BMS, Pfizer, and Takeda Back IL-2 Immunotherapy NKTR-214 as It Enters Clinical Trials in China

By Medicine View

On November 24, China's National Medical Products Administration (NMPA) Center for Drug Evaluation (CDE) announced that Nektar Therapeutics and Bristol-Myers Squibb (BMS) had submitted a clinical trial application for NKTR-214. Public information indicates that this is an agonist targeting the IL-2 signaling pathway, which has previously received Breakthrough Therapy Designation from the FDA. In 2018, BMS entered into a research and development collaboration worth up to $3.6 billion with Nektar to comprehensively study the therapeutic effects of NKTR-214 in combination with various immune checkpoint inhibitors from BMS’s pipeline across multiple types of cancer.

In addition to the partnership with BMS, Nektar Therapeutics has also partnered with several large pharmaceutical companies, including Pfizer and Takeda, to test the efficacy of NKTR-214 in combination with other anti-cancer therapies. In the list of "Top 10 Most Anticipated Drug Launches of 2021" released jointly by Fierce Pharma and Evaluate in February this year, NKTR-214 was ranked on the list with projected sales of $1.72 billion by 2026.

Screenshot source: CDE official website

So why is NKTR-214 (bempegaldesleukin, Bempeg) so highly anticipated? This has to do with its target of action, IL-2.

IL-2 Therapy: One of the First Approved Immunotherapies for Cancer TreatmentIL-2 therapy was one of the first immunotherapies to be approved for cancer treatment. As a cytokine, it has the ability to activate CD8-positive T cells and natural killer cells while promoting their proliferation. It was once approved by the U.S. FDA for the treatment of melanoma and renal cell carcinoma. However, IL-2 also has the ability to activate regulatory T cells (Tregs) with immunosuppressive functions, which can instead suppress the anti-cancer immune response of T cells and may lead to other toxic side effects.

Therefore, a key focus in the IL-2 field is the development of activators that can selectively activate the IL-2 receptor signaling pathway in CD8-positive T cells. NKTR-214 is an agonist that preferentially binds to the CD122 receptor in the IL-2 signaling pathway, and it has the potential to stimulate the proliferation of CD8+ effector T cells, natural killer cells, and CD4+ helper T cells by selectively activating the IL-2 signaling pathway.

In the Phase 1/2 clinical trial PIVOT-02 for the treatment of first-line unresectable or metastatic melanoma patients, the combination therapy of NKTR-214 and the PD-1 inhibitor Opdivo achieved an objective response rate (ORR) of 53%. At a median follow-up time of 12.7 months, the complete response rate reached 34%, and the proportion of patients achieving complete response continued to increase with longer follow-up. This indicates that among patients experiencing a response, the depth of response brought by the combination therapy continues to improve.

Based on these positive results, the FDA granted breakthrough therapy designation to the NKTR-214 and Opdivo combination treatment for previously untreated patients with unresectable or metastatic melanoma. Additionally, NKTR-214 received orphan drug designation from the FDA for the treatment of stage IIb to IV melanoma.

As is known to all, although immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors, have achieved remarkable efficacy in the treatment of various cancers, many patients still do not respond to these therapies. Therefore, one of the important research directions in cancer immunotherapy is to find "good helpers" for immune checkpoint inhibitors and build combination therapies to expand the efficacy and application scope of checkpoint inhibitors. The positive results achieved by NKTR-214 in clinical trials signify an important breakthrough for this IL-2 signaling pathway-targeted agonist in enhancing the efficacy of immune checkpoint inhibitors.

▲NKTR-214 is undergoing multiple registration clinical trials (Screenshot source: Nektar Therapeutics official website)

Currently, NKTR-214 is being evaluated in multiple registrational clinical trials for indications including metastatic melanoma, renal cell carcinoma, muscle-invasive bladder cancer, and squamous cell carcinoma of the head and neck. In China, NKTR-214 has also received tacit approval for a clinical trial, in combination with Opdivo, to treat previously untreated patients with advanced or metastatic renal cell carcinoma.

We hope that NKTR-214 will proceed smoothly in these clinical studies and bring new, more effective treatment options to cancer patients as soon as possible.

References:

[1] Center for Drug Evaluation, National Medical Products Administration of China. Retrieved Nov. 24, 2021, from https://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d

[2] The 10 most-anticipated drug launches of 2021 . Retrieved Feb 22, 2021. From https://www.fiercepharma.com/special-report/10-most-anticipated-drug-launches-2021

[3] Nektar Therapeutics Presents Biomarker and Clinical Data from PIVOT-02 Phase 2 Study of Bempegaldesleukin with Nivolumab at 2019 ASCO Annual Meeting. Retrieved August 1, 2019, from https://ir.nektar.com/news-releases/news-release-details/nektar-therapeutics-presents-biomarker-and-clinical-data-pivot

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