and  a 9 year post approval safety track record in Japan.

Building the program: Case study in resourcefulness

We had found a needle in a haystack; still, we had two hurdles yet to cross before we could invest further. First, the marketed product in Japan was in granule form meant for pediatric dosing – its stability and the amount of granules needed to treat adults with cUTI were not ideal. We put our meager budget to work to convince ourselves that we could address these limitations.  Our team worked with a CRO on key experiments supporting a tablet formulation that was room temperature stable, and that ultimately formed the basis for important patents filed for SPR994. 

Second, of course, we needed to close a mutually agreeable partnership with Meiji. We were fortunate that our CSO had a prior collaboration with Meiji.  With the help of a mutual colleague based in Japan, we arrived at a collaboration in which we shared our IP and regulatory filings with Meiji in Asia, and Meiji shared its data and manufacturing capability with us.   The team’s ingenuity and grit were on display here: our development team was very creative with a limited budget to answer our key formulation questions and build the initial foundation for a patent. The BD teams at Spero and Meiji bridged differences in culture, time zones, and opinions on key issues, with our COO even taking one of the final negotiations, a three hour call, in the basement of a Viennese palace while on holiday.

Some valuable lessons

I reflect on some of the decisions we made that set the stage to create SPR994:

  • Balancing focus and growth – listen to the team and create a structure: For emerging companies this is a constant tension – double down on what seems to be working or create optionality for the future.   The passion of the team once we found what became SPR994 was a major driver in finding this balance; I credit our Board for placing trust in our ability to execute and run with the project.  Having clear goals, a discrete budget, and clear go/no go (either we found a project with legs after 4 months, or we moved on) helped make that balance work.
  • Partial funding doesn’t mean partial potential: At Spero, we have always taken a risk gated approach to drug development. We ratchet up money and time when programs cross important stage gates; as leaders we had to focus on balancing good fiscal discipline and ensuring that a limited budget didn’t impact the ATP behind the SPR994 program. I credit the SPR994 program team for their passion and advocacy throughout as this was critical to keep the program going in the early days as other projects competed for time and capital.  We often return to this example now when our teammates offer up ideas they are passionate about but hesitate when they’re not “fully funded.”
  • Orthogonal expertise drives ingenuity: At each twist and turn of the SPR994 story, it took an expert (on the antimicrobial landscape, formulation, in Japanese language, etc.) to break through where the obvious step would have been to fold our tents.  This experience and others have taught me that the best place to nurture and grow long shots is where one’s expertise is better than anyone else’s. Temptations abound in a scaling company to pursue ideas that seem great on surface but where one doesn’t necessarily  have world-beating expertise. It take a degree of humility and introspection to appropriately identify when one has this expertise, and when one does not.

From improbable beginnings, SPR994 has become our lead program and an engine of Spero’s growth.  Because of the Meiji data and the unmet need, we have collaborated with the FDA on an accelerated path towards approval, and are now enrolling the single Phase 3 trial needed for approval in complicated urinary tract infections. We are proud of what we have created to date with our partner Meiji, and excited to continue to advance the program towards patients that need it.

Ankit Mahadevia

Serial biotech entrepreneur and executive
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