Heterodimeric interleukin 15

Pictured: 3D artistic illustration of a bladder being afflicted by cancer cells/iStock, wildpixel The FDA on Monday greenlit ImmunityBio’s first-in-class IL-15 superagonist nogapendekin alfa inbakicept-pmln, which will now carry the brand name Anktiva, for the treatment of non-muscle invasive bladder cancer. The approval allows the use of Anktiva with Bacillus Calmette-Guérin (BCG), a vaccine that prevents tuberculosis and other mycobacterial infections, in BCG-unresponsive patients with carcinoma in situ. The treatment can be used in non-muscle invasive bladder cancer (NMIBC) patients with or without papillary tumors. Approximately 80% of new bladder cancer diagnoses are NMIBC, according to ImmunityBio. Anktiva’s approval used the FDA’s Assessment Aid, which is a voluntary submission that applicants can facilitate and expedite the review process. ImmunityBio expects to make Anktiva available in the U.S. by mid-May 2024, the company said. Patrick Soon-Shiong, ImmunityBio’s global chief scientific and medical officer, in a statement called Monday’s approval “an important milestone” not only for the company but also for NMIBC patients. “By orchestrating the innate and adaptive immune system and driving long-term complete remission, Anktiva has the potential to play a key role as the immunotherapy beyond checkpoints in multiple tumor types,” Soon-Shiong said. Anktiva is a therapeutic fusion protein that combines a mutant version of the IL-15 cytokine with an IL-15 receptor fusion protein. This structure allows Anktiva to stimulate the proliferation of CD8+ T cells and natural killer cells while also activating CD4+ T helper cells, which boosts the division of memory killer T cells. Anktiva also sidesteps the activation of regulatory T cells. “This novel mechanism of action, which mimics the biology of the dendritic cell, begins the evolution of immunotherapy beyond T cells alone,” Soon-Shiong said. Anktiva previously won the FDA’s Breakthrough Therapy designation for NMIBC. However, in May 2023, the regulator rejected ImmunityBio’s Biologics License Application, citing problems documented during a pre-license inspection of a third-party manufacturer. ImmunityBio resubmitted the application in October 2023, which the regulator considered as a complete response. Monday’s approval is backed by data from the Phase II/III QUILT-3.032 study, an open-label, single-arm, multicenter study with 190 participants, of whom 77 had evaluable data. Patients received maintenance treatment with Anktiva and BCG for up to 18 months. The complete response rate was 62% for these patients, with duration of response exceeding 47 months at the November 2023 cut-off. QUILT-3.032 is ongoing, with the final median duration of response yet to be determined. Additional updates from the trial will be presented at the upcoming annual conference of the American Urological Association in May 2024. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Shenzhen Salubris commits additional funding to continue research and development of novel, complex biologics First patient enrolled in RENEU-HF, the Phase 2 clinical trial of JK07 in heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) Clinical trial application filed for JK06, SalubrisBio’s first-in-class biparatopic ADC GAITHERSBURG, Md.--(BUSINESS WIRE)-- Salubris Biotherapeutics, Inc. (SalubrisBio), a clinical-stage biotechnology company dedicated to discovering and developing novel complex biologic therapeutics, today announced a new capital infusion of $35 million to fund continued research and development of clinical and pre-clinical programs. SalubrisBio also provided progress updates for JK07, the first investigational antibody fusion protein for heart failure, JK08, the first investigational IL15-CTLA4 antibody fusion for solid tumors and JK06, a first-in-class biparatopic antibody-drug conjugate (ADC) targeting a known tumor antigen. “We are pleased with the clinical progress across our pipeline of novel, complex biologic therapeutics, positioning us for multiple inflection points over the coming year and into 2025,” said Sam Murphy, Chief Executive Officer of SalubrisBio. “Enrollment of the first patient in our Phase 2 clinical trial of JK07 is an important milestone in our heart failure program. Promising 6-month, Phase 1b data reported last year suggests that JK07 has the potential to improve heart function and long-term outcomes. We look forward to building on these promising findings and potentially delivering a new treatment option that can restore quality of life for heart failure patients.” JK07 Phase 2 Study Design RENEU-HF (NCT06369298) is a Phase 2, randomized, double-blind, placebo-controlled, multiple-dose trial designed to evaluate the efficacy and safety of JK07 in patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The study is expected to enroll 282 subjects who will be randomly assigned (1:1:1) to receive multiple doses of JK07 low dose, JK07 high dose, or placebo. The co-primary endpoints for HFrEF are improvement in ejection fraction, and safety and tolerability, and the primary endpoint for HFpEF is safety and tolerability. Together, HFrEF and HFpEF affect an estimated 6.2 million Americans1 and more than 64 million people worldwide2. Heart failure is a chronic condition in which patients experience progressively worsening symptoms and quality of life, hospitalizations and death. JK08 Phase 1b/2 Study Progress The ongoing Phase 1b/2, open label, dose escalation and cohort expansion study (NCT05620134) is designed to evaluate the safety and preliminary anti-tumor activity of JK08 in patients with unresectable locally, advanced or metastatic cancer. More than fifty subjects have received JK08 monotherapy in the ongoing dose escalation cohorts, and the first patient has now been dosed in the cohort expansion phase, which will further define the safety and initial efficacy of JK08 in combination with targeted agents including pembrolizumab. SalubrisBio plans to report additional data from this study in the second half of 2024. “We are encouraged by the early data observed in the ongoing dose escalation portion of the JK08 Phase 1b/2 study and look forward to exploring the clinical benefit of combining JK08 with pembrolizumab in solid tumors,” added Murphy. JK06 CTA Filing JK06 is positioned to be the first biparatopic ADC targeting a known tumor antigen for which no approved therapies currently exist. Given limited expression and internalization, this antigen is ideally suited for the biparatopic design intended to overcome both limitations, and JK06 has demonstrated low picomolar affinity and robust internalization of the target. It has further demonstrated a highly favorable risk:benefit pro and will now be evaluated in a dose-escalation study, including a basket of solid tumors. About JK07 JK07 is a recombinant fusion protein consisting of a fully human immunoglobulin IgG1 monoclonal antibody and an active polypeptide fragment of the human growth factor neuregulin [NRG-1]. NRG-1 is a clinically validated growth factor that has shown promising activity in heart failure, but also undesirable side effects. Research has shown that NRG-1 induces signaling through interaction with two different receptors – ErbB3 and ErbB4. The ErbB4 pathway appears to be responsible for the regenerative effects in the heart, while the ErbB3 pathway appears primarily responsible for safety and tolerability limitations of recombinant NRG-1. By blocking ErbB3 signaling with an antibody fusion design, JK07 selectively stimulates the ErbB4 pathway with a favorable pharmacokinetic profile, which has the potential to significantly widen the therapeutic window of NRG-1 and yield better clinical effects. About JK08 JK08 is a recombinant fusion protein consisting of a CTLA-4-specific antibody and an IL-15 fusion domain. The JK08 design builds upon a breadth of clinical studies with CTLA-4 antibodies and recombinant IL-15 molecules, which together portend synergistic effects in an antibody fusion construct. The CTLA-4-specific antibody ipilimumab validated CTLA-4 as a target for cancer therapy, but response rates are limited. Analysis of clinical samples demonstrated that NK cell activity signatures and ADCC biomarkers correlate with ipilimumab responses. Recombinant IL-15 has exhibited potent stimulation of NK cell expansion and enhancement of ADCC in pre-clinical and clinical studies. Through the incorporation of a CTLA-4 antibody and IL-15 into a single molecule, JK08 can channel the potent immune stimulation of IL-15 through the CTLA-4 antibody domain towards depletion of T-regulatory cells and targeted reversal of immunosuppression which may contribute to cancer progression. About SalubrisBio SalubrisBio is a clinical-stage biotechnology company dedicated to discovering and developing complex biologics for cardiovascular, oncology, and neurodegenerative diseases. SalubrisBio was founded in August 2016 as a wholly-owned subsidiary of the China-based pharmaceutical company Shenzhen Salubris Pharmaceuticals Co. Ltd. Headquartered in the US, SalubrisBio reflects Shenzhen Salubris Pharmaceuticals’ commitment to innovation and expansion into the global market and retains the core philosophy of developing therapeutics for large patient populations with significant unmet needs. _________________________ 1 Centers for Disease Control and Prevention, Heart Failure, , (accessed May 8, 2023). 2 Groenewegen, A., Rutter, F., Mosterd, A., & Hoes, A. (2020). Epidemiology of heart failure. European Journal of Heart Failure, 22(8), 1342-1356.