Exciting Early Results With Novel Cell Therapy for Focal Epilepsy

BOSTON -- Implantation of so-called inhibitory neurons helped two patients with severe, drug-resistant focal epilepsy achieve marked reductions in seizure frequency, researchers reported.

Prior to treatment, these patients were experiencing an average of 32 and 14 seizures per month, respectively, over many years, according to investigator David Spencer, MD, of Oregon Health & Science University in Portland. Within months of cell implantation, seizure frequency was reduced by more than 90% in both.

In fact, the first of those patients had no further seizures starting in the second month after implantation, with a total of 6 months of follow-up. The second patient, with 2 months of follow-up, had experienced just one seizure after the procedure.

These were the first results from an ongoing phase I/II trial in which the sponsor hopes eventually to enroll up to 40 patients. They were reported in an abstract to be presented next week at the American Academy of Neurology (AAN) annual meeting, and at a press conference held in advance of the conference.

The treatment consists of human cortical-type GABAergic interneurons (GABA stands for gamma aminobutyric acid, a neurotransmitter). This cell type helps inhibit neuronal excitation. Seizures result from abnormal excitatory bursts, and patients with epilepsy often show loss of interneurons, according to previous research by the founders of the new therapy's developer, Neurona Therapeutics of South San Francisco, California.

Thus, the firm's product, dubbed NRTX-1001, is intended to introduce more inhibitory activity, specifically for focal epilepsy centered in the mesial temporal lobe. NRTX-1001 cells are derived from an allogeneic human embryonic stem cell line, induced to become inhibitory GABA-secreting interneurons. In the current study, said Spencer, they are implanted into the patient's seizure focus through a small hole in the back of the skull with MRI guidance. (In the two patients with results, the focus was in the right temporal lobe.)

Many patients with drug-resistant focal epilepsy are candidates for surgery, Spencer explained. In fact, he said, it posed a thorny ethical problem for the trial, since patients were asked to undergo an experimental procedure in place of an established remedy, albeit one with significant risks.

"I was trying to find that balance or clinical equipoise between going forward with an existing therapy which is tissue-destructive versus an experimental therapy which is potentially restorative," he said at the press conference. "One of the positive things actually, though, hidden in that, is that ... if [participants] do not have a good outcome or adequate response to cell therapy, they can still go forward with epilepsy surgery in the future. So, it doesn't preclude using a standard or approved therapy in the future."

Thus far, the two patients have not shown any indication that the treatment is not durable, nor have they shown adverse neurological or behavioral effects. "Animal studies to date have shown good integration into the existing circuits in the brain and good survivability," Spencer said. "Some of the studies in rodents have been carried out at least to 1 year showing good viability and survivability of the cells. At our site at the Oregon Primate Center, we did -- just prior to this human study -- we did implants into non-human primates, and also showed good evidence of integration and survivability of the cells."

These two patients are in the phase I portion of the trial, for which Neurona hopes to include as many as 10. Spencer said that his group hopes to enroll three more patients in the near future, with five more to follow, perhaps with higher numbers of cells per implant. If all goes well, a phase II study will follow comparing NRTX-1001 in 20 patients to a sham treatment in 10. The trial's ClinicalTrials.gov listing gives a target date of May 2025 for primary completion; Spencer said it may be "several years."

Neurona also believes the same approach could be effective in Alzheimer's disease, with preclinical studies now underway.

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