The Gateway Forum

Right time, right team to open up an emerging class of drug targets

July 21, 2020
By Joanne Kotz (CEO) and Joel Barrish (CSO)

Few people have the privilege – and experience the excitement and fear – of starting a biotech from a blank slate. As we begin the next phase of Jnana, including kicking off a new partnership, we’ve been looking back to where we started 3 years ago and ahead to the road to patients.

To ensure health, our bodies need hundreds of metabolites to be in exactly the right place at the right time. The 450 member SLC (solute carrier) family of metabolite transporters are tasked with the critical job of getting metabolites, the chemical building blocks and nutrients essential for life, where they need to be. Yet SLCs have largely been absent from targeted drug discovery efforts. A shockingly low 20 of the 450 SLC transporters are currently targeted by approved drugs.

In 2017, we founded Jnana to close this gap. Stuart Schreiber and Ramnik Xavier, core members of the Broad Institute, spotted the compelling opportunity. We joined forces with them to cofound the company and get it off the ground. We had unwavering conviction that targeting SLCs would create new routes to treat serious disease.

We also knew the path forward would be challenging. No systematic drug discovery technologies existed for SLCs. Relatively few SLCs had been validated as targets. There were (and still are) no other companies focused on this target class. We were going to need a fearless and innovative team and bold investors and partners.

Here, we tell the story of the early days of Jnana: why the time was right and how a group of people –founders, team, investors, and partners – have come together with the shared vision of forging a new ‘SLC path’ to highly effective therapeutics for patients.

founding-team
Jnana founding team (from left to right): Ramnik Xavier, Joel Barrish, Stuart Schreiber, Joanne Kotz

Jnana gets its start

(by Joanne)

For me, Jnana started from a dinner conversation. Stuart asked what I thought of the idea of a new company focused on SLCs. From my time at the Broad, I knew the target class was highly promising and almost entirely unexplored. The answer was obviously yes.

The answer to his follow up question – did I want to be a part of founding the company – was an equally obvious yes. I had begun my career in research and gradually moved to opportunities at the intersection of three of my passions: science, business and collaborative teams. While at the Broad and subsequently at the venture capital group F Prime, I had seen firsthand the power of bringing together a small group of passionate people from diverse backgrounds to solve drug discovery challenges. The opportunity to team up with Joel, Ramnik and Stuart to open an important new path to therapeutics was impossible to resist.

Leading up to 2017, emerging human biology data from the Broad and elsewhere was linking SLCs to a broad range of diseases and pointing to a great therapeutic opportunity in this historically understudied target class. Stuart has had a long-standing focus on metabolites, including paradigm-defining advances such as deciphering the mechanism of action of rapamycin. Ramnik’s research has pushed the boundaries of understanding how host- and microbiome-derived metabolites impact immune and gut homeostasis. Not surprisingly, new links between metabolite transporters and disease immediately caught their attention.

The more Stuart, Ramnik, Joel and I talked, the more convinced we were that the time was right to break open SLC drug discovery. The ability to drug SLCs lagged far behind the rapidly evolving understanding of their biology. As proteins with the job of binding and moving chemicals, SLCs were – in the view of Joel and Stuart — calling out for a small molecule drug discovery approach. We thought new small molecule discovery technologies held promise. Our plans for a company came together quickly from there.

Coming up with a company name took longer. After sifting through many, many options, we landed on a name that spoke to us. Jnana (pronounced je-na-na) is a Sanskrit word meaning knowledge gained through experience. This captured both the knowledge the team brought to Jnana and the SLC experience we were about to build. For me and Joel, this concept also underscored the culture we were committed to fostering. We both believe innovation and progress comes from empowered people and teams constantly learning from each other.

With our vision for the company, we needed investors with the courage to enter a new area where the therapeutic opportunity was large, but substantial innovation was going to be required. In an already ‘hot’ drug discovery area, investments can be driven by FOMO. Without this driver, we needed investors with the conviction to pioneer a new space. Fortunately, the teams at Polaris, Versant, Avalon, AbbVie Ventures and Pfizer Ventures were undaunted and came together in fall 2017 to back our Series A and work with us to build Jnana.

Building a platform and pipeline

(by Joel)

After more than 30 years in Biopharma, experiencing the awesome challenges of drug discovery and development, along with the gut-wrenching failures that come with my chosen profession, I’ve developed the expected skepticism of any idea that appears too good to be true. So, when I first began discussions with Joanne, Stuart and Ramnik about how we could break open SLC drug discovery, I found it hard to believe that it hadn’t been done before. I spent a career working on GPCRs and, especially, kinases where I started multiple projects almost 10 years before the first kinase inhibitor, Gleevec, was approved. I understood the value of taking a target class approach, developing strategies and technologies that could be applied across a broad swath of targets, optimizing each over time. Despite their unique challenges, there was no doubt in my mind that we would be able to bring the same thinking and analogous approaches to the SLC world – I was in!

Starting with a blank slate is exciting – the ability to create a platform, a pipeline, a team from scratch is why one comes to biotech. It’s also one of the scariest things I’ve ever been involved in! We knew that the drug discovery platform would be the central foundation for the company, enabling everything we did, yet the challenge of doing this with such a diverse target class was daunting. There are 65 subclasses of SLCs with variations in structural motifs, metabolite substrates, and cellular locale. They are also difficult to express and purify and are not readily amenable to biophysical methods. How could we develop a single technology that would allow us to identify chemical equity for any SLC?

Fortunately, the answer to that question came with hiring the right team and developing the right culture. Four of our first hires, Giovanni Muncipinto, Lyn Jones, Matt Labenski, and Justin Rettenmaier are separately brilliant, creative chemists and chemical biologists who came together to develop the ideal solution. They first realized that the optimal approach was one that was more general in nature, one that was less SLC-specific but could in theory be applied to other proteins or even other macromolecules. Second, as devotees of Stuart Schreiber and his philosophy of the power of binding events, particularly between small and large molecules, the team focused on identifying SLC binders that could lead to all kinds of pharmacological modalities – not only inhibitors but compounds that could activate the transporter or affect its cellular location or half-life. Being able to identify binders to fully interrogate the SLC protein and discover any ligandable site – orthosteric or allosteric – was paramount.

Leveraging recent advances in chemical biology and chemoproteomics combined with additional proprietary methodologies, the result of this home-grown effort was RAPID (Reactive Affinity Probe Interaction Discovery), an approach to quickly identify progressible small molecules, within weeks. A defining moment for the platform was the recognition by the team that the initial covalent binders (Reactive Affinity Probes or RAPs) to any SLC could be used in a competitive displacement binding assay to screen large libraries of small molecules. With a general solution to hit generation in hand, we were then able to turn to applying it to targets and diseases where we could have significant impact on patients.

As with the platform blank slate, choosing where to begin our journey to identify SLC modulators that could impact disease was a formidable task. SLC regulation of critical metabolites is important in many diseases. Having spent decades focused on immune-meditated diseases, I have been excited by the growing body of data implicating metabolism in controlling the fate and function of immune cells and in turn being able to broadly impact these diseases. Because of their nuanced ability to regulate metabolites – due to selective cell and disease state expression along with specific cellular location and directionality – modulating SLCs is an ideal approach to addressing unmet need in these patients. We decided to focus a significant portion of our early biology efforts on important immune cell pathways to help unveil SLC targets important in immune-mediated disorders.

It also became clear to us that there are certain diseases where metabolite levels – systemic or organ-specific – are critical drivers of the disease. In many of those cases, there is an SLC that is clearly associated with controlling those metabolite concentrations. The attraction of these metabolite-dependent diseases is that the translational path to the clinic and beyond is clearly defined by those metabolite levels.

All eyes on patients

We are excited to advance a pipeline of programs to identify therapeutics for patients who urgently need them. Partnerships with biopharma organizations are an essential part of our strategy, allowing us to address not only immune-mediated and metabolite-dependent diseases beyond our internal pipeline but also other disease areas where SLCs are compelling targets. Jnana’s CBO Caroline Stark Beer has championed this approach and has been an amazing partner in helping realize the strategy.

Early on, we partnered with Neurocrine Biosciences, known for their own SLC inhibitor Ingrezza, to harness the power of the RAPID platform in neurological diseases. We are especially excited to now partner with Roche, an organization that shares our vision for using SLC modulation to make an impact across diseases. We look forward to working with colleagues at Roche to leverage the power of collaboration and mutual learning to break open new therapeutic space.

As we say at Jnana, ‘Time wasted is not our own, it belongs to patients’. It’s time to make our vision a reality.

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