This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-βR1/ALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heightened TGF-β/SMAD-driven Astrocytic and Fibrotic Signaling

Sponsor
Gipfel Life Sciences GmbH
Study ID
NCT07321860
Phase
PHASE2/PHASE3
Status
Not Yet Recruiting

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Conditions

  • ALS (Amyotrophic Lateral Sclerosis)

Eligibility Criteria

Sex
ALL
Age
18 Years - 80 Years
Healthy Volunteers
Accepted

Interventions

Study Details

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to muscle weakness, respiratory decline, and eventual mortality. A growing body of translational and clinical evidence implicates neuroinflammation, reactive astrocytosis, and maladaptive TGF-β signaling as central contributors to disease progression. Elevated levels of Gremlin-2 (GREM2) have been identified as a marker of dysregulated TGF-β-linked astrocytic activity and fibrotic gene programs in some ALS patients, and preclinical data suggest that attenuating these pathways may mitigate glial toxicity and improve neuronal survival. Galunisertib, a selective ATP-competitive TGF-β receptor type I (TGF-βR1/ALK5) inhibitor, has been developed to block SMAD2/3 phosphorylation and TGF-β-mediated transcriptional programs. Meanwhile, nerandomilast, a selective PDE4B inhibitor, elevates intracellular cAMP in immune and glial cells, shifting pro-inflammatory signaling toward resolution and antagonizing secondary fibrotic and inflammatory cascades. Preclinical models show that PDE4 inhibition and TGF-β pathway blockade concurrently reduce maladaptive glial phenotypes and fibrotic mediators. This study investigates the combination of galunisertib + nerandomilast in ALS patients with elevated GREM2, hypothesizing that dual targeting of TGF-β-mediated astrocytic reactivity and PDE4B-regulated inflammatory signaling will translate into slowing of disease progression and favorable pharmacodynamic effects on central biomarkers of neuroinflammation and neurodegeneration.

Key Dates

Start date
Jun 30, 2026
Status verified
Jan 2026
Primary completion
Jun 30, 2027
Completion
Jan 1, 2028

Study Design

Enrollment
60 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Active Comparator: Galunisertib + Nerandomilast Combination
  • Placebo Comparator: Placebo

Primary Outcome Measure

Pharmacodynamic Biomarkers - Change from Baseline in GREM2 and TGF-β Pathway Marker Levels [ Time Frame: Time Frame: Baseline to 24 Weeks ]

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