ISB-2001

Preclinical research on the trispecific antibody, ISB 2001, published in Nature Cancer leveraged virtual trials to select a higher starting dose that would lower costs and reduce cycle timesRADNOR, Pa., Sept. 18, 2024 (GLOBE NEWSWIRE) -- Certara, Inc. (Nasdaq: CERT), a global leader in model-informed drug development, today shared the results from its collaboration with Ichnos Glenmark Innovation (IGI) on the first-in-human dose prediction and selection for ISB 2001. IGI’s drug candidate is a trispecific T-cell engager (TCE) being studied as a potential cancer treatment. Preclinical research and biosimulation findings were recently published in Nature Cancer. This publication highlighted ISB 2001’s therapeutic potential for relapsed/refractory multiple myeloma patients. Difficulties translating data from animals to patients traditionally limit first-in-human (FIH) dose selection to the most conservative approach. IGI sought to optimize the FIH dose of ISB 2001 to maximize patient safety and efficacy. They turned to Certara to develop an innovative virtual clinical trial platform leveraging their expertise in QSP (quantitative systems pharmacology) and PBPK (physiologically-based pharmacokinetics). “We were honored to work with IGI to develop a comprehensive biosimulation approach that allowed the team to successfully test ISB 2001 in virtual trials,” said Piet van der Graaf, PharmD, Ph.D., Senior Vice President and Head of Applied Biosimulation, Certara. “Our unique expertise and experience using virtual patients plus mechanistic modeling solutions allowed us to accelerate the speed at which ISB 2001 gets to patients. Virtual patient technology is the future of optimizing dosing for human patients.” As a result of this collaboration, the clinical starting dose increased by approximately 50-100 fold over the conventional starting dose. Using this higher dose reduces the likelihood of exposing cancer patients to ineffective doses. Accepted by the U.S. FDA and Australian HREC, this approach paves the way for determining FIH dosing for ISB 2001 and other TCEs. In addition, leveraging virtual trials to optimize ISB 2001 dosing saves time and costs. This efficiency is key as the industry faces mounting pressure to get drugs to patients faster. Using a more optimized dose eliminates time spent dosing patient cohorts with sub-therapeutic doses. This approach also minimizes the quantity of animal studies needed aligning with U.S. and European regulatory goals including the FDA Modernization Act 2.0. “The collaboration with Certara was important for the success of ISB 2001," said Mario Perro, Ph.D., Head of Biologics Research, IGI. "With the innovative QSP model adapted for our trispecific T cell engager, we could predict a first-in-human dose with an acceptable safety margin that will expose fewer patients to sub-therapeutic dosing.” To learn more about this research collaboration, please read this article, “ISB 2001 trispecific T-cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells.” To learn more about the phase 1 clinical trial informed by this research, please refer to “Study of ISB 2001 in Relapsed/Refractory Multiple Myeloma.” About CertaraCertara accelerates medicines using biosimulation software, technology, and services to transform traditional drug discovery and development. Its clients include more than 2,400 biopharmaceutical companies, academic institutions, and regulatory agencies across 66 countries. Learn more at certara.com. Certara Contact:Sheila Rocchiosheila.rocchio@certara.com Media Contact:Alyssa Horowitzcertara@pancomm.com

When pitted against Johnson & Johnson's Tecvayli and Bristol Myers Squibb’s candidate alnuctamab in human cell lines, ISB 2001 had a 20-to 260-fold stronger cancer-killing potency. For Ichnos Glenmark Innovation, good things come in threes. The alliance between Ichnos Sciences and Glenmark Pharmaceuticals has developed a trispecific, T-cell activating antibody that shrank multiple myeloma tumors in mice and killed cancer cells in human tissue more effectively than Johnson & Johnson's Tecvayli.The results were published in Nature Cancer on Sept. 11. The drug candidate, ISB 2001, is now in a phase 1 clinical trial.“This is our lead asset, so it's important for us as not only our contribution to the myeloma therapeutic space, but also it's an opportunity to demonstrate the value of our platform,” IGI President and CEO Cyril Konto, M.D., told Fierce Biotech in an interview. That platform, called BEAT (Bispecific Engagement by Antibodies based on the T Cell Receptor), enabled the team to attach binding sites for a T cell surface protein called CD3 onto an antibody heavy chain that also had a binding site for B-cell maturation antigen (BCMA), a known target on multiple myeloma cancer cells. The other heavy chain of the vaguely Y-shaped antibody targets CD38, another myeloma target.Binding to all three targets brings the T cell and the tumor together, Konto said. From there, the T cells can attack and kill the cancerous cells.When pitted against bispecifics such as Janssen's Tecvayli and Bristol Myers Squibb’s candidate alnuctamab in human cell lines, ISB 2001 had a 20-to 260-fold stronger cancer-killing potency. The trispecific also beat Tecvayli at killing tumors taken from multiple myeloma patients.To further test ISB 2001’s cancer-killing prowess, the researchers grafted human myeloma tumor cells onto mice and treated them with the antibodies. At a 0.1-mg/kg dose, ISB 2001 completely eradicated the tumors of all eight mice; Tecvayli, meanwhile, had no complete regressions and showed 30.8% tumor growth inhibition.T-cell activators like ISB 2001 run the risk of over-activating the immune cells and sparking cascades of inflammatory cytokines.“Often, greater potency comes at the cost of more side effects,” Sigrid Ruuls, Ph.D., and Paul Parren, Ph.D., wrote in a Nature Cancer commentary piece on the new study. “Even though ISB 2001 showed greater T cell-mediated cytotoxicity of tumor cells than that of teclistamab and another control CD3xBCMA bispecific, T cell cytokine secretion was not higher. Thus, there could be a larger therapeutic window for ISB 2001 than for other TCEs.” Ichnos has enrolled about 20 patients in the phase 1 trial so far, Konto said, and the company hopes to present preliminary data in multiple myeloma patients at a conference later this year.Glenmark, a multinational company with headquarters in India, is the sole backer of IGI. Ichnos was originally spun out of Glenmark in 2019.IGI has another antibody, a bispecific called ISB 1442, currently in a phase 1/2 trial for relapsed or refractory multiple myeloma. And a small molecule from the Glenmark side of the collaboration targets the T-cell regulator CBL-B, which Konto said could potentially be used in combination with ISB 2001 down the line if all goes well.“We're bringing the T cell and the tumor all together, and with a small molecule, we could improve the potency of the T cells themselves,” Konto said. “On paper, it looks great.”