Axel Hoos wants to take small molecules further at Scorpion, leaving Big Pharma in the dust

Axel Hoos, M.D., Ph.D., left GSK almost a year ago, setting off to reinvent small-molecule drugs as CEO of Scorpion Therapeutics. It's a type of drug that's ripe for innovation, he figures, as other companies shift to new, hotter treatments like CAR-T.

“It's actually quite amazing that the entire industry has not yet categorically stepped up the quality of making small molecules,” Hoos said in an interview with Fierce Biotech. “We could have done this earlier.”

Scorpion Therapeutics CEO, Axel Hoos
CEO Axel Hoos, M.D., Ph.D. (Scorpion Therapeutics)

And it seems the Big Pharma scene Hoos left behind is taking note. While biotechs around him struggle and lay off staff, Scorpion is staying in the shade. It has booked a major partnership with AstraZeneca—and other potential partners have come calling. Plus, Scorpion has zeroed in on two clinical candidates to advance toward the clinic in 2023. 

“Even in this market, when everybody's a bit more hesitant, we are still getting a lot of interest,” Hoos said. “There is no Big Pharma that can do right now what we can do—and they are picking up on that.” 

Hoos, who came to Scorpion from GSK almost exactly a year ago, took the biotech's reins from interim CEO Adam Friedman, M.D., Ph.D., last July. Friedman had held the interim title for five months after Scorpion’s founding CEO Gary Glick, Ph.D., departed in February 2021.

Scorpion applies its precision oncology drug-hunting platform to validated oncogene targets to create small molecules. But it also explores the potential to develop drug candidates for undruggable targets. The 2.0 platform includes genomewide CRISPR with medicinal chemistry and data capabilities such as chemical proteomics and supercomputing.

In plain English, the platform combines several innovations to develop small molecules that are more selective, which improves treatment efficacy and reduces toxicity. Scorpion's speedy development of two clinical candidates over the last two and a half years speaks to the platform's quality and potential, Hoos said.

“We’re elevating the whole game of small molecule creation,” Hoos said. “It's a total suite of technologies drawing from 20 years of history and innovation.”

Instead of focusing on the entire tech suite necessary to develop best-in-class small molecules, Hoos believes drug development has relied too much on individual tools. He compared it to taking one tool—say a hammer—to fix a problem. With a hammer, everything can only be approached as a nail. In contrast, Scorpion is building out a toolbox so it can choose the right tool for the right target to make the right molecule, Hoos said.

“Small molecules have been around for so long, some people are no longer excited about them—they think CAR-T is much more interesting and, in principle, that's true,” Hoos said.

But the chief executive wanted to aim for best-in-class small molecules because he believes that work can come to fruition more quickly than other modalities—and therefore will help patients sooner.

Hoos calls it operationalizing innovation: He goes where he believes the biggest impact can be made in the near future, a philosophy he followed during his time leading oncology teams at both GSK and Bristol Myers Squibb. 

Scorpion’s first clinical candidate, announced in March of this year, is a mutant-selective PI3Kα inhibitor dubbed STX-478. Hoos believes STX-478 has the potential to overcome selectivity and efficacy limitations associated with current agents for an array of tumor types. The biotech expects to submit an application with the FDA in the first half of 2023 that, if approved, would allow initial human testing. Scorpion plans to target solid tumors with activating mutations at H1047 in PI3Kα, which encompasses multiple indications including breast cancer.

The second clinical candidate, announced at the end of June, is an oral small-molecule drug known as STX-721 for non-small cell lung cancer that expresses EGFR with exon 20 insertion mutations. Several therapies are already on the market targeting that same cancer type, and multiple others are in development, which means Scorpion has a lot to prove.  

“For us to come out and have another one doesn't really make sense unless you believe you can do something vastly different—which we do,” Hoos said.

Scorpion is designing STX-721 to reduce treatment toxicity, boost activity against disease and lengthen the treatment window time, he said.

Scorpion is using AstraZeneca’s Tagrisso as a benchmark for STX-721. Though it didn’t come to market first, Tagrisso is the leading EGFR treatment for lung cancer, Hoos said, with about an 80% response rate, a longer treatment window and moderate toxicity—including potential fetal damage for pregnant patients, possible pneumonitis and a risk of cardiomyopathy.

Scorpion considers Tagrisso a benchmark for quality, though STX-721 wouldn't compete against the drug directly since it is for a different indication. Scorpion expects to present preclinical data at a medical meeting this fall and to apply for human testing in the first half of 2023. 

At the beginning of the year, Scorpion put its name on the map after striking a partnership with Big Pharma AstraZeneca. For an upfront payment of $75 million, AstraZeneca now gets to work with the biotech to develop drugs against the transcription factors that control gene expression, with specific interest in the platform’s potential to tackle undruggable targets.

The partnership kicked up plenty of interest in Scorpion, and the biotech is actively exploring other partnership possibilities, though Hoos couldn’t disclose any specifics. 

The current biotech market, rife with layoffs and a downturn in investment, has not affected Scorpion's strategy for the most part, Hoos said—although he did note that the the timeline for the biotech’s next funding round is now muddier. Scorpion raised a $102 million series A in October 2020, followed by a $162 million series B less than three months later.

Hoos still anticipates growth across the board for the biotech. With a current team of around 100 people, Scorpion's clinical side will soon expand—including by adding a new chief medical officer to oversee the expected move into the clinic next year. 

“We haven’t encountered a failure yet,” Hoos said, attributing the preclinical success to sound science and a strong team. However, he acknowledged the attrition that can occur in discovery—and that there will be failures at some point.

“The two programs that are going to the clinic will be litmus test programs,” the Scorpion leader said. “The preclinical profile looks really fantastic, but we have to make sure it holds true. That's the test. That’s what we will have to prove.”