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JAG1 Modulator for Alagille Syndrome

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Alagille syndrome

PreclinicalActiveSmall moleculeCholestatic liver diseaseMixed· medium conf4 evidence-linked claims3 snapshots

Overview

Disease area
Cholestatic liver disease
Indication
Alagille syndromeMONDO:0007318
Mechanism of action
Notch pathway modulation to restore bile duct development
Development stage
Preclinical
Institution
Riverside Children's Research Center
Principal investigators
E. Okafor, L. Brandt
Targets
JAG1NOTCH2
Pathways
Notch signaling
Trial registry
NCT06850038

Intake & funding

Applications
  • E. OkaforfundedUSD750,0002024-09-15
    Scholar award
Funding events
  • trancheUSD250,000Series A2025-07-01
  • awardUSD750,000Demo Translational Institute2025-01-20

Timeline

state through time · newest first
  1. Q3 2025Series A term sheet signed
    Milestones
    • ·Pre-IND meeting granted
    Accomplishments
    • ·FDA aligned on accelerated-approval framing for orphan pediatric indication
    Challenges
    • ·GLP tox start delayed one quarter by CRO capacity
    Next steps
    • ·Complete GLP tox
    • ·Finalize pediatric formulation
    Risk themes:Timeline slippage on tox
  2. Q2 2025Series A diligence underway
    Milestones
    • ·Candidate selection completed
    Accomplishments
    • ·Oral bioavailability confirmed in two species
    • ·KOL panel aligned on pruritus + biochemical endpoints
    Challenges
    • ·CMC route still high cost of goods
    Next steps
    • ·Initiate GLP tox
    • ·Pre-IND meeting request
    Risk themes:Cost of goodsCompetitive IBAT inhibitors entrenched
  3. Q1 2025Seed extension committed
    Milestones
    • ·Lead series nominated
    • ·Notch reporter assay qualified
    Accomplishments
    • ·Restored ductular marker expression in patient-derived organoids
    Challenges
    • ·Limited pediatric natural-history data for endpoint selection
    Next steps
    • ·Begin IND-enabling tox planning
    • ·Engage cholestasis KOLs on endpoints
    Risk themes:Endpoint uncertaintyPediatric formulation not started

Scientific assessment

2 claims
  • Target ValidationStrong

    JAG1 loss-of-function variants cause ~94% of Alagille cases; haploinsufficiency of Notch ligand drives bile-duct paucity, giving a clear genetic rationale for restoring Notch signaling.

    datasetMONDO:0007318· 2024-02-01
  • DifferentiationModerate

    Pathway-restoring small molecule differentiates from symptomatic IBAT inhibitors (e.g., maralixibat) by addressing the developmental defect rather than pruritus alone.

    internalmemo-2024-03

Translational assessment

1 claims
  • Patient PopulationModerate

    Recruiting natural-history and interventional cohorts anchor endpoint selection in pediatric cholestasis.

    trialNCT06850038· 2025-01-15

Regulatory assessment

1 claims
  • Orphan / Rare DiseaseContext

    Ultra-rare pediatric indication supports orphan designation and a rare-pediatric-disease priority-review voucher path.

    regulatoryorphan-strategy

Commercial assessment

0 claims

No evidence linked yet.

Execution assessment

0 claims

No evidence linked yet.

Structured reviews

2 reviews
Mixed· medium confIndustryTranslational advisor2025-05-02
Strengths

Clear orphan pathway and PRV potential.

Weaknesses

Cost of goods and entrenched IBAT competitors temper commercial upside.

Improvement areas

Develop a sharper differentiation and pricing thesis.

Internal rubric input (reviewer scoring — not a success probability)
Scientific validity
Translational readiness
Regulatory pathway
Commercial potential
Execution strength
Supportive· medium confAcademicHepatology panel2025-03-12
Strengths

Strong genetic rationale; disease-modifying mechanism differentiated from symptomatic care.

Weaknesses

Pediatric endpoints and natural-history data remain thin.

Improvement areas

Lock endpoint strategy with regulators before IND.

Internal rubric input (reviewer scoring — not a success probability)
Scientific validity
Translational readiness
Regulatory pathway
Commercial potential
Execution strength

Outcome

  • Active
    Advancing through IND-enabling studies.2025-07-15

AI brief

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