RTB101 Well-tolerated, Crosses Blood-Brain Barrier in Therapeutic Quantities, According to Interim Results

RTB101, an investigational therapy being developed to treat Parkinson’s disease, is well-tolerated, can cross the blood-brain barrier, and reaches potentially therapeutic concentrations in cerebrospinal fluid (CSF), according to interim results of a Phase 1b/2a study.

Developed by resTORbio, RTB101 is an orally-administered compound meant to induce autophagy in neuronal cells by inhibiting a protein called target of rapamycin complex 1 (TORC1).

Autophagy is the process by which cells clear away defective and unnecessary components, such as toxic misfolded protein aggregates. This process is vital to cellular health and survival, and defective autophagy is thought to contribute to the progression of Parkinson’s disease.

A key clinical finding in Parkinson’s is the presence of protein aggregates called Lewy bodies in dead and dying nerve cells.

Multiple preclinical models have shown that TORC1 inhibition alleviates the symptoms of neurodegenerative diseases, including Parkinson’s.

“Preclinical data suggest that induction of autophagy has the potential to slow the progression not only of Parkinson’s disease but also of multiple other neurodegenerative diseases that are characterized by the accumulation of toxic protein aggregates in cells such as Huntington’s and Alzheimer’s disease,” Joan Mannick, MD, co-founder and chief medical officer of resTORbio, said in a press release.

To date, three separate treatment cohorts in the trial have shown evidence that RTB101 reaches concentrations that inhibited TORC1 activity and induced autophagy in neuronal cells in preclinical models.

The trial is evaluating the safety and tolerability of RTB101 among Parkinson’s patients, either alone or in combination with sirolimus (brand name Rapamune, among others). The company plans to enroll 45 patients with mild Parkinson’s disease, with or without mutations in the GBA gene, and who are being treated with standard therapies.

Trial participants have so far been randomized into three cohorts and dosed once weekly with 300 mg of RTB101 alone, 2 mg of sirolimus alone, or a combination of 300 mg RTB101 and 2 mg of sirolimus. The trial will also evaluate escalating doses of 2 mg, 4 mg, and 6 mg of sirolimus in combination with 300 mg of RTB101.

Interim results show that all three dosing regimes have been well-tolerated and RTB101 successfully crossed the blood-brain barrier (BBB), a semipermeable membrane that protects the brain and spinal cord from the external environment. The BBB is a major barrier for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.

Furthermore, RTB101 was measured at concentrations in the CSF (the liquid that surrounds the brain and spinal cord) that have the potential to induce autophagy based on past preclinical trials.

Enrollment into the study group receiving 300 mg of RTB101 in combination with 4 mg of sirolimus once weekly is ongoing.

In addition to easing other symptoms of the disease, resTORbio hopes that by inducing autophagy, RTB101 will ease the levodopa-induced dyskinesia experienced by many patients.