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Retrotope Reports Mixed Data from Phase 2/3 Trial of RT001 for Infantile Neuroaxonal Dystrophy

October 6, 2021

Retrotope reported that data from its phase 2/3 clinical trial of RT001 in patients with infantile neuroaxonal dystrophy and its concurrent natural history study of disease onset and progression missed the primary endpoint but demonstrated statistically significant improvements in overall survival and progression free survival for patients treated with RT001 as compared to control.

Photo: Peter Milner, chief medical officer of Retrotope

Infantile neuroaxonal dystrophy (INAD) is an ultra-rare, progressive, and fatal infantile genetic neurological disorder and part of a spectrum of diseases called PLA2G6-associated neurodegeneration. An inborn genetic defect in the PLA2G6 enzyme results in the inability to effectively clear the toxic by-products of lipid peroxidation (LPO), which create a “death signal” that results in rapid neuronal cell death in a developing infant’s brain. This causes irreversible loss of vital functions, including gross motor, communication skills, bulbar function, recurrent aspiration pneumonia, and eventual death within a matter of years.

Symptoms usually present between 6 months and 18 months of age and there is often rapid onset of motor and intellectual regression. Later, diminished muscle tone (hypotonia) and spasticity develop. The disease also leads to problems with vision and the eyes, the autonomic nervous system, and, in a minority of individuals, seizures. Usually, disease progression is rapid, and the disorder is invariably fatal in childhood. There are currently no approved treatments for INAD.

RT001 is an isotopically stabilized, synthetic linoleic acid (LA) that down-regulates LPO in order to protect membranes from degeneration. RT001 has been safely administered orally on a daily basis to more than 100 patients, spanning more than 1,000 patient months.

The survival endpoints of the study included a combination of efficacy and safety measures. Additionally, clinical improvements were observed in patients receiving RT001 as measured by the Modified Ashworth Spasticity Scale, the study’s primary efficacy endpoint, and other measurements of efficacy as compared to patients in the natural history study. However, Retrotope said these single efficacy outcomes did not reach statistical significance likely due to the small study size.

“INAD is an ultra-rare, relentlessly progressive and fatal disease that currently has no approved treatments. This trial compared a group of children with INAD treated with RT001 with a natural history cohort, and the results indicate that RT001 slows progression and prolongs survival compared to no treatment,” said Alex Fay, assistant professor of neurology, University of California, San Francisco and one of the study’s principal investigators. “The findings are striking and suggest that RT001 has the potential to deliver a meaningful impact on neurological function and survival of children with INAD.”

The treatment study of RT001 included 19 INAD patients and the concurrent natural history study included 36 INAD patients as the control arm. There were no significant differences in the baseline characteristics between the two patient populations. Patients in the treatment study received RT001 for a minimum period of one year with a 30-day treatment free follow up period. Patients treated with RT001 showed an improvement of 6.42 rank points on the Modified Ashworth Spasticity Scale as compared to control patients. Similar treatment benefits were seen favoring RT001-treated patients as compared to controls across all five of the analyzed efficacy outcome scales, ranging from improvements of 4.5 to 7.3 rank points.

Study investigators evaluated progression free survival (absence of pneumonia or death event) as a pre-specified secondary endpoint, with results demonstrating a statistically significant 82.5 percent reduction in morbidity risk for RT001-treated patients as compared to controls. Additionally, the pre-specified exploratory endpoint of survival demonstrated a statistically significant mortality risk decrease of 88.8 percent for treated patients as compared to control patients. Overall, the number of confirmed deaths during the study were dramatically lower in RT001-treated patients (2/19, 11 percent) than in the control patients (11/36, 31 percent). Similarly, the number of patients with progression (confirmed pneumonia or death) during the study, were far lower in treated patients (4/19, 21 percent) than in control patients (12/36, 33 percent).

INAD is an ultra-rare, progressive, fatal, infant genetic neurological disorder, making it ethically challenging to enroll infants and toddlers battling this disease into a placebo-controlled trial. Due to this limitation, Retrotope established a development strategy for RT001 in INAD comprised of an open-label treatment study to assess the clinical impact of RT001 in INAD patients and a corresponding open-label natural history trial designed to establish historical control baselines for disease progression and severity. The company previously submitted a statistical analysis plan to the U.S. Food and Drug Administration for these studies that involved comparisons between RT001-treated patients in the treatment study and untreated control patients in the natural history study.

“The INAD patient community is in desperate need of therapeutics that can alter the course of this fatal disease, which often involves devastating cases of pneumonia as a precursor to death. The data reported by Retrotope are currently among the most compelling study results that we have seen with regard to making a difference in the lives of INAD patients and their families,” said Leena Panwala, co-founder and executive director of the INADcure Foundation. “Even though we know their drug won’t cure INAD, it showed evidence of slowing progression in some areas and reducing some complications of the disease.”

Retrotope intends to submit a pre-New Drug Application meeting request with the FDA to discuss these study results and a path for submitting a regulatory approval application for RT001 in this ultra-rare, fatal disease. FDA has previously awarded Retrotope rare pediatric disease designation for RT001 in the treatment of INAD.

“With clear evidence of benefit on patient survival, as well as consistent improvements observed in all analyzed efficacy endpoints including those which measured vital function and activities of daily living, we believe these study results support the potential of RT001 to address a critical unmet need in this orphan disease patient population,” said Peter Milner, chief medical officer of Retrotope.

Author: Rare Daily Staff

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