NEW YORK – The management team at IDRx is trying once again to discover drug combinations, except this time the biotech veterans at the helm of the new startup have reunited to use a rational approach to simultaneously target cancer driver and resistance mutations instead of an automated high-throughput screening strategy.
The genesis of IDRx, which launched earlier this month having raised $122 million in Series A funding, traces back more than 20 years to CombinatoRx. That company was founded in 1999 by biotech entrepreneur Alexis Borisy to discover therapeutic drug combinations using a robotic mass screening platform.
Starting with a library of about 2,000 approved compounds, CombinatoRx set out to test as many as 2 million pairs of compounds in cell-based assays that recapitulated disease biology. At that time, the first antiretroviral combination therapies had revolutionized HIV therapy, and chemotherapy combinations had long been a mainstay of cancer treatment. Systematically creating and marketing combination therapies for indications with unmet need seemed like the logical next step in drug development.
However, like many high-throughput screening strategies of the late '90s and early 2000s, CombinatoRx's "brute force" discovery strategy failed to produce any drug compounds that ultimately reached the market. "We were limited by two things: One is that the empirical screening approach was obviously much less efficient than being hypothesis-driven," explained IDRx Cofounder and CEO Ben Auspitz, who worked at CombinatoRx with Borisy. "But the other is that we were limited by the chemistry at the time. We were screening with things that were readily available and off-patent in the year 2000. We really didn't have any true precision medicine."
Auspitz and Borisy eventually left CombinatoRx, which later merged with Neuromed, renamed itself Zalicus, sold off its combination high-throughput screening platform, and in 2015 was acquired by India's Sun Pharmaceutical. Borisy went on to cofound precision cancer medicine-focused firms such as Foundation Medicine and Blueprint Medicines, and he became a partner at the biotech investment firm Third Rock Ventures. In 2020, he founded EQRx, a pharma startup dedicated to disrupting the high-priced market for new, on-patent medicines.
Auspitz also became active in venture capital and through his role at F-Prime, he connected with Nicholas Lydon, a leader in the development of Novartis' Gleevec (imatinib), one of the earliest cancer therapies designed to target a genetic biomarker, and George Demetri, director of the Sarcoma Center at the Dana-Farber Cancer Institute and a leading expert on gastrointestinal stromal tumors (GIST).
These relationships provided the spark for a new company centered on developing drug combinations targeting well-characterized driver and resistance mutations in GIST. And with the addition of Borisy and another CombinatoRx alum, Robert Forrester, the founding team emerged for IDRx, whose name is a play on CombinatoRx, referencing the substitution of "intelligent design" for the brute force robotic approach that failed at the older company.
Boston-based IDRx was incubated by Borisy Labs, which provided IT, finance, human resources, and legal services so that its founding team could focus on the technical side of operating the company. The leaders decided IDRx would develop drugs that target primary driver mutations in cancer with a wide enough therapeutic window for potential use in early cancer settings and combine them with other drugs that target resistance mutations to stave off relapse and extend response.
Often, precision cancer therapies fall short of achieving ideal outcomes. because while they may hit a targeted driver mutation very hard, the patient's cancer quickly adapts and acquires other mutations that cause resistance. "The concept of IDRx is, in cases where we understand the biology of the tumor very well, we can a priori design the combination of targets so that you're not just hitting the driver, you're hitting the most likely escape mutations that will emerge under therapy or may already be latent in the tumor," said Auspitz.
IDRx's leaders will first attempt to develop a pair of compounds for KIT-driven (non-PDGFRA-driven) GIST, the biology of which has been extensively characterized by the scientific community. Two compounds in development at the firm, IDRX-42 and IDRX-73, are small molecule tyrosine kinase inhibitors designed to inhibit mutations in KIT-driven GIST.
IDRX-42, licensed from Merck KGaA, targets mutations in exons 9, 11, and 17, while IDRX-73, licensed from Blueprint Medicines, targets the exon 13 resistance mutation. "Between the two of them, we hope we're covering the entirety of the meaningful driver and resistance mutations," said Auspitz.
The company will use its recently raised Series A funds to conduct a Phase I, dose-escalation, single-agent study of IDRX-42 involving patients with KIT-driven GIST. After establishing a safe and effective dose for IDRX-42, for which the US Food and Drug Administration has granted orphan drug status, IDRx will combine it with IDRX-73, currently in preclinical stage but advancing toward clinical trials. IDRx hopes to report results from the Phase I single-agent trial of IDRX-42 in 2023, but Auspitz said the pace of patient accrual will ultimately determine the exact timeline.
According to Auspitz, IDRx's founders are inspired by drug discovery pioneers including former National Cancer Institute Director Vincent DeVita, who wrote in his book, "The Death of Cancer," about the development of early multi-drug regimens comprising three or four drugs that were combined empirically to overcome resistance through overlapping mechanisms of action. IDRx's approach is different, focused on biologically driven rational design rather than trial and error, Auspitz said, but acknowledged that "in a lot of ways, you could say this is a back-to-the-future approach." And while toxicity has often been a problem with drug combinations, through its rational design, IDRx has attempted to avoid overlapping toxicities with IDRX-42 and IDRX-73.
IDRx is not disclosing any other disease areas of interest outside of GIST at this time, but it plans to use the same approach to tackle other diseases and potentially higher order combinations of three, four, and five compounds or more. "The vision is to be responsive to the biology, so that if you observe under dual blockade with two molecules there are other pathways that are important, and we have some hypotheses of what those might be; you could think about adding a third element to the combination," said Auspitz. "But, today, it's a two-way combination we're advancing."
Jorge Conde, a general partner at Andreessen Horowitz (a16z), which led the Series A financing with Casdin Capital, said that IDRx's leadership team was a big draw for the investment firm. "An entrepreneur that has been wrestling with a problem for a long period of time is likely to come up with solutions that are only obvious in retrospect, … dots that are only connected when you're working backwards," said Conde. "IDRx … is a pretty canonical example of exactly that journey."
Another factor working in IDRx's favor, Conde said, was timing. Quoting a16z Cofounder Marc Andreessen, Conde said, "There are no bad ideas, there's just bad timing." Combination therapies are not new in cancer, and patients receive them all the time. What has changed since CombinatoRx two decades earlier, he added, "is the intentionality and focus of thinking that the fundamental unit of a program for development is the combination itself," rather than a molecule that gets combined with others later in practice.
In terms of IDRx's lead program, Conde was convinced this was a worthy program to pursue because it had "the buy-in from all of these world experts" who had been coming at this problem from different directions — Lydon with his experience developing Gleevec and Demetri with his expertise in GIST as well as other competencies within the founding team.
Auspitz said that the $122 million financing was sized to generate data on the IDRX-42/IDRX-73 combination in GIST, which he expects to take roughly three years.
"I expect they'll essentially be able to do two things with this money," Conde reflected. "The first, is have a meaningful impact on GIST, of course. The second, is more broadly prove the theory that thoughtfully, intelligently designed compounds can have an outsized impact on treating disease."