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

Official title

Randomized, Double-Blind, Placebo-Controlled Phase 2a Study of Partial TGF-βR1 (ALK5) Inhibition With Galunisertib Combined With PDE4 Inhibition With Nerandomilast in GREM2-Positive ALS

Overview

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.

Interventions

• Drug Galunisertib + Nerandomilast Combination
  Galunisertib + Nerandomilast Combination

Primary outcome measures

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

Eligibility criteria

Inclusion criteria

Participants must meet all of the following criteria:

• Age:

• 18 to 80 years, inclusive, at the time of informed consent.
• Diagnosis of ALS:

• Diagnosis of amyotrophic lateral sclerosis according to revised El Escorial criteria or equivalent, confirmed by a qualified neurologist.
• GREM2-Positive Status:

• Evidence of elevated GREM2 at screening, defined as:
• CSF GREM2 above a pre-specified threshold OR
• Plasma GREM2 above a pre-specified threshold with supportive evidence of astrocytic or TGF-β pathway activation (e.g., elevated GFAP or TGF-β-responsive biomarker).
• Biomarker thresholds will be defined prospectively in the protocol and laboratory manual.
• Disease Duration:

• Time from first ALS-related symptom onset ≤ 24 months at screening.
• Functional Status:

• ALS Functional Rating Scale - Revised (ALSFRS-R) total score ≥ a protocol-defined minimum (e.g., ≥ 25) at screening, sufficient to allow detection of functional change.
• Respiratory Function:

• Slow vital capacity (SVC) or forced vital capacity (FVC) ≥ 50% of predicted at screening.
• Stable Background ALS Therapy:

• If receiving riluzole and/or edaravone, participants must be on a stable dose for ≥ 30 days prior to screening and willing to maintain the regimen throughout the study.
• Ability to Consent:

• Ability to understand and provide written informed consent personally or via a legally authorized representative, in accordance with local regulations.
• Contraception:

• Women of childbearing potential and men with partners of childbearing potential must agree to use effective contraception during the study and for a defined period after the last dose.

Exclusion criteria

Participants will be excluded if any of the following apply:

• Non-ALS Motor Neuron Disease:

• Diagnosis of primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), or other non-ALS motor neuron disorders.
• Advanced Respiratory Insufficiency:

• Requirement for invasive mechanical ventilation at screening or anticipated need within the immediate study period.
• Clinically Significant Hepatic Disease:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN) at screening.
• Known cirrhosis or active chronic liver disease.
• Clinically Significant Cardiac Disease:

• Uncontrolled arrhythmia, recent myocardial infarction, unstable angina, or clinically significant cardiac dysfunction that may increase risk with study participation.
• Active or Uncontrolled Infection:

• Active systemic infection requiring treatment at screening or known chronic infection that could interfere with immune or biomarker assessments.
• Immunocompromised State:

• History of organ transplantation, active malignancy requiring systemic therapy, or chronic immunosuppressive therapy (excluding stable low-dose corticosteroids, if allowed by protocol).
• Prior Exposure to TGF-β Pathway Inhibitors:

• Previous treatment with galunisertib or other direct TGF-β or ALK5 inhibitors within a protocol-defined washout period.
• Recent Investigational Therapy:

• Participation in another interventional clinical trial or receipt of an investigational drug within 30-60 days prior to screening (exact window defined in protocol).
• Concomitant Medications with High Interaction Risk:

• Use of strong CYP modulators or medications known to significantly interfere with galunisertib or nerandomilast metabolism, unless safely discontinued.
• Pregnancy or Breastfeeding:

• Pregnant or breastfeeding women.
• Other Medical Conditions:

• Any medical, neurological, or psychiatric condition that, in the investigator's judgment, could:
• Interfere with study participation or compliance,
• Confound interpretation of efficacy or biomarker outcomes,
• Increase risk to the participant.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07321860 · GALNERAN-KI

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗