Science
Our approach
At Enemsa Pharma, we focus on therapeutic areas with significant unmet medical need where dysregulation of the Integrated Stress Response (ISR), NMDAR signaling, mitochondrial oxidative stress, inflammation, or fibrosis plays a critical role in disease progression. Our lead asset, Icerguastat, a Phase‑1‑completed ISR modulator, serves as a flexible plug‑and‑play foundation for rapid combination‑therapy innovation.
This platform allows us to efficiently pair Icerguastat with late‑stage or marketed drugs, accelerating synergy assessment and enabling faster progression toward clinical development.
We build comprehensive, IND ready data packages – including in vitro and in vivo efficacy, pathway engagement, translational biomarkers, ADMET, DDI, and CMC – to demonstrate the broad therapeutic potential of our combinations.
This rigorous approach supports both internal clinical advancement and co‑development or partnership opportunities with pharmaceutical companies.
Our lead combination therapy, Icerguastat + Ambroxol, leverages the complementary mechanisms of action of both compounds. Preclinical research has shown remarkable synergy between the two agents in in‑vitro models of neurodegenerative diseases. Enemsa Pharma will first advance this combination in Parkinson’s disease patients carrying GBA1 mutations.
In parallel, Enemsa Pharma is assessing the efficacy of Icerguastat combined with current standards of care in an animal model of pulmonary disease, further expanding the therapeutic potential of our ISR‑modulating approach.
Our first combination therapy, Icerguastat + Riluzole, has been developed for the treatment of Amyotrophic Lateral Sclerosis (ALS). We successfully completed an exploratory Phase 2 clinical study in patients with bulbar‑onset ALS, demonstrating a favorable safety and tolerability profile alongside measurable clinical benefits across multiple validated endpoints. The study confirmed engagement of key disease‑relevant pathways and showed improvements in meaningful biomarkers, providing strong validation of our therapeutic hypothesis.
Ultimately, our mission is to alleviate the life altering symptoms of neurodegenerative and cardiopulmonary diseases and to slow – or potentially reverse – their progression, bringing meaningful therapeutic advances to patients with high unmet medical needs.
About Icerguastat
Icerguastat (also named sephin1 or IFB-088) is a first‑in‑class, orally available, brain‑penetrant small molecule modulating NR2B‑containing NMDAR (A) and PPP1R15A/PP1c phosphatase complex (B), while limiting mitochondrial ROS production (C).
This multifunctional compound displayed multiple efficacy signals across many disease animal models, such as Amyotrophic Lateral Sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), Alzheimer’s Disease (AD), Multiple Sclerosis (MS), Spastic Ataxia-5 (SPAX-5).
Icerguastat is a de‑risked backbone asset with a completed phase 1 in healthy volunteers showing a safe, well‑tolerated profile and a chronic‑tox package (ADMET, up to 9‑month toxicology studies) that supports long‑term use. An exploratory Phase 2 in bulbar‑onset ALS patients confirmed Icerguastat safety, target engagement and promising biomarker effects.
Parkinson’s Disease with GBA1 Mutations
Parkinson’s disease is a progressive neurodegenerative disorder of the central nervous system characterized primarily by motor symptoms such as tremor, rigidity, bradykinesia, and postural instability. It results from the gradual loss of dopamine‑producing neurons in the substantia nigra and often includes non‑motor symptoms like sleep disturbances, mood changes, and cognitive impairment. Symptoms typically develop gradually and worsen over time.
Parkinson’s disease associated with GBA1 mutations (GBA1‑PD) is the most common genetic form of Parkinson’s disease and is characterized by reduced glucocerebrosidase (GCase) activity, impaired lysosomal degradation, and accelerated accumulation of misfolded proteins such as α‑synuclein. These pathogenic mechanisms contribute to earlier onset and faster progression compared with idiopathic Parkinson’s disease. Despite the strong biological understanding of this disease pathway, no disease‑modifying therapy has yet been approved.
Ambroxol, a long‑established therapeutic molecule, has emerged as a promising candidate for disease modification in Parkinson’s disease. A Phase 2 clinical study in GBA1‑PD patients demonstrated increased GCase activity in the brain together with a reduction in α‑synuclein levels, providing strong biological proof of concept. Building on these encouraging results, two Phase 3 trials are currently ongoing to further evaluate ambroxol’s impact on disease progression in Parkinson’s disease.
To further enhance therapeutic impact, Enemsa Pharma is developing a combination strategy pairing Ambroxol with icerguastat. Compounds that prolong the phosphorylation of eIF2α, like Icerguastat, modulate the cellular stress response pathway, promote neuronal resilience, and reduce α synuclein-related toxicity as well.
When combined with Ambroxol’s ability to boost GCase activity and restore lysosomal function, Enemsa Pharma dual‑mechanism approach aims to correct the core biological defects of GBA1‑PD more effectively than either agent alone, with the ambition to deliver a first‑in‑class disease‑modifying therapy for these high‑risk patients.
Such a combination therapy targeting GCase-related pathway abnormalities could also slow disease progression in both idiopathic PD and Dementia with Lewy Body (DLB), because of the considerable overlap in pathobiology between GBA1-PD, idiopathic PD and DLB with GBA1 mutations.
Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a severe and rapidly progressive neurodegenerative disease marked by the degeneration of upper and lower motor neurons, leading to muscle weakness, loss of motor function, and ultimately respiratory failure. Among its clinical presentations, bulbar‑onset ALS represents a distinct and particularly aggressive phenotype, accounting for roughly one‑third of cases and associated with faster progression and poorer survival outcomes. Despite decades of research, ALS remains an area of profound unmet medical need, with currently available therapies offering only limited impact on disease progression.
Icerguastat, which is a selective modulator of the integrated stress‑response pathway (ISR), works by prolonging the phosphorylation of eIF2α, allowing motor neurons to better withstand chronic proteotoxic and cellular stress. This mechanism is highly relevant in ALS, where dysregulated protein homeostasis and pathological aggregation – including TDP 43 pathology – play central roles in neurodegeneration. Preclinical studies in SOD1 and TDP‑43 models have demonstrated that Icerguastat supports motor neuron survival, improves motor performance, and modulates key disease‑related markers.
Riluzole, the long‑established standard of care in ALS, reduces glutamatergic excitotoxicity but provides only modest clinical benefit on its own.
Combining Riluzole with Icerguastat provides a complementary, dual‑mechanism therapeutic strategy for ALS. While Riluzole acts upstream to reduce glutamatergic excitotoxicity, Icerguastat enhances the resilience of stressed motor neurons by stabilizing eIF2α phosphorylation and modulating downstream stress‑response pathways.
Enemsa Pharma has shown that this combination delivers synergistic neuroprotective effects in vitro, preserving neuromuscular junction integrity in a co‑culture of primary rat motoneurons and myotubes exposed to glutamate.
Encouraging signals have also emerged clinically. In a randomized Phase 2a trial in bulbar‑onset ALS, the Icerguastat + Riluzole combination reduced cytoplasmic TDP‑43, the molecular hallmark of ALS; slowed the decline in respiratory function, a major determinant of patient survival; and demonstrated good safety and tolerability over six months of treatment.
Taken together, these findings provide compelling clinical evidence of biological target engagement and support the potential of icerguastat to deliver meaningful disease modifying benefit to ALS patients when combined with the current standard of care.
