Inflectis

Nantes, France – February 6^th, 2025 – InFlectis BioScience SAS, a drug discovery company pioneering development of therapeutics harnessing the Integrated Stress Response (ISR) for a spectrum of neurological diseases, today announced the successful completion of its P288ALS TRIAL study (NCT05508074). This study was designed as a randomized, double-blind, placebo-controlled, parallel-group phase 2a trial comparing its drug candidate IFB-088 (25 mg BID) plus riluzole with placebo plus riluzole, in patients afflicted with bulbar-onset ALS, a particularly severe ALS subtype.

The primary objective was the assessment of safety of IFB-088. The sample size was powered to demonstrate safety with a total of 51 bulbar-onset ALS patients randomized (2:1, treatment:placebo with standard of care), among whom 41 have data available at 6 months. Secondary endpoints included a range of validated efficacy parameters and biomarkers.

Overall, IFB-088 was found to be safe and well-tolerated with non-meaningful observations, meeting the primary objective of the study and confirming the findings of the Phase 1 study in healthy volunteers.

The study also showed promising results for IFB-088 on efficacy parameters although the sample size was not powered to demonstrate efficacy. A trend in favor of a lower functional decline measured with ALSFRS score in IFB-088-treated patients was shown in the Intent-to-Treat population (51 patients). In the per protocol population (40 patients), this difference in functional decline measured with ALSFRS score between the placebo and IFB-088-treated patients was statistically significant with a decline of -0.95 pts ALSFRS/month in IFB-088 treated group versus a -1.42 pts ALSFRS/month in the placebo group over the six months; this difference is also clinically meaningful. The evolution of clinical scores on the ALS-MiToS and King’s College scales, and of respiratory function decline assessed by measurement of slow vital capacity (SVC) in the per protocol population, confirm this trend in favor of IFB-088. Overall, these clinical results confirm previous findings of the ProMISe Phase 2 study with IFB-088 parent drug, guanabenz, in ALS patients, carried out by IRCCS “Carlo Besta” Neurological Institute in Milan, Italy.

The clinical trial also confirmed that both the integrated stress response (ISR) and oxidative stress pathways were engaged in bulbar ALS patients upon IFB-088 treatment. Biomarker measurements demonstrated IFB-088’s activity on these metabolic pathways. Biomarker assessments also substantiated the efficacy of IFB-088 on critical ALS pathological pathways including TDP-43 mis-localization, oxidative stress, neurodegeneration and inflammation. These results validate preclinical findings and support the underlying medical hypotheses.

“These findings confirm the hypotheses raised from preclinical studies and strongly support the premise of moving IFB-088 to pivotal study,” said Dr. Anne Visbecq, InFlectis Chief Medical Officer.

“The positive results, supported by both clinical outcomes and biomarker validation, while confirming our previous work, strengthen the therapeutic potential of targeting the integrated stress response (ISR) and oxidative stress pathways in bulbar onset ALS. These findings provide a strong foundation for further clinical development and bring us one step closer to delivering an innovative and effective treatment to patients,” said Prof. Giuseppe Lauria, Principal Investigator, Professor of Neurology at University of Milan, Scientific Director at IRCCS “Carlo Besta” Neurological Institute.

InFlectis BioScience received a 2023 Hoffman ALS Clinical Trial Award from the ALS Association. Kuldip Dave, Ph.D., Senior Vice President for Research at the Association, said: "New treatments are urgently needed to make ALS a livable disease, so we are thrilled to see IFB-088 hit its primary endpoint of safety and tolerability. This is a critical first step in taking the program forward into larger trials that can determine efficacy."

Pierre Miniou, Chief Executive Officer of InFlectis, declared: “We are very encouraged by the results we observed with IFB-088 and appreciate the financial support of ALS Association and AFM-Téléthon. These compelling findings position IFB-088 for forthcoming pivotal studies and pave the way for new treatment possibilities for ALS. InFlectis BioScience is now seeking global partners to complete the development and registration of IFB-088 in ALS and leverage the company’s assets in a broader pipeline of neurological indications with unmet medical needs, such as Charcot-Marie-Tooth Disease."

About IFB-088 (icerguastat)

InFlectis is developing IFB-088 (also named sephin1), a first-in-class, multi-functional, brain-penetrant, orally administered small molecule that selectively inhibits the dephosphorylation of eIF2α. By doing so, IFB-088 amplifies the integrated stress response (ISR), acting as a formidable shield against various cellular stresses, including endoplasmic reticulum (ER) stress which is a hallmark of neurodegeneration. IFB-088 also selectively antagonizes NMDA receptors containing the NR2B subunit, which are involved in glutamate excitotoxicity that triggers calcium influx, mitochondrial dysfunction, and ROS production, and ultimately contributes to neurodegeneration. IFB-088 also reduces mitochondrial ROS production in an NMDAR-independent manner. Hence, IFB-088 normalizes dysregulated calcium homeostasis and oxidative stress to provide neuroprotection in different diseases context. This approach holds promise for designing disease-modifying therapeutics to fight intractable diseases such as ALS.

About Bulbar-Onset ALS

ALS is increasingly being recognized as a heterogeneous disease. To optimize assessment in a small study, InFlectis has focused IFB-088 development to date on bulbar-onset ALS patients, who account for ~30% of all ALS patients and represent a more homogeneous patient population. Bulbar ALS is a distinct phenotype identified with specific clinical parameters; disease onset primarily affects the brainstem, impacting muscles responsible for speech, swallowing, and limb functions. Patients experience slurred speech (dysarthria) and difficulty swallowing (dysphagia) early in the disease progression. Bulbar-onset ALS usually exhibits a rapid evolution and poor prognosis (~26 months from symptom onset to death). Treatment options remain a high unmet medical need for this patient group.

About the ALS ASSOCIATION

The ALS Association is the largest philanthropic funder of ALS research in the world. The Association funds global research collaborations, assists people with ALS and their families through its nationwide network of care and certified clinical care centers, and advocates for better public policies for people with ALS. The ALS Association is working to make ALS a livable disease while urgently searching for new treatments and a cure. For more information about the ALS Association, visit our website at als.org.

About AFM-Téléthon

The French Muscular Dystrophy Association (AFM) - AFM-Telethon - is a major player in biomedical research for rare diseases in France and worldwide. It currently funds about 350 research programs and 40 clinical trials in different genetic diseases affecting the eye, blood, brain, immune system, motor neurons and muscles... The AFM-Telethon has also created three research and development institutes dedicated to gene therapy, stem cells and myology. To learn more visit www.afm-telethon.fr/en

InFlectis BioScience Announces Promising Results for IFB-088 in a Phase 2a Clinical Study in Bulbar-Onset ALS Patients