Authors :
Presenting Author: Heather Olson, MD, MS – Boston Children's Hospital
Eorna Maguire-Lobos, BA – Boston Children's Hospital
Katheryn Mansour, BS – Boston Children's Hospital
Grace Correa, MSN, RN, CPNP – Boston Children's Hospital
Jason Lerner, MD – Biohaven Pharmaceuticals
Michael Bozik, MD – Biohaven Pharmaceuticals
Steven Dworetzky, PhD – Biohaven Pharmaceuticals
Heather Sevinsky, MS – Biohaven Pharmaceuticals
Kelly Sweeney, BSN, RN – Biohaven Pharmaceuticals
Prokash Paul, PhD – Certara Inc.
Rachael Kendrick, PharmD – Certara Inc.
Stephanie Donatelli, MD – Boston Children's Hospital
Archana Patel, MD, MPH, MSc – Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Wiltrout Kimberly, MD – Boston Children's Hospital
Christelle Moufawad El Achkar, MD – Boston Children's Hospital
Annapurna Poduri, MD, MPH – Boston Children's Hospital
Rationale:
KCNQ2-developmental and epileptic encephalopathy (DEE) is a severe neonatal-onset epilepsy syndrome. Most Kv7.2 pathogenic variants are associated with loss-of-function of the Kv7.2/7.3 channel with decreased channel opening. Opakalim (BHV-7000) is a 3rd generation activator of the Kv7.2/7.3 channel that has previously demonstrated the ability to restore channel function near wild type levels (i.e., current density and activation V1/2) across 50 different pathogenic KCNQ2 variants (Vanoye et al. AES 2024 Poster 1.431). An 8-year-old boy with KCNQ2-DEE, heterozygous for a Kv7.2 G281E mutation, experiences multiple daily brief tonic seizures at baseline, despite treatment with multiple ASMs including a 1st generation potassium channel activator. He has had episodes of status epilepticus, severe dystonia and irritability with prior attempts to wean the 1st generation potassium channel activator.
Methods:
This 8-year-old boy was initiated on opakalim by compassionate use IND. He received a test dose of 1mg of opakalim as a spray-dried dispersion suspension with pharmacokinetic testing to determine maintenance dosing. Then, he completed inpatient cross-titration from a 1st generation potassium channel activator. Medication levels, vision assessments, EKG and seizure diaries were documented for >3 months before initiation. The CDKL5 Clinical Severity Assessment (CCSA) scale, validated for a similar genetic DEE, was used for comparison pre and post treatment. Results:
A test dose of opakalim was well tolerated. Pharmacokinetic testing determined that at a dose of 15mg QID estimated exposures of opakalim are comparable to the 75mg extended release QD dose being evaluated in focal epilepsy. Opakalim was well tolerated with no adverse events attributed to drug in the 1st month of therapy. He had initial improvement with no documented tonic seizures for 2 weeks after reaching the goal dose of 15mg QID, followed by return to baseline seizure frequency. EEG demonstrated near-continuous focal and generalized spike and waves and generalized slowing. Overnight EEG at baseline captured 12 tonic seizures with sustained motor activity ≥3 seconds compared to none ≥3 seconds 12 days later after initiation of opakalim. He was reported to have increased alertness and interaction after the medication transition. Baseline CCSA clinician domain scores were motor 79, communication 82, vision 65. Caregiver CCSA domain scores were epilepsy 39, alertness/interaction 55, behavior 35, feeding 78. CCSA scale will be repeated in 3 months.Conclusions:
Opakalim demonstrates early tolerability and initial improvement in seizures followed by return to baseline seizure frequency, with no worsening compared to prior treatment with another potassium channel activator despite a history of severe exacerbation with attempts to wean. He also showed encouraging improvement in alertness. Follow-up evaluations will determine additional changes in EEG or clinical status.
Funding:
Biohaven Pharmaceuticals