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

Gipfel Life Sciences GmbH

Status and phase: Begins enrollment in 4 months; Phase 3; Phase 2

Conditions: ALS (Amyotrophic Lateral Sclerosis)

Treatments: Drug: Galunisertib + Nerandomilast Combination

Study type: Interventional

Funder types: Industry

Identifiers

NCT07321860

GALNERAN-KI

Details and patient eligibility

About

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.

Enrollment: 60 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

Participants must meet all of the following criteria:

1. Age:

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

2. Diagnosis of ALS:

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

3. 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.

4. Disease Duration:

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

5. 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.

6. Respiratory Function:

   • Slow vital capacity (SVC) or forced vital capacity (FVC) ≥ 50% of predicted at screening.

7. 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.

8. Ability to Consent:

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

9. 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:

1. Non-ALS Motor Neuron Disease:

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

2. Advanced Respiratory Insufficiency:

   • Requirement for invasive mechanical ventilation at screening or anticipated need within the immediate study period.

3. 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.

4. Clinically Significant Cardiac Disease:

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

5. Active or Uncontrolled Infection:

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

6. Immunocompromised State:

   • History of organ transplantation, active malignancy requiring systemic therapy, or chronic immunosuppressive therapy (excluding stable low-dose corticosteroids, if allowed by protocol).

7. 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.

8. 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).

9. 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.

10. Pregnancy or Breastfeeding:

    • Pregnant or breastfeeding women.

11. 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

---

60 participants in 2 patient groups, including a placebo group

Galunisertib + Nerandomilast Combination

Active Comparator group

Treatment:

Drug: Galunisertib + Nerandomilast Combination

Placebo

Placebo Comparator group

Treatment:

Drug: Galunisertib + Nerandomilast Combination