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

Prior treatment

• 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.

Other illness

• 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 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).
• 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.

Lab values

• 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.

Other

• Participants will be excluded if any of the following apply:
• Pregnancy or Breastfeeding:
  • Pregnant or breastfeeding women.

• 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.