Phase 1/2 Trial to Test Investigational Therapy RTB101 in Parkinson’s Disease

RTB101 Phase 1/2 trial

A new Phase 1/2a clinical trial will investigate resTORbio’s therapy candidate RTB101, alone or in combination with sirolimus, as a potential treatment for Parkinson’s disease.

Researchers plan to enroll 45 patients with mild Parkinson’s disease, both with and without mutations in the GBA gene, and who are being treated with standard therapies.

The trial is intended to assess the safety and tolerability of RTB101 alone or in combination with sirolimus (sold under the brand name Rapamune, among others). The participants will be randomized into five groups where, with the exception of one group that does not receive RTB101, they’ll be given 300 mg of RTB101 once weekly either alone or combined with three escalating doses of sirolimus (2 mg, 4 mg, and 6 mg) or a matching placebo. Patients will be dosed for four weeks.

Its primary objective is safety and tolerability, and as secondary goal, researchers will measure the levels of RTB101 in the blood and the cerebrospinal fluid (CSF; the liquid surrounding the brain and spinal cord). Exploratory goals include measuring biomarkers in blood and CSF, and various clinical assessments. Data from the trial is expected in 2020.

“We believe that TORC1 may be an important therapeutic target for several neurodegenerative diseases associated with aging, in which misfolded proteins aggregate and cause neuronal toxicity. As such, we are excited to initiate our first clinical trial in PD and expand our pipeline into neurodegenerative disease,” Chen Schor, co-founder, president, and CEO of resTORbio, said in a press release.

Aging is the largest risk factor for the development and progression of Parkinson’s disease. In patients with the disease, a protein called the mechanistic target of rapamycin, or mTOR, is frequently over-activated in the brain, preventing the cells from reacting in a functional and timely manner to threats, such as the buildup of toxic forms of the alpha-synuclein protein.

mTOR is a central regulator of cellular growth, survival, and protein synthesis, among other processes. It works by regulating multiprotein complexes known as TORC1 and TORC2 (target of rapamycin complex 1 and 2).

In preclinical studies, inhibition of TORC1 prolonged the lifespan and enhanced several body functions, including immune responses, memory, and mobility, and delayed the onset of aging-related diseases in mice.

Proposed mechanisms for TORC1’s inhibition in Parkinson’s disease is linked to cells’ natural recycling system called autophagy. TORC1 is a natural inhibitor of autophagy. In the case of Parkinson’s disease, defective autophagy prevents the clearance of toxic protein aggregates such as alpha-synuclein.

Inhibiting TORC1 with the small molecule RTB101, alone or combined with sirolimus (an inhibitor of the master regulator mTOR), activates autophagy, promoting the clearance of these harmful protein aggregates. As a result, the treatment halts neuronal loss and improves motor function.

RTB101 has been shown to potently activate autophagy in the central nervous system (brain and spinal cord) and co-administration with sirolimus means that the concentration required for RTB101 to work is potentially lower — both therapies will act synergistically.

Caused by mutations in the GBA gene, impaired activity of the enzyme glucocerebrosidase (GCase), which is responsible for breaking down and recycling cell waste, has been linked to neurodegeneration and accumulation of alpha-synuclein in Parkinson’s disease. Treatment with RTB101 has also been shown to modulate the activity of GCAse.

“Multiple preclinical models of PD [Parkinson’s disease] have demonstrated the potential benefits of TORC1 inhibition, and intermittent TORC1 inhibition with a synergistic combination of RTB101 and sirolimus may serve as a promising approach for the treatment of PD. We look forward to reporting data from this trial in 2020,” Schor said.

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ITI-214 Safe, Well-tolerated in Mild to Moderate Parkinson’s Patients, Phase 1/2 Trial Shows


Treatment with the experimental oral therapy ITI-214 was safe and well-tolerated in patients with mild to moderate Parkinson’s disease, according to a Phase 1/2 clinical trial.

Trial findings also suggested that ITI-214 may ease motor symptoms in these patients.

The study, “A Phase I/II Clinical Study of  ITI-214, a Novel Phosphodiesterase-I (PDE1) Inhibitor, for the Treatment of Parkinson’s Disease (PD),” was presented during AD/PD 2019 — The 14th International Conference on Alzheimer’s and Parkinson’s Diseases, taking place March 26-31 in Lisbon, Portugal.

ITI-214 is a selective blocker of an enzyme called phosphodiesterase 1 (PDE1), implicated in the breakdown of cAMP and cGMP. These two messenger molecules act within cells of the nervous system in response to diverse signals. Because altered PDE1 activity has been reported in both neurological and cardiovascular diseases, blockers such as ITI-214 are intended to restore its normal function.

Work in rodent models suggested that ITI-214, being developed by Intra-Cellular Therapies, may relieve motor and non-motor symptoms of Parkinson’s. In preclinical studies, the investigational therapy also reduced neuroinflammation through its effect on microglia — key immune cells in the central nervous system — and prevented neurodegeneration.

Data from four Phase 1 trials in healthy volunteers showed that treatment with ITI-214 was generally well-tolerated and safe.

Researchers are now presenting clinical data from the randomized, double-blind, placebo-controlled Phase 1/2 trial (NCT03387215) that primarily evaluated the safety and tolerability of increasing doses of ITI-214 in patients with mild to moderate Parkinson’s.

As secondary goals, the seven-day Intra-Cellular Therapies-sponsored study assessed the compound’s pharmacokinetics — its absorption, distribution, metabolism, and excretion in the body — as well as biomarkers of inflammation, and motor and non-motor effects through the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale.

The 40 participants (50 years and older) were maintained on stable Parkinson’s therapy. All five doses of ITI-214 — 1, 3, 10, 30, and 90 mg — were found safe and generally well-tolerated. In addition, the findings showed signals of less motor dysfunction and dyskinesia — involuntary, jerky movements — with some of the administered doses.

“Clinical data indicate that ITI-214 is safe and generally well tolerated across a range of doses in patients with mild to moderate [Parkinson’s],” the scientists wrote.

Noting that the signals of clinical improvement warrant further evaluation, the team added that “selective PDE1 inhibition may represent a novel approach for the treatment of motor and non-motor symptoms associated with [Parkinson’s].”

Of note, all seven of the study’s authors are employees of Intra-Cellular.

Besides Parkinson’s, ITI-214 is being evaluated in a Phase 1/2 trial (NCT03387215) in patients with heart failure, which is supported by results showing increased heart contraction strength in dogs and rabbits.

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Investigational Gene Therapy AXO-Lenti-PD Tested in Phase 1/2 Clinical Trial in Parkinson’s Patients


The first patient has been dosed in Axovant’s Phase 1/2 clinical trial testing the investigational gene therapy AXO-Lenti-PD for the treatment of Parkinson’s disease.

The patient reported no complications associated with surgery or administration of the therapy and was discharged as planned in the initial trial design. Preliminary data from the first group of patients treated in the trial are expected to be announced during the first half of 2019.

Currently recruiting participants, the trial (NCT03720418) is expected to enroll about 30 patients ages 48-70 who have had bilateral idiopathic (of unknown cause) Parkinson’s disease for at least 5 years.

The study, being conducted in the United Kingdom and France, consists of two parts. In part A, researchers will evaluate the safety and tolerability of increasing doses of the investigational gene therapy, and select the optimal dose to be used in further testing.

Part B is a randomized, double-blind phase in which patients will receive either the designated dose from Part A or an imitation surgical procedure (ISP). Patients will be followed for about 6 months to assess AXO-Lenti-PD’s safety and potential to enhance motor function and improve movement control.

AXO-Lenti-PD, also known as OXB-102, is a gene therapy that uses a harmless virus-based system to deliver three genes that encode critical enzymes involved the synthesis of dopamine — the signaling molecule, or neurotransmitter, produced at low levels in Parkinson’s patients.

This treatment is expected to provide significant and long-lasting clinical benefits to patients with Parkinson’s disease upon a single administration.

The gene therapy was initially designed by Oxford BioMedica, which in June 2018 granted the exclusive worldwide rights over AXO-Lenti-PD’s development and marketing to Axovant Sciences.

“We are very excited to bring AXO-Lenti-PD into clinical development and believe it will be an important new therapy for patients with Parkinson’s disease who suffer from motor fluctuations on the current standard of care,” Pavan Cheruvu, MD, the CEO of Axovant, said in a press release. “This marks the first of our gene therapy programs to enter the clinic, and our focus now is on rapid execution of the clinical study.”

A recently completed Phase 1/2 trial of ProSavin (NCT00627588), AXO-Lenti-PD’s predecessor, demonstrated favorable safety and tolerability and a significant improvement of motor function at 6 and 12 months in Parkinson’s patients. This benefit was sustained for up to six years.

Compared with ProSavin, preclinical studies of AXO-Lenti-PD showed increased production of the key enzymes, as well as at least a fivefold greater potency in improving behavior and movement in an animal model of the disease.

“Building upon the evidence of safety and durable improvements in motor symptoms seen up to six years in the prior clinical study of ProSavin, we feel a sense of urgent responsibility to accelerate the development of AXO-Lenti-PD,” Cheruvu said.

“Mid- to late-stage Parkinson’s disease remains a challenge to treat, with current therapies leading to debilitating adverse events and unpredictable therapeutic effects over time,” said Stéphane Palfi, MD, PhD, coordinating investigator of the AXO-Lenti-PD trial.

“We are pleased to advance AXO-Lenti-PD in the clinic and are eager to see the trial expand upon the long-term safety and efficacy results we observed in the Phase 1/2 clinical trial of ProSavin,” he said.

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