Bempeg Failure Unlikely to Affect Other IL2 Drugs

After the engineered IL2 cytokine bempegaldesleukin (bempeg; Nektar Therapeutics/Bristol Myers Squibb) fell flat in late-stage trials, its makers halted clinical development of the drug, which had been the focus of a multibillion-dollar deal a few years ago.

But with a pipeline of other IL2-based therapies—including fusion proteins, cytokine mimetics, engineered variants, and bispecific antibodies in various stages of development—researchers still believe that they can harness the cytokine's immune-modulatory potential to shrink tumors with minimal toxicity.

“Bempeg is a poor example of IL2 engineering, and there's a lot more to be expected from other IL2 programs,” says Fahar Merchant, PhD, president and CEO of Medicenna Therapeutics in Toronto, Canada, a company with its own IL2 therapeutic in early clinical testing.

The first IL2 drug therapy, a recombinant cytokine called aldesleukin (Proleukin; Clinigen), was approved in 1992, but oncologists have long sought a better alternative. Even though aldesleukin yielded some dramatic responses, it proved difficult to use. At high doses, the drug killed cancer cells but caused severe toxicities, including potentially fatal capillary leak syndrome. At low doses, it dampened the body's immune responses with limited antitumor activity.

Bempeg was designed to offer a more tolerable and effective option. With a half dozen polyethylene glycol (PEG) groups attached, this pegylated form of IL2 gave the engineered cytokine a longer half-life, as it became active only after the chemical tags were released. The positioning of PEG molecules was also meant to bias the cytokine's activity toward engaging the β-chain of the IL2 receptor—necessary for activating cancer-fighting CD8⁺ T cells—and away from the α-chain, the binding of which can stimulate immunosuppressive regulatory T cells (Clin Cancer Res 2016;22:680–90).

Initial clinical data looked promising, which is why Bristol Myers Squibb paid Nektar $1.85 billion in 2018 to secure rights to the drug. But pivotal trials in melanoma and renal cell carcinoma found no clinical benefit in patients who received bempeg with the PD-1 blocker nivolumab (Opdivo; Bristol Myers Squibb) compared with standard therapy for each disease, the companies announced in March and April. A single-arm study of the combination in patients with bladder cancer did not show signs of efficacy either.

“It just goes to show how unpredictable things can be when you get to phase III,” says former Nektar scientist Deborah Charych, PhD, who helped design bempeg—especially when evaluating a novel agent in tandem with another immunotherapy. “We may have to be more creative in how we combine this particular mechanism of action.”

Nektar's oncology efforts now center on NKTR-255, an IL15 receptor agonist in early clinical development.

Other companies are forging ahead with IL2-based anticancer therapeutics—and they generally see bempeg as a flawed molecule rather than IL2 as a flawed target. Bempeg, says Merchant, “was really a slow-release version of Proleukin,” not a drug with selective affinity for the β-chain of the IL2 receptor.

Merchant thus doesn't expect the failure of bempeg to have broad implications on the viability of other “not alpha” IL2 contenders in clinical development. These include Medicenna's MDNA11, which entered phase I testing last year, and more advanced candidates such as nemvaleukin alfa (Alkermes), now being evaluated in a phase III trial for ovarian cancer, and SAR444245 (Sanofi), in phase II trials for multiple tumor types.

As K. Christopher Garcia, PhD, of Stanford University School of Medicine in California, an originator of Medicenna's technology and a cofounder of Synthekine, another company with a selective IL2 therapeutic in development, points out: “There will be many different flavors of IL2 that could likely be clinically differentiated.” –Elie Dolgin

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