Immunic, Inc. Publishes Positive Results From the Single & Multiple Ascending Dose Parts of its Phase 1 Clinical Trial of IMU-935, a Potentially Best-in-Class Oral IL-17 Inhibitor
Immunic, Inc. recently announced positive unblinded safety, tolerability and pharmacokinetic (PK) results from Part A (single ascending doses, SAD) and Part B (multiple ascending doses, MAD) of its phase 1 clinical trial of IMU-935 in healthy human subjects. In addition, the company announced newly available preclinical in vivo data showing that IMU-935 maintains normal thymocyte maturation in relevant acute and chronic mouse models.
In the SAD portion of the phase 1 clinical trial, healthy human subjects were randomized in a double-blinded fashion to either placebo or treatment with single ascending doses of a new powder-in-a-capsule formulation of IMU-935 at 100 mg, 200 mg, 300 mg and 400 mg. A dose-proportional PK profile was observed across the investigated dose range. Moreover, single ascending doses of IMU-935 were found to be safe and well-tolerated and no maximum tolerated dose was reached. No serious adverse events occurred. These favorable results allowed a smooth transition to the MAD part of the trial using the new formulation.
In the MAD part of this phase 1 clinical trial, healthy human subjects were dosed for 14 days with 150 mg once daily (QD) or 150 mg twice daily (BID) of IMU-935 or placebo in a double-blinded fashion. PK analysis showed that stable steady-state plasma concentrations were achieved within the first week of dosing with an accumulation factor for IMU-935 allowing predictable trough levels during daily dosing. PK parameters in steady-state revealed a Tmax of 2.4 to 2.8 hours post-dose, a plasma half-life of 29 to 38 hours and dose proportional increases in Cmax and AUC. The observed average steady-state trough levels in both MAD cohorts exceeded the known IC90 values for IL-17F release obtained from ex vivo stimulated human lymphocytes. Multiple ascending doses of IMU-935 were found to be safe and well-tolerated and no maximum tolerated dose was reached. Treatment emergent adverse events (TEAEs) were generally mild in severity with moderate TEAEs reported in one of eleven IMU-935 treated subjects compared with one of four subjects on placebo. No serious adverse events were reported. Finally, no dose-dependent changes in laboratory values (including no effects on liver enzymes or in hematological parameters), vital signs or in electrocardiographic evaluations were found. Taken together, the SAD and MAD parts of this phase 1 clinical trial did not identify any specific adverse events or laboratory abnormalities that require further investigation or special interest in future clinical trials, including no observed evidence of hepatotoxicity for IMU-935.
In light of the favorable safety data observed in healthy human subjects, the company has initiated Part C of the ongoing phase 1 clinical trial, where moderate-to-severe psoriasis patients are to be randomized to 28-day treatment with IMU-935 or placebo. Planned assessments include safety, tolerability, PK and pharmacodynamic markers, as well as skin evaluations.
“The unblinded data set from the SAD and MAD parts of our phase 1 clinical trial in healthy human subjects showed a very attractive safety, tolerability and pharmacokinetic profile for IMU-935,” stated Andreas Muehler, MD, Chief Medical Officer of Immunic. “These data are consistent with our preclinical data and support our vision of establishing IMU-935 as the potentially best-in-class RORγt inverse agonist.”
In previous preclinical in vitro data, it was shown that IMU-935 selectively inhibits Th17 differentiation and IL-17 production, whereas RORγt was unaffected by IMU-935 during thymocyte maturation and, therefore, does not harm normal thymocyte maturation. Newly obtained data from acute and chronic treatment of mice corroborated in vivo that IMU-935 is the first molecule observed to impact neither thymus size, thymocyte numbers, nor the maturation status of thymocytes, in contrast to two other known RORγt inhibitors. With these in vivo data, Immunic believes that the company may have the first clinical-stage RORγt inverse agonist which circumvents thymocyte maturation issues.
“We are very excited by both these outstanding safety, tolerability and PK results in healthy human subjects and the new preclinical work corroborating selectivity of IMU-935, our selective oral IL-17 inhibitor, in vivo,” added Daniel Vitt, PhD, Chief Executive Officer and President of Immunic. “As expected, the phase 1 clinical trial of IMU-935 was expanded in late October to include a third portion, Part C, comprised of moderate-to-severe psoriasis patients given IMU-935 daily over 28 consecutive days. We look forward to reporting initial results from this Part C portion in psoriasis patients in the second quarter of 2022.”
IMU-935 is a highly potent and selective inverse agonist of RORγt (retinoic acid receptor-related orphan nuclear receptor gamma truncated) with additional activity on DHODH (dihydroorotate dehydrogenase). The nuclear receptor RORγt is believed to be the main driver for the differentiation of Th17 cells and the expression of cytokines involved in various inflammatory and autoimmune diseases. This target is believed to be an attractive alternative to approved antibodies for targets such as IL-23, IL-17 receptor and IL-17, itself. IMU-935 shows strong cytokine inhibition targeting both Th17 and Th1 responses in preclinical testing, as well as indications of activity in animal models for psoriasis and inflammatory bowel disease. Preclinical experiments indicate that, while leading to a potent inhibition of Th17 differentiation and cytokine secretion, IMU-935 did not affect thymocyte maturation. IMU-935 is an investigational drug product that has not been approved in any jurisdiction.
Immunic, Inc. (Nasdaq: IMUX) is a clinical-stage biopharmaceutical company with a pipeline of selective oral immunology therapies focused on treating chronic inflammatory and autoimmune diseases. The company is developing three small molecule products: its lead development program, vidofludimus calcium (IMU-838), a selective immune modulator that inhibits the intracellular metabolism of activated immune cells by blocking the enzyme DHODH and exhibits a host-based antiviral effect, is currently being developed as a treatment option for multiple sclerosis, ulcerative colitis, Crohn’s disease, and primary sclerosing cholangitis. IMU-935, a selective inverse agonist of the transcription factor RORγt, is targeted for development in psoriasis, castration-resistant prostate cancer and Guillain-Barré syndrome. IMU-856, which targets the restoration of the intestinal barrier function, is targeted for development in diseases involving bowel barrier dysfunction. For further information, visit www.imux.com.
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