Sanofi bet big on engineered IL-2 in 2019, dropping $2.5 billion to acquire Synthorx and its lead program, THOR-707. Now, the French pharma is reporting early phase 1 data showing the treatment could deliver the promise of cytokines for cancer treatment without their nasty side effects.
As of the data cutoff in March, the company had tested multiple dose levels of the treatment alone or in combination with Merck’s blockbuster PD-1 blocker, Keytruda, in 45 patients. The patients had undergone a median of three prior therapies and had different kinds of advanced cancers, the most common of which were melanoma, colorectal cancer and sarcoma, according to data presented virtually at the American Association for Cancer Research (AACR) meeting Saturday.
RELATED: Sanofi inks $2.5B Synthorx takeover to gain IL-2 cancer drug
An analysis of 30 patients who received THOR-707 alone or in tandem with Keytruda showed the treatment shrank tumors in three patients. One patient, with a skin cancer called basal cell carcinoma, had never tried PD-1 inhibitors before and saw an 80% decrease in tumor size after taking eight cycles of the combination treatment. The other two patients had head and neck cancer and had previously undergone anti-PD-1 treatment. One saw their tumor shrink by about half (47%) after 11 cycles of the combination treatment, while the other saw their tumor shrink by about one-third after two cycles of the combination treatment.
Besides these partial responses, the study also found that THOR-707 boosted patients’ markers of immune activity, including their levels of CD8+ killer T cells and natural killer cells. The higher the dose, the greater the effect on these markers—and adding Keytruda bolstered them even more.
Cytokines like IL-2, short for interleukin-2, emerged decades ago as promising cancer treatments. By boosting killer T-cell counts, they can dial up the immune system and boost the efficacy of drugs like Keytruda.
However, their use has been limited, because they evolved as signaling molecules, not drugs, and so affect many different cells, causing nasty side effects. One of those effects is vascular leak, where fluids and proteins leak from blood vessels into surrounding tissues, causing organ damage. Synthorx found a way around those side effects by engineering a synthetic IL-2 and installing a new amino acid at one position in recombinant IL-2.
Sanofi’s study found no vascular leak or eosinophilia, or high levels of white blood cells called eosinophils, which can cause tissue damage, and one of the biggest safety concerns with IL-2 therapies. The study found no dose-limiting toxicities, namely side effects like vascular leak that are serious enough to stop a patient from stepping up to a higher dose.
“Novel approaches, such as not-alpha IL-2, seek to activate this powerful immune pathway while mitigating current challenges with dosing and safety to potentially expand the patient population who could benefit from treatment,” said Filip Janku, M.D. Ph.D., an associate professor of investigational cancer therapeutics, at the University of Texas MD Anderson Cancer Center, in a statement on Friday.
“Preclinically, THOR-707 appeared to activate an anti-tumor immune response without an increased risk of alpha-mediated toxicities, such as eosinophilia or vascular leak syndrome. While early, the interim clinical data at AACR align very closely to what we saw in preclinical research and suggest further study of this not-alpha IL-2 molecule is warranted, both alone and in combination with a synergistic treatment such as anti-PD-1," Janku said.
Several companies are working to deliver the benefits of cytokines without their drawbacks, including Bristol Myers Squibb and partner Nektar Therapeutics, which are developing bempegaldesleukin, or bempeg, a pegylated IL-2 that could boost the effects of BMS’ PD-1 med Opdivo. Other players in the field include Asher Bio, which is working on cytokines that only affect targeted cells, and Synthekine, which is engineering synthetic cytokines, as well as making changes to wild-type cytokine.