Nektar Announces Publication in Blood of Phase 1 Data for Novel IL-15 Agonist NKTR-255 in Combination with Autologous CD19-22 CAR-T Cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

Rhea-AI Summary

Nektar Therapeutics (Nasdaq: NKTR) has published Phase 1 data in Blood for its novel IL-15 agonist NKTR-255 combined with autologous CD19-22 CAR-T cell therapy in patients with B-cell Acute Lymphoblastic Leukemia (B-ALL). The study showed:

• 89% of patients (8 out of 9) achieved measurable residual disease (MRD) negative remission
• 67% relapse-free/progression-free survival at 12 months, double that of historical controls (38%)
• No dose-limiting toxicities related to NKTR-255
• Significant increases in proinflammatory cytokines and chemokines, suggesting lymphocyte trafficking to tissues

The combination therapy showed promising efficacy in relapsed or refractory B-ALL patients, with potential to improve durability of CAR-T cell therapies.

Positive

• 89% of patients (8 out of 9) achieved measurable residual disease (MRD) negative remission
• 67% relapse-free/progression-free survival at 12 months, double that of historical controls (38%)
• No dose-limiting toxicities related to NKTR-255 were observed
• Median relapse-free survival for the combination therapy has not been reached after 14 months of follow-up
• Only 33% of patients (3 out of 9) relapsed with the combination therapy

Negative

• None.

Insights

Medical Research Analyst

This publication in Blood presents promising Phase 1 data for NKTR-255 in combination with CD19-22 CAR-T cell therapy for B-cell acute lymphoblastic leukemia (B-ALL). The results show significant improvements over historical controls:

• 89% of patients achieved measurable residual disease (MRD) negative remission
• 67% 12-month relapse-free/progression-free survival, compared to 38% for historical controls
• Median relapse-free survival not yet reached after 14 months, versus 3.9 months for CAR-T alone

The combination therapy demonstrated a favorable safety profile, with manageable side effects similar to CAR-T alone. Importantly, NKTR-255 appears to enhance CAR-T cell trafficking and persistence, potentially addressing a key limitation of current CAR-T therapies. While these results are encouraging, it's important to note this is a small, single-arm study. Larger, randomized trials will be necessary to confirm efficacy and long-term outcomes.

Financial Analyst

This clinical data publication represents a significant milestone for Nektar Therapeutics (NKTR), potentially increasing the value of their NKTR-255 asset. Key financial implications include:

• Enhanced partnership potential: Positive data could attract collaborations or licensing deals with major oncology players.
• Market opportunity expansion: Success in B-ALL could lead to trials in other hematological malignancies, broadening the addressable market.
• Competitive positioning: NKTR-255's ability to improve CAR-T outcomes differentiates it in the crowded immuno-oncology space.

However, investors should consider that NKTR, with a market cap of $250 million, faces financial constraints. The company will likely need additional funding to advance NKTR-255 through later-stage trials. While this data is promising, it's early-stage and significant clinical and regulatory hurdles remain before potential commercialization.

– Relapse-free/progression-free survival for NKTR-255 plus CD19-22 CAR-T cell therapy at 12 months was double that of historical controls (67% vs 38%) –

– Eight of nine patients achieved complete remission, all without detectable MRD –

SAN FRANCISCO, Oct. 17, 2024 /PRNewswire/ -- Nektar Therapeutics (Nasdaq: NKTR) today announced the publication of the first clinical data from a Phase 1 study evaluating NKTR-255 in combination with an autologous bispecific chimeric antigen receptor (CAR)-T cell therapy targeting CD19 and CD22 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in Blood, the peer-reviewed medical journal of the American Society of Hematology.

NKTR-255 is a novel IL-15 receptor agonist currently being studied in clinical trials in combination with cellular therapies and immune checkpoint inhibitors. NKTR-255 has shown in previous clinical studies that it can proliferate a range of immune cells and augment lymphocyte trafficking.^1,2

The data published in Blood showed favorable efficacy with eight out of nine patients (89%) whom successfully received CAR19-22 followed by NKTR-255 achieving measurable residual disease (MRD) negative remission. The study further demonstrated that, at 12 months, relapse-free/progression-free survival for NKTR-255 in combination with the CD19-22 CAR-T cell therapy was double that of historical controls (67% vs 38%).

"We are encouraged by these first clinical data that clearly demonstrate the ability of NKTR-255 to potentiate CAR-T cell therapy," said Mary Tagliaferri, MD, Senior Vice President and Chief Medical Officer at Nektar. "Data showed NKTR-255 in combination with CD19-22 CAR-T cell therapy resulted in a 67% 12-month relapse-free survival rate in relapsed or refractory B-ALL and investigators observed significant increases in proinflammatory cytokines and chemokines which suggest lymphocyte trafficking to tissues."

The Phase 1 single-center, single-arm dose-escalation study was conducted by Stanford Medicine and evaluated NKTR-255 in combination with CD19-22 CAR-T cell therapy in patients with relapsed or refractory B-ALL (NCT03233854).

"While CAR-T cell therapies have transformed the treatment landscape for B-cell malignancies, there remains a significant unmet need to drive durable treatment outcomes as relapse occurs in the majority of patients," said David Miklos, MD, Chief of BMT and Cell Therapy Program at Stanford Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy.

The primary outcomes of this study were feasibility and safety. Secondary endpoints were assessed for patients who received NKTR-255 (n=9) and included pharmacokinetics of NKTR-255 as measured by IL-15 levels in blood and efficacy as measured by remission free survival (RFS). Exploratory endpoints included cytokine profiling, CAR19-22 expansion in blood, bone marrow, and cerebrospinal fluid (CSF), and long-term CAR-T persistence.

Key findings are summarized below:

• No dose-limiting toxicities related to NKTR-255 were observed. The most common adverse events in patients receiving NKTR-255 in combination with the CD19-22 CAR-T cell therapy were fevers, chills, and myelosuppression, which were either self-limiting or manageable with supportive care. The toxicities observed with the combination treatment were similar to those seen after CD19-22 CAR-T cell therapy alone.
• Cytokine and chemokine profiling showed significant increases in IL-15 levels. Increase in CXCL9 and CXCL10 were associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood, and ten-fold increases CAR-T cells in CSF, suggesting lymphocyte trafficking to tissue.
• Favorable efficacy was observed in patients with relapsed or refractory B-ALL treated with NKTR-255 in combination with CD19-22 CAR-T. Eight out of nine patients achieved complete remission with or without hematologic recovery, all without detectable MRD.
• Compared to Stanford's control group previously treated with the CD19-22 CAR-T cell therapy, NKTR-255 when added to the cell therapy increased the 12-month relapse free survival from 38% to 67%. The median RFS for the CAR T cell only cohort was 3.9 months. For the cohort treated with NKTR-255 and the CD 19-22 CAR-T cell therapy, the median RFS has not been reached with over 14 months of follow up. Only three patients who received combination therapy (33%) relapsed, suggesting administration of NKTR-255 to the CD19-22 CAR-T cell therapy helps prevent early disease recurrence.

The full citation of this article can be accessed here (Volume 144, Issue 16, Pages 1649-1753).

About NKTR-255

NKTR-255 is a biologic that targets the IL-15 pathway in order to activate the body's innate and adaptive immunity. Through optimal engagement of the IL-15 receptor complex, NKTR-255 is designed to enhance functional NK cell populations and formation of long-term immunological memory, which may lead to sustained and durable anti-tumor immune response.

In addition to studies in combination with CAR T cell therapies, NKTR-255 is being studied in a Phase 1 clinical trial sponsored by AbelZeta Pharma, Inc., which is evaluating C-TIL051, a tumor-infiltrating lymphocyte therapy, in anti-PD1 resistant metastatic non-small cell lung cancer (NCT05676749). The JAVELIN Bladder Medley study (NCT05327530), sponsored by Merck KGaA, is also ongoing to evaluate NKTR-255 in combination with avelumab as a maintenance treatment in patients with locally advanced or metastatic urothelial carcinoma.(NCT05327530)

About Nektar Therapeutics

Nektar Therapeutics is a clinical-stage biotechnology company focused on developing treatments that address the underlying immunological dysfunction in autoimmune and chronic inflammatory diseases. Nektar's lead product candidate, rezpegaldesleukin (REZPEG, or NKTR-358), is a novel, first-in-class regulatory T cell stimulator being evaluated in two Phase 2b clinical trials, one in atopic dermatitis and one in alopecia areata. Our pipeline also includes a preclinical candidate NKTR-0165, which is a bivalent tumor necrosis factor receptor type II agonist antibody. Nektar, together with various partners, is also evaluating NKTR-255, an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer, in several ongoing clinical trials. Nektar is headquartered in San Francisco, California. For further information, visit www.nektar.com and follow us on LinkedIn.

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements which can be identified by words such as: "will," "expect," "develop," "potential," "advance," "anticipate," "can," and similar references to future periods. Examples of forward-looking statements include, among others, statements regarding the therapeutic potential of, and future development plans for, NKTR-255. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results to differ materially from those indicated in the forward-looking statements include, among others: (i) our statements regarding the therapeutic potential of NKTR-255 are based on preclinical and clinical findings and observations and are subject to change as research and development continue; (ii) NKTR-255 is an investigational agent and continued research and development for this drug candidate is subject to substantial risks, including negative safety and efficacy findings in future clinical studies (notwithstanding positive findings in earlier preclinical and clinical studies); (iii) NKTR-255 is in clinical development, and the risk of failure is high and can unexpectedly occur at any stage prior to regulatory approval; (iv) the timing of the commencement or end of clinical trials and the availability of clinical data may be delayed or unsuccessful due to regulatory delays, slower than anticipated patient enrollment, manufacturing challenges, changing standards of care, evolving regulatory requirements, clinical trial design, clinical outcomes, competitive factors, or delay or failure in ultimately obtaining regulatory approval in one or more important markets; (v) patents may not issue from our patent applications for our drug candidates, patents that have issued may not be enforceable, or additional intellectual property licenses from third parties may be required; and (vi) certain other important risks and uncertainties set forth in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on August 9, 2024. Any forward-looking statement made by us in this press release is based only on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

Contact:

For Investors:

Vivian Wu of Nektar Therapeutics
628-895-0661

For Media:

David Rosen of Argot Partners
(212) 600-1902
david.rosen@argotpartners.com 

1. Hirayama A. et al. Pharmacodynamic Analysis of CAR-T Cell Persistence in Patients with Hematologic Malignancies Treated with NKTR-255, an IL-15 Receptor Agonist That Enhances CD8 ⁺ T-Cells: Preliminary Results from a Phase 1 Study. Poster presented at: 63^rd ASH Annual Meeting; Dec 11-13, 2021; Atlanta, GA
2. Altan M. et al. NKTR-255+cetuximab in patients with solid tumors: interim safety and efficacy results from the phase 1b dose-escalation study. Poster presented at: SITC 2021; Nov 10-14, 2021; Washington, D.C.

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FAQ

What are the key results of Nektar's Phase 1 study for NKTR-255 in B-ALL patients?

The Phase 1 study showed 89% of patients achieved MRD negative remission, 67% relapse-free survival at 12 months, and no dose-limiting toxicities related to NKTR-255 when combined with CD19-22 CAR-T cell therapy in B-ALL patients.

How does NKTR-255 improve CAR-T cell therapy outcomes in B-ALL?

NKTR-255 appears to potentiate CAR-T cell therapy by increasing proinflammatory cytokines and chemokines, suggesting improved lymphocyte trafficking to tissues. This resulted in doubled relapse-free survival rates compared to historical controls.

What is the significance of the NKTR-255 study results for Nektar Therapeutics (NKTR)?

The positive Phase 1 results suggest that NKTR-255 could potentially enhance the durability and efficacy of CAR-T cell therapies, addressing a significant unmet need in B-cell malignancies treatment and potentially expanding Nektar's market opportunities.

What are the next steps for NKTR-255 in B-ALL treatment?

While not explicitly stated in the press release, the positive Phase 1 results typically lead to further clinical development. Nektar Therapeutics may proceed with larger Phase 2 or Phase 3 trials to confirm the efficacy and safety of NKTR-255 in combination with CAR-T cell therapy for B-ALL patients.