PDD Patients Given Anavex 2-73 at High Dose Show Range of Benefits

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by Steve Bryson, PhD |

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Anavex 2-73 (blarcamesine), an investigational oral therapy for Parkinson’s disease dementia, led to clinically meaningful improvements within all four MDS-UPDRS assessments for patients treated daily at high dose, according to new data from a completed Phase 2 trial.

These benefits, in both motor and non-motor Parkinson’s symptoms, were also significantly tied to a rise in Anavex 2-73’s target receptor, called SIGMAR1, confirming the therapy’s mechanism of action and this receptor as a reliable biomarker of response.

Its developer Anavex Life Sciences now plans to launch a Phase 3 study of the therapy’s effects on cognition and other disease symptoms in patients with and without dementia, according to a company press release.

“I am impressed with the robust improvement of the MDS-UPDRS across all sub-score parts I-IV coupled with the biomarker correlated outcome measures and I support the implementation of the ANAVEX 2-73 Phase 3 studies in Parkinson’s disease and Parkinson’s disease dementia, respectively,” said the trial’s principal investigator, Jaime Kulisevsky, MD, PhD.

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New data were presented as a poster by Kulisevsky, a professor of neurology at the Medicine Autonomous University of Barcelona and director of the Movement Disorders Unit at Sant Pau Hospital in Spain, at the AD/PD 2022 International Conference on Alzheimer’s & Parkinson’s Diseases and related neurological disorders held March 15–20.

The poster is titled, “ANAVEX2-73 (blarcamesine) – Analysis of Movement (MDS-UPDRS) and Cognitive (CDR System) Pharmacodynamic-Biomarker Outcome Measures of Placebo-Controlled Phase 2 Trial in 132 Parkinson’s Disease Dementia Patients.

Anavex 2-73 is a small molecule activator of the receptor SIGMAR1, which is diminished in the brains of Parkinson’s patients as well as those with Alzheimer’s and Rett syndrome. The protein receptor is involved in various processes related to maintaining healthy brain cells.

By activating SIGMAR1, Anavex 2-73 aims to restore brain cell health and slow neurological decline by targeting protein misfolding and aggregation, lessening the resulting inflammation, problems in energy-producing mitochondria, and oxidative stress — an imbalance between the production and clearance of toxic reactive species generated by metabolism that are harmful to cells.

The proof-of-concept Phase 2 ANAVEX 2-73-PDD-001 study (NCT03774459) evaluated the therapy’s safety and early effectiveness in 132 adults, ages 50–85, with Parkinson’s disease dementia (PDD). Participants, recruited at multiple sites in Spain and Australia, were randomly assigned 30 or 50 mg oral capsules of ANAVEX 2-73 or a placebo capsule, once daily for 14 weeks (about 3.5 months).

Previously reported results showed Anavex 2-73 significantly improved several cognitive skills, including episodic memory, and lessened REM sleep behavior disorder. This disorder, characterized by physically acting out dreams, is associated with greater cognitive impairment and a higher risk of dementia. The therapy was also reported to be safe and well tolerated at high dose, with a safety profile superior to that of other common dementia medications.

More recent data confirmed these cognitive and sleep benefits and also showed the therapy’s high 50 mg dose led to a 10.98 points drop in the MDS-UPDRS total score, indicating an easing in disease severity across several measures. At the same time, the total score in the placebo group rose by 3.53 points, representing a 14.51-point difference and an 18.9% relative improvement over 14 weeks.

Anavex 2-73’s use also resulted in a significant increase in SIGMAR1 messenger RNA (mRNA) levels, the molecule that carries genetic instructions to make SIGMAR1. This rise was associated with gains in attention assessments, and with better MDS-UPDRS total scores and those of MDS-UPDRS Part III, which tests motor abilities.

New findings describe the details of each MDS-UPDRS assessment section in high-dose patients.

In MDS-UPDRS Part I, measuring non-motor experiences of daily living including cognition, mood, psychosis, and sleep issues, 12 out 13 items assessed improved (92.23%). MDS-UPDRS Part II examines motor experiences of daily living, from speech and eating to doing hobbies, and 10 out of 13 items improved (76.92%).

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In Part III for motor function, ranging from speech to hand movements, posture to gait, 30 out of 34 items showed score gains (88.23%), while five out of seven items (71.42%) improved in MDS-UPDRS Part IV scores for motor complications like dyskinesia (uncontrolled movement) and levodopa treatment “off” periods.

A dose-dependent increase in scores for episodic memory — the ability to remember new shared information and personal experiences — was also reported. While the placebo group scores fell by 20.82 points, the scores for those treated with Anavex 2-73 rose by 21.40 points, a 44.22-point improvement in episodic memory scores.

“ANAVEX 2-73 (blarcamesine) demonstrated dose-dependent efficacy for both motor impairment (MDS-UPDRS) and cognition … which correlated with SIGMAR1 mRNA as a pharmacodynamic biomarker, respectively,” said Christopher Missling, PhD, president & CEO of Anavex. “These results support continued development of ANAVEX2-73 in Parkinson’s disease and Parkinson’s disease dementia.”

Patients who finished ANAVEX 2-73-PDD-001 were invited to continue or start  treatment with Anavex 2-73 in ANAVEX 2-73-PDD-EP-001 (NCT04575259), a 48-week (almost one year) extension study of the therapy’s long-term safety and efficacy, as well as potential treatment effects on gut bacteria. It is due to be finished in June.

“We would like to thank all the patients and participating families as well the investigators and clinical site coordinators for their dedication to this study,” Missling added.

Up to 80% of Parkinson’s patients are estimated to develop disease-related dementia, which affects mental abilities that include memory and attention, completing tasks, and making judgments, and treatments options are limited.

“PDD [Parkinson’s disease dementia] is a debilitating disorder with significant co-morbidities and there has not been a mechanistically novel medication approved for PDD in over 20 years,” Kulisevsky said. “Hence, new therapies are urgently needed to alleviate this suffering and disability.”