On April 22, 2020 Alkermes plc (Nasdaq: ALKS) reported the publication of preclinical data demonstrating the selectivity and anti-tumor efficacy of its investigational, immunotherapy candidate, ALKS 4230, in the Journal for ImmunoTherapy of Cancer (JITC) (Press release, Alkermes, APR 22, 2020, View Source [SID1234556504]). ALKS 4230, a novel cytokine, is an investigational, engineered fusion protein designed to selectively expand tumor-killing immune cells while avoiding the interleukin-2 (IL-2)-induced activation of immunosuppressive cells by preferentially binding to the intermediate-affinity IL-2 receptor complex.

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The manuscript, titled "ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy," provides an in-depth explanation of the design of ALKS 4230 and includes data from multiple assays that demonstrated that ALKS 4230 selectively activated the intermediate-affinity IL-2 receptor as intended. Additionally, data from a mouse B6F10 lung metastasis model demonstrated that treatment with ALKS 4230 achieved a maximum of 100% inhibition of tumor growth with one of the doses tested, as compared to treatment with recombinant human IL-2 (rhIL-2), which achieved a maximum of 70% inhibition of tumor growth with one of the doses tested. In this model, equivalent anti-tumor activity of ALKS 4230 was observed whether it was administered intravenously or subcutaneously.

"Targeting the IL-2 pathway has shown significant efficacy in renal cell carcinoma and melanoma, however the broader and more prevalent use of this approach in treating cancer has been limited by the toxicity profile and side effects associated with currently available IL-2-based therapy," said Marc Ernstoff, M.D., Roswell Park Comprehensive Cancer Center, and publication co-author. "These preclinical data demonstrated that ALKS 4230 selectively activated and expanded cancer-fighting cells in mice with less toxicity than conventional high-dose IL-2 therapy. These data support further clinical evaluation of ALKS 4230 as a potential novel cytokine-based cancer immunotherapy."

Key findings published in the manuscript include the following:

ALKS 4230 demonstrated a similar potency to rhIL-2 in activating mouse CD8+ T cells and Natural Killer (NK) cells. However, ALKS 4230 was ~ 1000 times less potent than rhIL-2 in activating regulatory T cells (Tregs), which are known to suppress cancer-fighting immune mechanisms.

ALKS 4230 treatment of peripheral blood mononuclear cells (PBMCs) from patients with melanoma or renal cell carcinoma resulted in the selective expansion of CD8+ T cells and NK cells with negligible effects on Treg expansion.

ALKS 4230 showed superior anti-tumor efficacy to rhIL-2 in a mouse B6F10 lung metastasis model and the ability to achieve equivalent anti-tumor efficacy when administered either intravenously or subcutaneously.

In mice, ALKS 4230 treatment induced markedly lower levels of cytokines typically associated with cytokine release syndrome, compared to rhIL-2.
"We leveraged our therapeutic development expertise and protein engineering capabilities to create ALKS 4230, a stable fusion protein. It is designed to minimize toxicity without compromising the proven anti-cancer effects of IL-2-based therapies," said Heather Losey, Ph.D., Director, Program Lead in Immuno-Oncology at Alkermes, and corresponding author of the publication. "We are encouraged by ALKS 4230’s preclinical profile, as discussed in this important peer-reviewed publication, including its selectivity for immune effector cells, pharmacokinetics and preclinical efficacy. We look forward to progressing the ARTISTRY clinical development program and seeing how the data mature for this novel, investigational immunotherapy."

ALKS 4230 is currently being studied in both monotherapy and combination settings as part of the Alkermes-sponsored ARTISTRY clinical development program.

About ALKS 4230
ALKS 4230 is an investigational, novel, engineered fusion protein comprised of modified interleukin-2 (IL-2) and the high-affinity IL-2 alpha receptor chain, designed to selectively expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by preferentially binding to the intermediate-affinity IL-2 receptor complex. The selectivity of ALKS 4230 is designed to leverage the proven anti-tumor effects of existing IL-2 therapy while mitigating certain limitations.

About the ARTISTRY Clinical Development Program
ARTISTRY is an Alkermes-sponsored clinical development program evaluating ALKS 4230 in patients with advanced solid tumors. ARTISTRY-1 is an ongoing phase 1/2 study in which ALKS 4230 is administered as an intravenous infusion daily for five consecutive days. ARTISTRY-1 has three distinct stages: an ongoing monotherapy dose-escalation stage, an ongoing monotherapy expansion stage, and an ongoing combination therapy stage with the PD-1 inhibitor KEYTRUDA (pembrolizumab) in patients with select advanced solid tumors.

ARTISTRY-2 is an ongoing phase 1/2 study in which ALKS 4230 is administered subcutaneously as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. ARTISTRY-2 is designed to explore the safety, tolerability and efficacy of ALKS 4230 administered subcutaneously and assess once-weekly and once-every-three-week dosing schedules.