Multiple Sclerosis, Primary Progressive

iStock, JHVEPhoto Oditrasertib, which blocks the inflammatory RIPK1 protein, earlier this year also failed a Phase II trial in amyotrophic lateral sclerosis, forcing the company to discontinue its development a few months later. Sanofi is discontinuing a Phase II multiple sclerosis study of its investigational RIPK1 blocker oditrasertib after the candidate failed to meet its primary and key secondary endpoints, according to an SEC filing on Thursday by partner Denali Therapeutics. Denali and Sanofi were evaluating oditrasertib in the mid-stage K2 study , a randomized, double-blinded and placebo-controlled trial that enrolled more than 170 patients with relapsing-remitting multiple sclerosis (MS), secondary progressive MS or primary progressive MS. The primary efficacy endpoint was oditrasertib’s effect on serum neurofilament light chain levels. No specific details were provided in Denali’s SEC document, nor did the company identify which particular secondary outcomes oditrasertib missed. The California biotech also did not address oditrasertib’s safety profile. Designed to be orally available, oditrasertib is an investigational inhibitor of the RIPK1 protein, which is a crucial signaling player in inflammatory and cell death pathways. In neurodegenerative diseases, RIPK1—along with other proteins from the same family— tends to be overactivated , leading to widespread inflammation and large-scale cell death in the brain. By targeting RIPK1, oditrasertib disrupts this pathological process, in turn preserving the integrity and function of the brain. Despite a promising mechanism of action, however, oditrasertib has had a challenging clinical showing recently. In April 2024, Sanofi announced plans to terminate a Phase II trial of oditrasertib in amyotrophic lateral sclerosis (ALS) after a disappointing mid-stage readout. A few months earlier, in February 2024, Sanofi and Denali announced that oditrasertib failed the Phase II HIMALAYA study in ALS , unable to significantly improve disease severity, as measured by the ALS Functional Rating Scale-Revised. Developing effective therapies for MS has proven difficult. In September 2024, another Sanofi asset, the BTK inhibitor tolebrutinib, failed to significantly improve relapse rates in two Phase III studies. Tolebrutinib redeemed itself a few weeks later by significantly delaying disability onset in patients with non-relapsing secondary progressive MS in a third Phase III trial. That same month, a study published in the peer-reviewed journal Neurology raised questions about the use of anti-CD20 antibodies in multiple sclerosis. According to its findings, there appear to be no significant difference in relapse or the progression of disability between patients who were given these therapies versus those who were untreated. The study focused on primary progressive multiple sclerosis, for which the only approved anti-CD20 therapy is Roche’s Ocrevus (ocrelizumab). Other agents in the same drug class are also approved for relapsing forms of MS, including Novartis’ Kesimpta (ofatumumab) and TG Therapeutics’ Briumvi (ublituximab).

THURSDAY, Sept. 26, 2024 -- For patients with primary progressive multiple sclerosis (PPMS), the time to confirmed disability progression (CDP) does not differ for those who are anti-CD20-treated and untreated, according to a study published online Sept. 25 in Neurology . Marion Hay, M.D., from Rennes University Hospital in France, and colleagues analyzed CDP in a cohort of patients with PPMS treated with anti-CD20 therapies versus a weighted untreated control cohort in a retrospective study using data from the French MS registry. A total of 1,184 patients met the inclusion criteria: 426 treated and 758 untreated (median age, 56 years; 52.7 percent female). Among treated patients, 295 and 131 received rituximab and ocrelizumab, respectively. The researchers found that anti-CD20-treated patients were younger and had more active disease at baseline. There was no statistical difference observed in time to first CDP. A nonsignificant trend toward fewer patients relapsing in the treated group was observed in time to first relapse analysis. No significant difference was seen between the two groups for magnetic resonance imaging activity. Male sex and MS duration were risk factors associated with CDP in the treated group. Serious infection incidence ratios were 6.67 and 2.67 per 100 person-years in the treated and untreated groups, respectively. "Our results indicate that there should be a constant evaluation of all available data to ascertain the best risk/benefit ratio for patients with PPMS, especially for newly diagnosed patients for whom inflammatory activity is very often not well defined," the authors write. Several authors disclosed ties to the pharmaceutical industry.

GDANSK, Poland I September 26, 2024 I PolTREG S.A. (Warsaw Stock Exchange: PTG), a clinical-stage biotechnology company developing cellular therapies for a range of autoimmune diseases, today announces it has launched a study with CAR-Treg cells in a humanized mouse model of neuroinflammatory disease. Data from the study are anticipated by March 30, 2025, and will help determine the pathway to clinical evaluation. The study will measure safety and efficacy of the CAR-Treg cell therapy, which will be administered systemically as well as intrathecally. PolTREG’s CAR-Treg cells are manufactured using the same technology platform as its lead product PTG-007, a polyclonal Treg cell therapy, for which PolTREG has gathered over a decade of clinical safety and efficacy data, largely in type-1 diabetes (T1D) patients. “This first preclinical study of our CAR-Treg cell therapy program to treat neurodegenerative disease is a significant milestone for PolTREG. This may be our first CAR-Treg cell therapy candidate, but we expect it to benefit tremendously from the experience our team built up during more than a decade in manufacturing, developing and treating patients with PTG-007. This lengthy track record gives us several competitive advantages, as the next-generation engineered Tregs that we are adding to our pipeline come from the same platform, and show a large degree of bioequivalence with PTG-007. Because of our proprietary technology and expertise, we expect to be able to develop our engineered therapies with greater ease than others in this field,” said Prof Piotr Trzonkowski, Chief Executive Officer of PolTREG. PolTREG’s CAR-Treg cells are derived from its PTG-007 Treg cells, an advanced autologous polyclonal product candidate for which the company has gathered 12 years of patient safety and efficacy data in Type 1 diabetes (T1D), using its leading technological and wholly owned GMP manufacturing facility in Poland. To the best of its knowledge, PolTREG is the only company in possession of such expertise, giving it potential technical, clinical safety and efficacy advantages in the autoimmune therapy field. In an exploratory Phase 1/2a safety study in relapsing-remitting multiple sclerosis (MS), patients who had received intrathecal administration of PTG-007 showed no increase in existing lesions in the brain, and almost no new lesions, a far superior result compared to those who had received the therapy intravenously, and a surprisingly positive signal for a small study of just 14 patients. To read the 2021 results of the study, click on this link. On successful completion of preclinical testing of the CAR-Treg, PolTREG expects to initiate, as early as next year, the first-in-human trial of the engineered candidate to treat MS and amyotrophic lateral sclerosis (ALS). The company also is developing two additional modalities of engineered Treg cell therapies, Antigen-specific Tregs and T-cell receptor (TCR) Tregs for autoimmune diseases, which are in early, proof-of-concept preclinical stages. PolTREG receives three new patents Separately, the United States Patent and Trademark Office (USPTO) has granted AZTherapies, a private, late-stage clinical biopharmaceutical company developing treatments for neurological conditions, from Boston, Massachusetts, a patent for the use of CAR-Treg therapy in autoimmune neurodegenerative diseases. PolTREG holds the exclusive global license to the therapy for all indications. Also in September, the Japanese Patent Office issued a patent for PolTREG’s method of producing antigen-specific Treg cells, under the product name PTG-020. Earlier in the month, PolTREG had already announced in a press release that the Chinese Patent Office issued a patent for PolTREG’s method of administering Treg cell therapy in MS directly into the central nervous system (intrathecal administration). About PolTREG PolTREG is a global leader in developing autoimmune therapies based on T-regulatory cells (Tregs). Its lead product, PTG-007, autologous Treg treatment for early-onset Type-1 Diabetes (T1D) is ready for Phase 2/3 clinical testing, for which the company is seeking a partnership. The company will launch Phase 2 trials for PTG-007 to treat Multiple Sclerosis (MS) in the second half of 2024, for RRMS and PPMS. PolTREG also has engineered Tregs, including CAR-Tregs, antigen-specific Tregs and TCR-Tregs, in the preclinical stage. PolTREG has completed four clinical trials with more than 100 patients treated with Tregs. For more information please visit www.poltreg.com. SOURCE: PolTREG