STK-012

Responding to some of the challenges of its peers, Synthekine built a molecule called an IL-2 alpha/beta, dubbed STK-012. IL-2 medicines have shown the ability to kill tumors. Unfortunately, they aren’t very specific and have come to be associated with toxicities. Synthekine is hoping to avoid activating lymphocytes such as natural killer cells that can cause these issues, creating a safer and more tolerable medicine. That’s what early data from a phase 1a/1b trial of STK-012 seem to show, CEO Debanjan Ray told Fierce Biotech on the sidelines of the American Association for Cancer Research annual meeting Monday. The results are very early, with just a handful of partial responses. And Ray is well aware of the struggles of other IL-2s in the clinic—see Sanofi’s many challenges with the target. Responding to some of the hurdles faced by his peers, Ray said that with STK-012, Synthekine has built a molecule called an IL-2 alpha/beta that is meant to stimulate CD25+ antigen-activated T cells but avoid the same reaction with the NK cells that can drive toxicity in IL-2 meds. The early-stage trial tested the med in 47 patients with advanced solid tumors including non-small cell lung cancer, renal cell carcinoma and ovarian cancer. Most of the patients had three or more lines of therapy prior to entering the trial, which tested seven dose levels on two dosing schedules. Of the 40 evaluable patients, three had a partial response as of data cutoff and 12 had stable disease. In a group of 15 patients who had not previously responded to immune checkpoint inhibitors and were minimally pretreated, three had a best overall response of partial response and six had stable disease. “The promise of IL-2 in the treatment of solid tumors has yet to be realized as IL-2 analogues developed to date have had limited efficacy and an unacceptable toxicity profile,” said Naiyer Rizvi, M.D., Synthekine’s chief medical officer, in a Tuesday statement. The therapy was associated with favorable safety, pharmacokinetics and pharmacodynamics, with a profile that was different from aldesleukin and non-alpha IL-2 analogues. The early data suggest that STK-012 is selective for T cells that express CD25. Ray also noted that the response was durable in multiple subjects, with some continuing to benefit for as much as a year after the data cutoff. Synthekine’s presentation included one patient case study of a 72-year-old female who had stage 4 clear cell renal cell carcinoma and had previously had two prior lines of therapy. The patient had “innumerable lung metastases and a large primary renal mass.” At Week 12, the photos show a reduction in tumors. “You don't need to be a radiologist to really see this difference,” Ray said. Synthekine has selected the every-three-weeks schedule to go forward. Ray said next steps include focusing on the ongoing dose expansion, monotherapy arm including one cohort focusing on renal cancer. While early, Synthekine’s work has attracted some Big Pharma partners, including Sanofi. The French pharma signed a $40 million deal with Synthekine in January to work on IL-10 receptor agonists designed to treat inflammatory diseases. Merck & Co. has also linked up with the biotech but for autoimmune diseases, signing a deal that could be worth up to $525 million in biobucks in November 2021. Editor's note: This story was updated at 5 p.m. ET to clarify details about the dose expansion and Synthekine's partnership with Sanofi.

Favorable tolerability pro no dose-limiting toxicities (DLTs) during the DLT period and no capillary leak syndrome (CLS) in dose escalation Multiple objective responses achieved with STK-012 monotherapy in dose escalation across subjects who progressed on prior immunotherapy Enrollment to expansion cohorts in non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are ongoing MENLO PARK, Calif.--(BUSINESS WIRE)-- Synthekine Inc., an engineered cytokine therapeutics company, today announced positive initial results from a Phase 1a/1b clinical trial of its α/β biased IL-2 partial agonist, STK-012, for the treatment of advanced solid tumors. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 in San Diego. STK-012 is a first-in-class α/β-IL-2R biased partial agonist engineered to selectively stimulate CD25+ antigen-activated T cells, which are associated with potent anti-tumor activity, and avoid broad stimulation of other lymphocytes, such as natural killer (NK) cells, which are associated with IL-2 toxicity. In the results presented, which included 47 patients treated in Phase 1a dose escalation, STK-012 monotherapy demonstrated a favorable safety, efficacy, pharmacokinetic and pharmacodynamic profile. “The promise of IL-2 in the treatment of solid tumors has yet to be realized as IL-2 analogues developed to date have had limited efficacy and an unacceptable toxicity profile,” said Naiyer Rizvi, M.D., chief medical officer of Synthekine. “We are excited to report multiple objective responses with STK-012 monotherapy, driven by robust induction of interferon‐gamma (IFNγ) and selective expansion of antigen activated T cells. At the same time, we do not see the severe toxicities typically associated with IL-2 treatments, such as hypotension, capillary leak syndrome (CLS), or transaminitis. We look forward to completing the dose expansion portion of this study to further evaluate its potential for patients.” Synthekine initiated the Phase 1b portion of its study in September 2023 after successfully completing the Phase 1a dose-escalation portion. The Phase 1b portion of the study includes dose expansion cohorts to evaluate STK-012 as monotherapy at the candidate recommended phase 2 dose (RP2D) in selected solid tumor types, including renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). Along with the Phase 1a results, Synthekine presented a case study on a subject with Stage IV ccRCC treated with STK-012 monotherapy in the ongoing Phase 1b portion of the study. The subject had 2 prior lines of therapy, including immune checkpoint inhibitor, before starting on STK-012 and went on to achieve a confirmed partial response with 85% reduction in target lesion size as best overall response. The poster, titled “Initial results from a Phase 1a/1b study of STK-012, a first-in-class α/β IL-2 receptor biased partial agonist in advanced solid tumors (NCT05098132),” will be presented today at AACR from 9 am to 12:30 pm PT. The poster will be on poster board 11 in the session “First-in-Human Phase I Clinical Trials 2.” Following presentation at the meeting, the poster will be available on Synthekine’s website. For additional information about the trial, please visit using the identifier NCT05098132. STK-012 Initial Phase 1a Monotherapy Dose Escalation Data As of February 26th, 2024, 47 subjects were treated with STK-012 monotherapy at 7 dose levels across the 2 dosing schedules (QW and Q3W) in the Phase 1a Majority of patients (60%) had three or more prior lines of therapy in the advanced setting and 79% had received prior immune checkpoint inhibitor (ICI) Treatment-related adverse events (TRAEs) were reversible with standard management and mostly Grade 1 or 2 in severity Most common TRAEs (≥10% of subjects) were maculopapular rash, fatigue, injection site reaction, nausea, diarrhea, pruritis, vomiting, and arthralgia Based on observed PK (half-life of ~4 days), only the Q3W schedule was advanced beyond the 0.75 mg dose during the STK-012 monotherapy dose escalation STK-012 demonstrated selectivity (pSTAT5 induction) for T cells that express IL-2Rα (CD25) STK-012 demonstrated dose proportional increase in IFNγ and activated proliferating CD8 T cells STK-012 showed limited expansion of NK cells and Tregs Of 40 efficacy evaluable subjects, partial response (PR) was observed in 3 (RCC, NSCLC and HNSCC) and 12 had stable disease (SD) as their best overall response (BOR) by RECIST V1.1 In the subset of 15 subjects who were ICI refractory and minimally pretreated (≤ 2 prior lines), 3 had BOR of PR and 6 had BOR of SD Durability of response was observed in multiple subjects About Synthekine Synthekine is harnessing the potential of cytokine therapeutics to develop selective immunotherapies designed to improve the treatment paradigm of cancer and inflammatory disease. Using insights on cytokine structure and function, the company engineers therapeutics designed to unlock the full efficacy potential of cytokines while avoiding their associated toxicities. Synthekine is applying principles of cytokine partial agonism and immunological specificity across multiple protein engineering platforms to create a broad and deep pipeline of product candidates. These novel immunotherapies include modified cytokines, cytokine-enhanced cell therapies and surrogate cytokine agonists. For more information, visit , and follow us on X @synthekine and LinkedIn.