ALS (Amyotrophic Lateral Sclerosis)Phase 2/3NCT07321860
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
A Phase 2/3 study testing Galunisertib + Nerandomilast Combination in people with ALS (Amyotrophic Lateral Sclerosis), run by Gipfel Life Sciences GmbH.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- ALS (Amyotrophic Lateral Sclerosis)
- What is being tested?
- Galunisertib + Nerandomilast Combination
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- No sites listed yet
- Study dates
- 30 Jun 2026to 1 Jan 2028
- Phase
- Phase 2/3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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:
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- 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.
About this study
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
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)
- Being tested
- Galunisertib + Nerandomilast Combination
- Medical subject headings
- Amyotrophic Lateral Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Galunisertib + Nerandomilast CombinationDrug
Galunisertib + Nerandomilast Combination
| Study group | Role | What they receive |
|---|---|---|
| Galunisertib + Nerandomilast Combination | Active comparator | Not described Receives: Drug: Galunisertib + Nerandomilast Combination |
| Placebo | Placebo comparator | Not described Receives: Drug: Galunisertib + Nerandomilast Combination |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Time Frame: Baseline to 24 Weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jan 2026
- Study start30 Jun 2026 (estimated)
- Primary completion30 Jun 2027 (estimated)
- Study completion1 Jan 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for ALS (Amyotrophic Lateral Sclerosis)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Gipfel Life Sciences GmbH
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07321860
- Sponsor's protocol ID
- GALNERAN-KI
- Status last verified
- Jan 2026
- First submitted
- 2 Jan 2026
- Last updated
- 7 Jan 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT07321860
- Acronym / sponsor ID
- GALNERAN-KI
- Conditions
- ALS (Amyotrophic Lateral Sclerosis)
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Gipfel Life Sciences GmbHIndustry (pharma, biotech, devices)
- Study start
- 30 Jun 2026 (estimated)
- Primary completion
- 30 Jun 2027 (estimated)
- Study completion
- 1 Jan 2028 (estimated)
- First posted
- 7 Jan 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Galunisertib + Nerandomilast Combination | Active comparator | Drug: Galunisertib + Nerandomilast Combination |
| Placebo | Placebo comparator | Drug: Galunisertib + Nerandomilast Combination |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Age:
- Diagnosis of ALS:
- GREM2-Positive Status:
- Disease Duration:
- Functional Status:
Key exclusion criteria (27 listed)
- Non-ALS Motor Neuron Disease:
- Advanced Respiratory Insufficiency:
- Clinically Significant Hepatic Disease:
- Clinically Significant Cardiac Disease:
- Active or Uncontrolled Infection:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Galunisertib + Nerandomilast CombinationGalunisertib + Nerandomilast Combination | Drug | Galunisertib + Nerandomilast Combination, Placebo |
Primary outcome
Pharmacodynamic Biomarkers - Change from Baseline in GREM2 and TGF-β Pathway Marker Levels
Time frame: Time Frame: Baseline to 24 Weeks
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
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jan 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Galunisertib + Nerandomilast Combination in people with ALS (Amyotrophic Lateral Sclerosis), run by Gipfel Life Sciences GmbH.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 7 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacodynamic Biomarkers - Change from Baseline in GREM2 and TGF-β Pathway Marker Levels (time frame: Time Frame: Baseline to 24 Weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jan 2026.