[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"health-studies-list:{\"overallStatus\":[\"RECRUITING\",\"AVAILABLE\",\"NOT_YET_RECRUITING\"],\"leadSponsorName\":\"Gipfel Life Sciences GmbH\",\"orderBy\":\"LastUpdateSubmitDate:desc\",\"size\":25,\"offset\":0}":3,"health-study-condition:":42},{"pageToken":4,"total":5,"offset":6,"count":5,"results":7},null,1,0,[8],{"id":9,"slug":10,"hasResults":11,"nctId":12,"briefTitle":13,"officialTitle":14,"acronym":4,"eligibilityCriteria":15,"healthyVolunteers":16,"sex":17,"minAge":18,"maxAge":19,"enrollmentInfo":20,"targetDuration":4,"studyType":23,"phases":24,"briefSummary":27,"conditions":28,"keywords":4,"overallStatus":30,"whyStopped":4,"lastUpdateSubmitDate":31,"lastUpdatePostDateStruct":32,"startDateStruct":35,"completionDateStruct":37,"leadSponsor":39,"locationsCount":4},"100617687","phase-2-this-study-evaluates-the-safety-target-engagement-and-preliminary-efficacy-of-galunisertib-tgf-r1alk5-inhibitorcombined-with-nerandomilast-pde4-inhibitor-in-grem2-positive-als-a-biomarker-defined-subgroup-hypothesized-to-reflect-heightened-tgf-smad-driven-astrocytic-and-fibrotic-signaling-100617687",false,"NCT07321860","This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-βR1\u002FALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heightened TGF-β\u002FSMAD-driven Astrocytic and Fibrotic Signaling","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","Inclusion Criteria\n\nParticipants must meet all of the following criteria:\n\n1. Age:\n\n   * 18 to 80 years, inclusive, at the time of informed consent.\n2. Diagnosis of ALS:\n\n   * Diagnosis of amyotrophic lateral sclerosis according to revised El Escorial criteria or equivalent, confirmed by a qualified neurologist.\n3. GREM2-Positive Status:\n\n   * Evidence of elevated GREM2 at screening, defined as:\n   * CSF GREM2 above a pre-specified threshold OR\n   * 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).\n   * Biomarker thresholds will be defined prospectively in the protocol and laboratory manual.\n4. Disease Duration:\n\n   * Time from first ALS-related symptom onset ≤ 24 months at screening.\n5. Functional Status:\n\n   * 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.\n6. Respiratory Function:\n\n   * Slow vital capacity (SVC) or forced vital capacity (FVC) ≥ 50% of predicted at screening.\n7. Stable Background ALS Therapy:\n\n   * If receiving riluzole and\u002For edaravone, participants must be on a stable dose for ≥ 30 days prior to screening and willing to maintain the regimen throughout the study.\n8. Ability to Consent:\n\n   * Ability to understand and provide written informed consent personally or via a legally authorized representative, in accordance with local regulations.\n9. Contraception:\n\n   * 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.\n\nExclusion Criteria\n\nParticipants will be excluded if any of the following apply:\n\n1. Non-ALS Motor Neuron Disease:\n\n   * Diagnosis of primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), or other non-ALS motor neuron disorders.\n2. Advanced Respiratory Insufficiency:\n\n   * Requirement for invasive mechanical ventilation at screening or anticipated need within the immediate study period.\n3. Clinically Significant Hepatic Disease:\n\n   * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \\> 2.5 × upper limit of normal (ULN) at screening.\n   * Known cirrhosis or active chronic liver disease.\n4. Clinically Significant Cardiac Disease:\n\n   * Uncontrolled arrhythmia, recent myocardial infarction, unstable angina, or clinically significant cardiac dysfunction that may increase risk with study participation.\n5. Active or Uncontrolled Infection:\n\n   * Active systemic infection requiring treatment at screening or known chronic infection that could interfere with immune or biomarker assessments.\n6. Immunocompromised State:\n\n   * History of organ transplantation, active malignancy requiring systemic therapy, or chronic immunosuppressive therapy (excluding stable low-dose corticosteroids, if allowed by protocol).\n7. Prior Exposure to TGF-β Pathway Inhibitors:\n\n   * Previous treatment with galunisertib or other direct TGF-β or ALK5 inhibitors within a protocol-defined washout period.\n8. Recent Investigational Therapy:\n\n   * Participation in another interventional clinical trial or receipt of an investigational drug within 30-60 days prior to screening (exact window defined in protocol).\n9. Concomitant Medications with High Interaction Risk:\n\n   * Use of strong CYP modulators or medications known to significantly interfere with galunisertib or nerandomilast metabolism, unless safely discontinued.\n10. Pregnancy or Breastfeeding:\n\n    * Pregnant or breastfeeding women.\n11. Other Medical Conditions:\n\n    * Any medical, neurological, or psychiatric condition that, in the investigator's judgment, could:\n    * Interfere with study participation or compliance,\n    * Confound interpretation of efficacy or biomarker outcomes,\n    * Increase risk to the participant.",true,"ALL","18 Years","80 Years",{"count":21,"type":22},60,"ESTIMATED","INTERVENTIONAL",[25,26],"PHASE2","PHASE3","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.\n\nGalunisertib, a selective ATP-competitive TGF-β receptor type I (TGF-βR1\u002FALK5) inhibitor, has been developed to block SMAD2\u002F3 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.\n\nThis 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.",[29],"ALS (Amyotrophic Lateral Sclerosis)","NOT_YET_RECRUITING","2026-01-05",{"date":33,"type":34},"2026-01-07","ACTUAL",{"date":36,"type":22},"2026-06-30",{"date":38,"type":22},"2028-01-01",{"name":40,"class":41},"Gipfel Life Sciences GmbH","INDUSTRY",""]