icerguastat (IFB-088) / InFlectis - LARVOL DELTA

Treatment Combining Riluzole and IFB-088 in Bulbar Amyotrophic Lateral Sclerosis (TRIALS Protocol) (clinicaltrials.gov) - P2 | N=51 | Completed | Sponsor: InFlectis BioScience | Active, not recruiting ➔ Completed

Trial completion • Amyotrophic Lateral Sclerosis • CNS Disorders

The GADD34 Inhibitor Sephin1 Promotes Airway Repair and Prevents Chemical-induced Bronchiolitis Obliterans in Rats Through the Integrated Stress Response (ATS 2025) - No abstract available

Preclinical • Pulmonary Disease • Respiratory Diseases • PPP1R15A

Sephin1 suppresses ER stress-induced cell death by inhibiting the formation of PP2A holoenzyme. (PubMed, Cell Death Dis) - "Phosphorylated AMPK is inactivated by PP2A through dephosphorylation of its Thr172, and Sephin1 inhibits the formation of the PP2A holoenzyme with the PP2A subunit B isoform delta. These results indicate that inhibition of PP2A holoenzyme formation is the molecular target of Sephin1 in this experimental system."

Journal • CNS Disorders • Targeted Protein Degradation • TNS1

Harnessing osmotic shock for enhanced intracellular delivery of (nano)cargos. (PubMed, Int J Pharm) - "When primary fibroblasts derived from amyotrophic lateral sclerosis (ALS)-patients were exposed to hypotonic shock in the presence of the therapeutic cargo icerguastat, there was an increased expression of miR-106b-5p compared to isotonic conditions. In conclusion, osmotic shock presents a promising strategy for improving drug delivery within cells and, potentially, in tissues such as muscles or skin, where localized drug administration is preferred."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • MIR106B

PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma. (PubMed, JHEP Rep) - "Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs...The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Solid Tumor • CD8 • GZMB • IFNG • PPP1R15A • S100A8 • TGFB1 • TNS1

Sephin1 enhances integrated stress response and autophagy to alleviate myocardial ischemia-reperfusion injury in mice. (PubMed, Biomed Pharmacother) - "Sephin1 enhances ISR and related protein synthesis suppression, ameliorates myocardial apoptosis, and promotes autophagy during MIR stress. Sephin1 could act as a noval ISR enhancer for managing acute myocardial ischemia disease."

Journal • Preclinical • Cardiovascular • Myocardial Ischemia • Reperfusion Injury

Improved Neuromuscular Junction in R98C Mpz Heterozygous Mice Treated with IFB-088 (AAN 2024) - "These data, combined with prior behavioral and physiological studies demonstrate that IFB088 improves the neuropathy of R98C MPZ CMT1B mice, a model of CMT1B involving UPR activation."

Preclinical • Genetic Disorders • Pain • MPZ • PPP1R15A

Treatment Combining Riluzole and IFB-088 in Bulbar Amyotrophic Lateral Sclerosis (TRIALS Protocol) (clinicaltrials.gov) - P2 | N=51 | Active, not recruiting | Sponsor: InFlectis BioScience | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders

PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS. (PubMed, PLoS One) - "Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders

Phase 2 trial of oral IFB-088 for bulbar-onset ALS now fully enrolled (ALS News Today) - "Enrollment is complete in a Phase 2 trial testing InFlectis BioScience’s oral candidate IFB-088 (icerguastat) in people with amyotrophic lateral sclerosis (ALS), the company has announced. The trial (NCT05508074) enrolled a total of 50 adults with bulbar-onset ALS, a form of the disease that first affects the muscles in the head and neck, leading to swallowing, chewing, and speech difficulties."

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders

Inhibition of PPP1R15A alleviates osteoporosis via suppressing RANKL-induced osteoclastogenesis. (PubMed, Acta Pharmacol Sin) - "Knockdown of PPP1R15A or application of Sephin1 (a PPP1R15A allosteric inhibitor in a phase II clinical trial) significantly inhibited osteoclastogenesis in vitro...PPP1R15A inhibition also suppressed pathogenic osteoclastogenesis in CD14 monocytes from osteoporosis patients. These results identify PPP1R15A as a novel regulator of osteoclastogenesis and a valuable therapeutic target for osteoporosis."

Journal • Osteoporosis • Rheumatology • CD14 • FOS • NFATC1 • PPP1R15A • TNS1

Integrated Stress Response in alpha synucleinopathy (Neuroscience 2023) - "While inhibition of Gadd34 is neuroprotective multiple models of neurodegeneration, inclusing motor neuron disease and multiple sclerosis, we show that neither the pharmacological inhibition of Gadd34, using Guanabenz and Sephin-1, or genetic loss Gadd34 function attenuated α-synucleinopathy in TgA53T model...Our data show that PERK-eIF2α pathway is an important pathological axis for α-synucleinopathy and different phosphatases are differentially involved in various neurodegenerative conditions. Moreover, we show that ISR components, particularly inhibition of CReP, is a therapeutic target for α-synucleinopathy."

Amyotrophic Lateral Sclerosis • CNS Disorders • Parkinson's Disease • PPP1R15A • PPP1R15B • TNS1

Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5. (PubMed, Brain) - "In agreement, pharmacological potentiation of ISR via Sephin-1, a drug that selectively inhibits the stress-induced eIF2alpha phosphatase GADD34 (encoded by Ppp1r15a), improved cell growth of SPAX5 fibroblasts, and cell survival and dendritic arborization ex vivo in primary Afg3l2-/- Purkinje neurons (PNs)...These data indicate that activation of the OMA1-DELE1-HRI pathway is protective in the context of SPAX5. Pharmacological tuning of the ISR may represent a future therapeutic strategy for SPAX5 and other cerebellar ataxias caused by impaired mitochondrial proteostasis."

Journal • Ataxia • CNS Disorders • Dystonia • Epilepsy • Movement Disorders • Ocular Inflammation • ATF4 • CHAC1 • OPA1 • PLAA • PPP1R15A

Protocol for PPP1R15A-inhibited mouse model establishment with subcutaneous B16F1 tumor and single-cell analysis. (PubMed, STAR Protoc) - "Here, we present a protocol for exploring the effects of PPP1R15A inhibitor, Sephin1, on antitumor immunity of B16F1 subcutaneous tumor in mice...We then detail procedures for gene differentiation, regulon and cell-cell communication analysis, and validation of single-cell analysis results. For complete details on the use and execution of this protocol, please refer to Wang et al.."

Journal • Preclinical • Oncology • PPP1R15A

Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy. (PubMed, Metab Brain Dis) - "Factors like disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress disturb the UPR sensor levels manifesting as DPN. We discuss new effective therapeutic alternatives for DPN that can be developed by targeting UPR pathways like synthetic ER stress inhibitors like 4-PhenylButyric acid (4-PBA), Sephin 1, Salubrinal and natural ER stress inhibitors like Tauroursodeoxycholic acid (TUDCA), Cordycepin, Proanthocyanidins, Crocin, Purple Rice extract and cyanidin and Caffeic Acid Phenethyl Ester (CAPE)."

Journal • Review • Alzheimer's Disease • CNS Disorders • Diabetes • Diabetic Neuropathy • Dyslipidemia • Gastroenterology • Gastrointestinal Disorder • Immunology • Metabolic Disorders • Movement Disorders • Oncology • Pain • Parkinson's Disease • Peripheral Neuropathic Pain

Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response. (PubMed, Glia) - "Finally, pharmacological suppression of the ISR blocks stress granule formation in vitro and partially lessens the beneficial effect of Sephin1 on disease progression in a mouse model of MS, experimental autoimmune encephalitis (EAE). Overall, our findings uncover distinct mechanisms of action of BZA and Sephin1 on oligodendrocyte lineage cells under inflammatory stress, suggesting that a combination therapy may effectively promote restoring neuronal function in MS patients."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • IFNG

The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response. (PubMed, Open Biol) - "Furthermore, the positive effect of Icerguastat depends on GADD34, a key component of the phosphatase complex in the PERK branch of the UPR. This study reveals a major contribution of the ER stress in OPMD pathogenesis and provides a proof-of-concept for Icerguastat interest in future pharmacological treatments of OPMD."

Journal • Muscular Dystrophy • PPP1R15A

Single-cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity. (PubMed, iScience) - "A special TCR + macrophage subtype in tumor was identified to be significantly depleted upon Sephin1 treatment, implying its key antitumor role. These results suggest that PPP1R15A has the potential to be an effective target for tumor therapy."

Journal • Immunology • Oncology • PPP1R15A • TNS1

Treatment Combining Riluzole and IFB-088 in Bulbar Amyotrophic Lateral Sclerosis (TRIALS Protocol) (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: InFlectis BioScience | Not yet recruiting ➔ Recruiting

Enrollment open • Amyotrophic Lateral Sclerosis • CNS Disorders • BDNF • CCL2 • IL10 • IL6 • NEFL • TARDBP • VEGFA

Amyloid Aβ Aggregates Say 'NO' to Long-Term Potentiation in the Hippocampus through Activation of Stress-Induced Phosphatase 1 and Mitochondrial Na/Ca Exchanger. (PubMed, Int J Mol Sci) - "The PP1/PP2A inhibitor, okadaic acid, but not the PP2B blocker, cyclosporin A, prevented Aβ-dependent LTP suppression for both simultaneous and delayed enzyme blockade protocols...A selective inhibitor of stress-induced PP1α, sephin1, but not of the PP2A blocker, cantharidin, is crucial for Aβ-mediated LTP suppression prevention...NO scavenger, PTIO, or nNOS blockade by selective inhibitor 3Br-7NI partly restored the Aβ-induced LTP decline. Thus, hippocampal NO production could be another marker for the impairment of synaptic plasticity in amyloidosis-related states, and kinase-phosphatase balance management could be a promising strategy for the compensation of Aβ-driven deteriorations."

Journal • Alzheimer's Disease • Amyloidosis • CNS Disorders

Treatment Combining Riluzole and IFB-088 in Bulbar Amyotrophic Lateral Sclerosis (TRIALS Protocol) (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: InFlectis BioScience

New P2 trial • Amyotrophic Lateral Sclerosis • CNS Disorders • BDNF • CCL2 • IL10 • IL6 • TARDBP • VEGFA

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1. (PubMed, Ann Clin Transl Neurol) - "Guanabenz proved itself as a viable treatment option for VWM. The exact mechanism through which guanabenz exerts its ameliorating impact on VWM requires further studies. Sephin1 is not simply a guanabenz replacement without α2-adrenergic effects."

Journal • Preclinical • EIF2B4

Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice. (PubMed, Mol Neurobiol) - "(Left panel) the accumulation of overexpressed PMP22 or misfolded mutant P0 in the Schwann cell endoplasmic reticulum (ER) leads to overwhelming of the degradative capacity, activation of ER-stress mechanisms, and myelination impairment. (Right panel) by prolonging eIF2α phosphorylation, IFB-088 reduces the amount of newly synthesized proteins entering the ER, allowing the protein quality control systems to better cope with the unfolded/misfolded protein and allowing myelination to progress."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Genetic Disorders • Multiple Sclerosis • Pain • MPZ

Long-term mitochondrial stress induces early steps of Tau aggregation by increasing reactive oxygen species levels and affecting cellular proteostasis. (PubMed, Mol Biol Cell) - "Inhibition of the ISR with ISRIB induced Tau dimerization, whereas ISR activation with salubrinal, guanabenz, and sephin1 partially reversed this process. Cells that were treated with ROS scavengers, N-acetyl-L-cysteine or MitoQ, significantly reduced the amount of ROS and Tau dimerization, indicating the involvement of oxidative stress in Tau aggregation. Our results indicate that long-term mitochondrial stress may induce early steps of Tau protein aggregation by affecting oxidative balance and cellular proteostasis."

Journal • Alzheimer's Disease • CNS Disorders • Metabolic Disorders

InFlectis BioScience granted Orphan Drug Designation for IFB-088 (icerguastat), a clinical stage treatment for Amyotrophic Lateral Sclerosis (Inflection Biosciences Press Release) - "InFlectis BioScience received Orphan-Drug Designation from the U.S. Food and Drug Administration (FDA) for its investigational treatment for Amyotrophic Lateral Sclerosis (ALS), IFB-088....The Company plans to initiate a Phase 2 trial in Europe (France and Italy) this summer....This is an important milestone for the company and a significant step forward in our US and European clinical development and regulatory strategy for IFB-088, 'Phase 2 clinical data from an analog to IFB-088 reported last year demonstrates the potential of an ISR modulator to slow the progression of ALS, in particular in bulbar-onset ALS patients.'We are now preparing the setup of clinical operations and planning to enroll the first patient this summer'...'In our development plan we expect to initiate larger studies in the U.S. and worldwide for the whole ALS population.' "

New P2 trial • Orphan drug • Amyotrophic Lateral Sclerosis • CNS Disorders