CAR-T, People, Startups, Venture

Looking for the next big breakthrough in CAR-T, Mike Gilman debuts Obsidian with $49.5M round

Biotech entrepreneur Michael Gilman is now on to his fourth startup Suzanne Kreiter, Boston Globe

Over the past couple of years, the pioneers in the CAR-T field have made some phenomenal leaps forward, and been hit with some of the most dramatic setbacks in biotech. They’ve offered advanced stage cancer patients a second lease on life, and run into daunting hurdles on the outer limits marked by the graves of patients. And now a biotech upstart is graduating from a substantial — and very quiet — seed effort in a drive to the clinic with a new tech specifically designed to address the biggest challenges in CAR-T.

Enter Obsidian Therapeutics, the latest in a string of biotech launches under the guiding hand of serial entrepreneur Michael Gilman — now on to his fourth startup alongside his other day job at Arrakis. And the crew there, with a staff of 20 set to grow to around 35 next year, have a $49.5 million round led by GV to fund the next stage of the journey.

While the first two now-approved CAR-Ts — engineered patient cells redirected to kill cancer cells — were approaching the market, Obsidian was working on a new technology that promises to fix some of the most important limiting factors that are holding these therapies back.

“This is going to be a big deal,” says Gilman, in what is fast becoming a big field.

So listen up.

Tom Wandless

This all started, Gilman tells me, with a phone call from Tom Wandless, who had been a student in Stuart Schreiber’s lab at Harvard working on a tech project picked up in the ’90s by Ariad, a company which gave Gilman his first job. The tech was later out-licensed to Bellicum and Wandless went on to set up his own lab at Stanford. Wandless kept at it, and 20 years later — in 2015  — he had an idea for a new biotech.

Gilman knows people who finance that kind of stuff.

They launched the company about 18 months ago, playing their cards close to the vest before wrapping the A round and setting up their virtual coming out party for today.

In simple terms, here’s what Wandless and his team did.

Building off some research work he’d done in the lab for years, the crew has been working with what he calls destabilizing domains, mutants which can be encoded in a “synthetic biologic cassette,” packaged in a vector and dispatched to tinker with an engineered CAR-T cell, to control proteins. Doing that, they intend to amp efficacy and dial down toxicity threats through a small molecule operating system managed by the attending physician — basically using easily accessed generics and other approved drugs.

The platform is built around a common biologic function for the disposal of dysfunctional proteins — mutated proteins that are only partially unfolded which are tagged by the body’s disposal system and taken out to the trash.

“The magic is when you provide a small molecule ligand it folds up and looks like it’s stabilized,” says Gilman, “you can now use the small molecule to regulate the stability of the protein.”

This is what Obsidian is calling an operating system for living medicines, with potential in gene therapy as well.

If you can regulate proteins, you can accomplish three things that limit CAR-Ts today, all of which revolve around the current spotlight in the clinic: Controlling the way this personalized therapy is dosed so you get maximum effect with manageable risks. The goal is durability without toxicity, preventing relapses as cells are exhausted.

First, Gilman ticks off, you can prevent cytokine release syndrome — the toxic storm that occurs in patients when a swarm of these engineered cells run into a galaxy of antigens associated with a high tumor burden — by “managing the proliferation of the cell in an orderly fashion, so they don’t slip out of control.”

You can replace the “brutal” flu/cy preconditioning regimen now in common use with a new approach that would allow a physician to take the therapy up to the right, safe maximum level for a particular patient, and then leave it there.

And you could potentially go back to a well known, and highly toxic, pro-inflammatory player like IL-12 and tame it for use in solid tumors, powering up the effect in order to make it work in solid tumors — one of the next big challenges in CAR-T which would open up the market to a whole new level.

Atlas seeded the 18-month lab project, and is stepping into the $49.5 million launch round alongside GV, the Google venture arm leading the round, Takeda Ventures, Vertex Ventures HC, Amgen Ventures, Alexandria Venture Investments, and ShangPharma Investment Group.

That suggests a few things about some of the most upbeat possible futures that await Obsidian.

Atlas is a venture group that enjoys nothing better than seeing its fledglings work with a well financed partner, if not actually doing a sale at an early stage of development. Gilman knows that as well as anyone, and he’s quick to acknowledge that there are a lot of possibilities for doing a partnership early on, with no need to necessarily recreate the entire CAR-T wheel at Obsidian. But, he adds, if you’re willing to write a big enough check, you can do all the manufacturing and everything that comes with that. And these days, there are several investors that specialize in those kinds of checks.

Also, there are other things this tech can be used for, leaving lots of work for the team no matter what happens with CAR-T.

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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