Epilepsy affects more than 3 million people in the United States. Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome of adults accounting for approximately 60% of all epilepsy cases. One-third of epilepsy patients are drug-resistant, defined as failure to adequately respond to at least two anti-epileptic drugs, and these patients have persistent, uncontrolled seizures that can be disabling and significantly impair quality of life.
Temporal lobe epilepsy (TLE) is the most common focal epilepsy syndrome of adults accounting for ~60% of all epilepsy cases. Mesial temporal lobe epilepsy (MTLE) is characterized by seizures that start in the temporal lobe and by MTS, or tissue damage, which is often most pronounced in the anterior hippocampus. Mesiotemporal focal seizures can involve alterations in mood and memory, subjective symptoms or “auras”, frozen or repetitive involuntary behaviors, and can evolve into transient loss of awareness and loss of consciousness events. Focal seizures can spread and “generalize” to the entire cerebral cortex and result in bilateral tonic-clonic convulsive seizures. Despite the use of anti-seizure drugs, many TLE patients continue to have focal seizures.
Drug-resistant TLE patients have few options. Surgical resection or ablation of the temporal lobe can be effective; however, most patients are not eligible or not interested in these tissue-destructive options due to invasiveness and the risk of serious irreversible adverse effects.
Surgical resection or ablation (LITT) of the affected temporal lobe can be effective in providing seizure freedom. Seizure freedom for at least 1 year is achieved in ~60-70% of people with drug-resistant MTLE who undergo elective surgical resection of the temporal lobe. A recent study reported 284 people who underwent epilepsy surgery and had a prospective median follow-up of 5 years: Kaplan-Meier estimates showed that 47% remained seizure free (apart from simple partial seizures) at 5 years, 38% remained seizure free at 10 years after surgery, 74% had a greater than 50% seizure reduction at 5 years after surgery, and 70% had a greater than 50% seizure reduction at 10 years after surgery.
Nevertheless, surgical resection and ablation are tissue-destructive, destroying the seizure focus and surrounding tissues, and can cause serious, irreversible adverse effects, including speech, memory, and cognitive impairments. Most people with refractory epilepsy who might benefit from surgery do not pursue it. Of the 100,000-200,000 people with drug-resistant MTLE nationwide, with an additional 5,000-10,000 diagnosed each year, only 1,000-2,000 resection surgeries are performed every year in the US. Moreover, many drug-resistant focal epilepsy patients are not eligible for resection or ablation surgeries.
GABAergic interneurons are an important target for the development of novel antiseizure therapeutics. Although many cell types are affected in MTLE with MTS, GABAergic inhibitory interneuron loss and dysfunction are central to focal seizure initiation in the hippocampus and propagation to other brain regions. Histopathological analysis post-mortem/post-resection has demonstrated a loss of interneurons from the epileptic hippocampus in people with TLE.
In rodent models of TLE, loss of GABAergic interneurons in the hippocampus has been correlated with increased seizure frequency, and selective ablation of hippocampal interneurons has been shown to induce seizures. Moreover, selective activation of endogenous interneurons and transplantation of exogenous rodent and human interneuron precursor cells in the epileptic hippocampus have both reduced seizure activity in rodent models of epilepsy. Therefore, transplantation of GABAergic interneurons into the epileptic hippocampus is a novel therapeutic strategy that has shown promise in preclinical rodent studies and could potentially provide a non-tissue-destructive therapeutic option for suppressing seizures in people with drug-resistant MTLE.
NRTX-1001
NRTX-1001 is an inhibitory GABAergic interneuron cell therapy derived from human embryonic stem cells (hESCs) for the prospective treatment of drug-resistant focal epilepsy. The cells are derived from a discarded embryo from an in vitro fertilization clinic, and the donor provided consent for research use. NRTX-1001 is delivered as a single dose by intracerebral injection into the seizure focus, where it is intended to distribute locally, functionally integrate, and provide GABA on-target. In addition, NRTX-1001 is expected to persist long-term following a single dose and not require repeated administration. Transplantation of medial ganglionic eminence (MGE) pallial-type GABAergic interneurons into the brain and spinal cord has been shown to be safe and effective in preclinical models. NRTX-1001 is derived from a hESC line, reproducibly manufactured, and contains a cell suspension enriched for post-mitotic MGE-type pallial (cortical/hippocampal) GABAergic interneurons.
NTE-001
The purpose of the NTE-001 study is to evaluate the safety (Phase 1 and 2) and efficacy (Phase 2) of NRTX-1001 for the treatment of drug-resistant unilateral mesial temporal lobe epilepsy (MTLE). NRTX-1001 contains medial ganglionic eminence (MGE) pallial-type GABAergic interneurons produced via human embryonic stem cells. In non-clinical models, human interneurons persist long-term in the epileptic hippocampus, resulting in stable mesiotemporal seizure freedom in most animals, reducing hippocampal pathology, and were tolerated at high doses.
The study is designed in two Phases. Phase 1 is to evaluate the safety of NRTX-1001 and Phase 2 is to evaluate the safety and efficacy of NRTX-1001 for the treatment of drug-resistant unilateral mesial temporal lobe epilepsy.
Phase 1 of the study is a multicenter, open-label, single-arm, first-in-human (FIH) dose escalation design.
Phase 2 of the study is a multicenter, double-blind, randomized, parallel-group design, in which subjects are randomized 2:1 to either active treatment with NRTX-1001 or sham surgery. The primary efficacy endpoint will be determined based on subject seizure records between 7 and 12 months after surgery.
For each subject, in both study phases, study evaluation will last for 2 years with follow-up from years 3 to 15.
NTE-002
The NTE-002 study is similar to NTE-001 but will focus on patients with bilateral mesial temporal lobe epilepsy. In this open-label single-arm study patients will receive NRTX-1001 to each medial temporal lobe. The study follows a similar evaluation plan as phase 1 of the NTE-001 study.