Seattle-based Neoleukin Therapeutics Inc. is targeting the end of 2020 for an IND submission related to prospective cancer immunotherapy NL-201, described as an engineered, hyperstable agonist of interleukin-2 (IL-2) and IL-15. It’s meant to eliminate alpha receptor binding and thereby overcome the problems with native IL-2. Although early stage, the candidate holds enough promise that Wainwright analyst Robert Burns felt comfortable referring to NL-201, in an April 13 report, as “cytokine mimetics’ new sheriff in town.”

Neoleukin CEO Jonathan Drachman, during the company’s March 12 conference call on earnings, talked up his firm’s approach as “a paradigm shift in the discovery of new biologics.” Natural cytokine IL-2, he noted, has been extensively studied and drugs are approved for the treatment of renal cell cancer and melanoma, turning up monotherapy response rates of about 15%, with 6% to 7% complete responses. But high-dose IL-2 brings significant toxicities that require drug administration in a hospital setting, and low doses don’t work well enough.

The biology underlying the problem is complex but seems to involve preferential binding of native IL-2 to the trimeric receptor, consisting of a high-affinity alpha chain as well as the signaling components: beta and gamma subunits. Expression of the alpha chain on endothelial cells and T regulatory cells drives biodistribution and localization to the cells, which can lead to vascular leak syndrome at high doses and immunosuppression at low doses. Neoleukin has designed “an entirely new de novo protein, one that does not exist in nature and is not based on the native sequence of IL-2,” Drachman said, and created “highly stable, compact and hydrophilic proteins, properties that make them less likely to be recognized as foreign by the immune system.”

The company, he said, has come up with a molecule that “is going to have a significantly improved therapeutic index, and we were very interested in seeing what the monotherapy activity is like. As far as combinations go, there are a lot of different possibilities. Checkpoint inhibitors are just one of them. One of the things that we're really excited about is because this [drug] activates IL-15 and natural killer [NK] cells just as potently as it does T cells, we believe this is something that could work really well with monoclonal antibodies that have antibody-dependent cell cytotoxicity [ADCC] and it could, in that way, enhance the ADCC and be quite synergistic. We think this could work really well with cellular therapies, whether it's NK cells or T cells or CAR T-cell therapies.” In Drachman’s view, NL-201 “could combine very well with almost any targeted therapy or chemotherapy which causes antigenic spread or increase in the immune microenvironment, so there's a lot more besides checkpoint inhibitors.”

Wainwright’s Burns is on board, despite the lack of clinical data. He pointed to human findings with various other IL-2 moieties, including Proleukin (aldesleukin, Société des Produits Nestlé SA); NKTR-214 (bempegaldesleukin), a pegylated version of IL-2 from San Francisco-based Nektar Therapeutics Inc.; and the RG-7461, from Roche Holding AG, of Basel, Switzerland. Results suggest potential objective response rates (ORR) of between 10% and 20% when used as a monotherapy across a range of solid tumor types. There was also a combo effort testing the Nektar prospect with Opdivo (nivolumab, Bristol Myers Squibb Co.) in melanoma that turned up a 53% ORR and complete response rate of 34%.

Upcoming Nektar data could help

Interest in the space was piqued by the disclosure in late 2019 that Paris-based Sanofi SA would acquire Synthorx Inc., of San Diego, for about $2.5 billion. The French drug developer was enticed by lead immuno-oncology product candidate, THOR-707, a variant of IL-2 in development for multiple solid tumor types as a single agent and alongside checkpoint inhibitors. The $68 per share price, a 279% premium, sent one of two signals to Wall Street, in the opinion of SVB Leerink analyst Daina Graybosch – each with implications for Synthorx differing from the other. Either the bidding process was fierce, which would validate the IL-2 class, or Sanofi got a peek at non-public, clinical biomarker and efficacy data, which could mean the pharma giant saw Synthorx’s IL-2 prospect as potentially best.

In any case, the deal shone a light on others in the space, including such names as Dublin-based Alkermes plc; Biontech SE, of Mainz, Germany; and Toronto-based Medicenna Therapeutics Corp. During the Neoleukin call, Guggenheim analyst Yue-Wen Zhu brought up the topic of possible T-cell exhaustion in the preclinical studies with NL-201. Drachman acknowledged that “one of the hardest, one of the most important things to figure out with immunotherapies is what's the right dose and schedule, because you can get exhaustion or refractory periods for immune responses. In our phase I trial, we will be looking not just at a dose escalation, but also at multiple schedules to try to understand what's the best schedule for having continued immune activation.”

Meanwhile, analyst Burns said upcoming Nektar data “may provide risk mitigation” for Neoleukin, “but is unlikely to have read-through if it proves negative.” Top-line data are expected in late 2020 and early 2021 from the combination of NKTR-214 plus Keytruda (pembrolizumab, Merck & Co. Inc.) and NKTR-214 plus Opdivo in non-small-cell lung cancer and melanoma, respectively. Those “could bode well for the future applicability” of NL-201 in such indications if they are positive, he said. “However, given the suboptimal dosing of NKTR-214 relative to [concentration of drug that gives a half-maximal response] levels, we would not consider negative data from these studies indicative of the potential for NL-201,” he added. Burns maintained that NL-201 could end up best in class, and started coverage of Neoleukin with a $22 price target when the company’s 52-week low was $2.19 and the 52-week high was $13.71.

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