Addressing Neonatal Brain Injury: HIE Treatment Development ReAlta Life Sciences’ Dr. Kia Motesharei

Main ideas / concepts covered

What HIE is (simple definition + diagnosis)

• Hypoxic-ischemic encephalopathy (HIE) is brain injury in newborns caused by insufficient oxygen and/or blood flow around birth.
• Common upstream causes mentioned:
  • Cord problems (e.g., wrapped/twisted around the neck, other cord-related issues)
  • Maternal trauma (e.g., motor accidents)
  • Placental problems
• Diagnosis is described as relatively easy shortly after birth:
  • Very low Apgar scores (noted as typically 1–3 for affected babies; normal is 8–10)
  • Babies may be “born blue”
  • Low blood gas levels

Current standard of care and why it’s not enough

• The current standard is supportive care plus therapeutic hypothermia (cooling).
• Cooling method described:
  • Transport to the NICU
  • Use cooling blankets/caps
  • Lower body temperature to about 92°F (~33–34°C)
  • Treatment lasts roughly 3–4 days
• Key limitation:
  • Cooling reduces inflammation but does not eliminate injury risk, especially in moderate-to-severe cases.
• Impact in severe disease:
  • Mortality up to ~40% in more severe cases.

Why HIE is difficult to treat

• Drug development is harder in pediatrics—and especially neonates due to safety concerns.
• Many therapies are developed first for adults, then expanded to children once safety is established.
• Neonates are described as having very little immune system maturity, making safety “gating” more challenging.
• As a result, companies may prefer repurposed drugs, but novel therapies are difficult to develop safely and effectively.

Role of inflammation in HIE

• Mechanistic sequence described:
  • Initial hypoxia/ischemia leads to brain cell death.
  • Reperfusion triggers an inflammatory response.
• Inflammation is portrayed as largely driven by the body’s immune system:
  • MPO activation (myeloperoxidase)
    • Can contribute to membrane leakage/breakdown, allowing harmful molecules to enter the brain
  • Neutrophils and neutrophil extracellular traps (NETs)
    • Also contribute to tissue damage
  • Complement pathway activation
• Therapeutic strategy described:
  • Rather than targeting a single pathway, the approach is to block two pathways:
    • Complement pathway
    • Neutrophil pathway
  • Goal: reduce the neuroinflammation cascade that worsens brain injury and leads later to neurodevelopmental disorders such as epilepsy and cerebral palsy.

Clinical trial design considerations (methodology-style steps)

• Design trials to run alongside the standard of care

  • Standard includes therapeutic hypothermia (cooling).
  • The drug study is planned to be delivered in parallel with cooling.

• Treat within a narrow time window after birth

  • Babies are cooled within 6–10 hours after birth.
  • Drug dosing must start within the same 6–10 hour window.
  • This creates recruitment/consent challenges because families have little time to decide.

• Operational consent and recruitment challenges

  • Parents learn about a devastating condition on what should be the happiest day of their lives.
  • Often mother and father are separated:
    • Trauma may have occurred to the mother as well.
    • Father travels with the baby to the NICU; mother remains at the hospital.
  • Many community hospitals lack NICUs:
    • Babies may be transported by ambulance/helicopter, adding complexity.

• Dose scheduling to match cooling timeline

  • First dose during the cooling period.
  • Dosing continues for the three days babies are on NICU cooling.

• Choose endpoints that can support faster regulatory decisions

  • Adult-like functional outcomes are difficult to measure quickly in infants.
  • Longer-term endpoints (around age two years) are harder to use for rapid approvals.
  • Endpoint strategy:
    • Primary accelerated endpoint: MRI on day 4 to measure extent of brain injury
    • Long-term monitoring: follow-up to two years for motor/cognitive assessments

• Continue for long-term efficacy assessment

  • Even with an accelerated approval path, follow-up includes:
    • Ongoing monitoring and performance testing at age two

Outcomes that matter short-term and long-term

• Short-term goal: reduce brain injury measured by MRI (especially day 4).
• Long-term goal: reduce neurodevelopmental impairment by minimizing brain injury:
  • Better cognitive and motor development
  • Lower incidence/severity of outcomes such as epilepsy or cerebral palsy
• Post-approval expectation (if safe and beneficial):
  • Administration should be simple in the NICU, since babies already have IV access and are under cooling care.
  • Post-approval consent burden may be reduced compared with trial settings.

Future outlook and unmet needs in the research pipeline

• Optimism is tempered by concerns:
  • Limited regulatory support compared with what companies want
  • Weak pipeline / limited investment due to the long development path and safety requirements
• The speaker hopes for:
  • Greater regulatory support
  • More investment and additional therapies/competition that benefits society
• Mentioned timing/data expectation (company-specific):
  • Phase 2 readout: targeted for end of Q3 2026
  • Expected data from about 70 babies
  • The drug referenced in the segment: topiramate

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Speakers / sources featured (as stated in the subtitles)

• Saumya Shashikumar (Host, Xtalks Life Science Podcast; from xtalks.com)
• Dr. Kia Motesharei / Kia Motorshaw (President and COO, ReAlta Life Sciences)
• Xtalks Life Science Podcast (podcast/source context)
• FDA (referenced as regulators involved in discussions)
• Honeycomb Worldwide (referenced in podcast disclaimer text)