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

NCT07321860 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: GALNERAN-KI
• Study Type: interventional
• Target: 60
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

ALS (Amyotrophic Lateral Sclerosis)

Outcome Measures

Primary Outcomes (1)

• Pharmacodynamic Biomarkers - Change from Baseline in GREM2 and TGF-β Pathway Marker Levels

  Pharmacodynamic Biomarkers - Change from Baseline in GREM2 and TGF-β Pathway Marker Levels (CSF or plasma; Time Frame: Baseline to 24 Weeks). Definition: GREM2 (Gremlin-2) concentration in cerebrospinal fluid or plasma will be measured at baseline and 24 weeks. GREM2 is a TGF-β-inducible protein  used to stratify patients (GREM2-positive) and serves as a proxy for TGF-β pathway activity. In addition, downstream TGF-β signaling biomarkers will be assessed over the same period, including phosphorylated SMAD2/3 (pSMAD2/3) in peripheral blood cells and plasminogen activator inhibitor-1 (PAI-1, SERPINE1) in plasma. These are direct readouts of TGF-β receptor activity  and are strongly upregulated by TGF-β signaling . Glial/neuroinflammatory markers such as glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in CSF or blood will also be measured, as they indicate astrocyte activation and neuroaxonal injury in ALS . Analysis: Changes from baseline in GREM2 and the

  Time Frame: Baseline to 24 Weeks

Study Arms (2)

Galunisertib + Nerandomilast Combination

ACTIVE COMPARATOR

Drug: Galunisertib + Nerandomilast Combination

Placebo

PLACEBO COMPARATOR

Drug: Galunisertib + Nerandomilast Combination

Interventions

Galunisertib + Nerandomilast Combination DRUG

Galunisertib + Nerandomilast Combination

Galunisertib + Nerandomilast Combination; Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet all of the following criteria:
• Age:
• 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:

You may not qualify if:

• 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:

Sponsors & Collaborators

• Gipfel Life Sciences GmbH: lead

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

LY-2157299

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 2, 2026
• First Posted: January 7, 2026
• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: January 7, 2026

Record last verified: 2026-01