Deep Brain Stimulation of the Fornix (DBSf) Shows Promise as Treatment for Patients with Mild Alzheimer's Disease

-- Analysis of Phase 2 Study Demonstrates Acceptable Safety, Increased Glucose Metabolism, and Suggests Clinical Benefit in Mild Alzheimer's Disease Patients

-- DBSf Clinical Development Program to Proceed to Phase 3

Nov 06, 2015, 08:00 ET from Functional Neuromodulation Ltd.

BOSTON, Nov. 6, 2015 /PRNewswire/ -- Functional Neuromodulation Ltd. announced that an analysis of the ADvance Study, a Phase 2 double-blind randomized controlled trial of DBSf for mild Alzheimer's disease (clinicaltrials.gov NCT01608061) is being presented today at the 2015 Clinical Trials in Alzheimer's Disease (CTAD) meeting in Barcelona, Spain.

"The company is taking a unique approach to Alzheimer's disease by treating it as a disorder of the memory circuit that has become less active due to neuronal deterioration. By applying electrical impulses to the circuit, ADvance results suggest that DBSf may keep the memory circuit active," said Anton P. Porsteinsson, MD, William B. and Sheila Konar Professor of Psychiatry at the University of Rochester and a member of the independent data safety monitoring board for the ADvance study.  Dr. Porsteinsson stated further, "The results are encouraging.  The study demonstrated an acceptable safety and a suggestion of clinical benefit in a subgroup of patients, which is supported by improvement in a biological marker.  This approach clearly merits further clinical investigation."

Treatment with DBSf suggested clinical benefit at 12 months in patients aged 65 and older based on Clinical Dementia Rating sum of boxes (CDR-SB) and the Alzheimer's Disease Assessment Scale cognitive subscale - 13 item, (ADAS-Cog 13).  In patients treated with DBSf, glucose metabolism, a biomarker for neuronal degeneration and disease progression, increased by 22% on average at 12 months while the placebo group declined by 1.2% on average.  The surgery and brain stimulation demonstrated acceptable safety and was well tolerated.

"DBSf has demonstrated a statistically significant increase in brain glucose metabolism and a signal that memory circuit activation may slow progressive cognitive changes in AD," said Vince Owens, CEO of Functional Neuromodulation.  "Based on these results, we are advancing the DBSf clinical program to Phase 3 with plans to initiate enrollment in mid-2016."

ADvance Trial

ADvance is a randomized, double blind, controlled trial of 42 patients age 45 to 85 with mild Alzheimer's disease to evaluate the potential clinical benefit and safety of DBS of the fornix, a major inflow and output pathway in the brain's memory circuit.  All patients were implanted with DBS systems and randomized to receive stimulation or sham stimulation for 12 months.  The study was supported through a grant from the National Institute on Aging, part of the National Institutes of Health, awarded to Andres Lozano, MD, PhD, R.R. Tasker Chair in Stereotactic and Functional Neurosurgery at the University Health Network and University of Toronto and Constantine Lyketsos, MD, MHS, Elizabeth Plank Althouse Professor, Johns Hopkins University, and Director, Johns Hopkins Memory and Alzheimer's Treatment Center. 

Rationale for DBS in Alzheimer's Disease

It is increasingly recognized that the pathological process in Alzheimer's disease causes focal synaptic dysfunction, the consequences of which produce widespread disturbances in the function of circuits and networks involved in cognition and memory. This notion is supported by the striking regional deficits in brain glucose utilization, impairments of the brain's default mode network, and aberrations in structural and functional brain connectivity characteristic of Alzheimer's disease.  These disruptions are implicated in the pathogenesis of cognitive impairment. Thus malfunction in one diseased area interferes secondarily with other areas less affected but whose function is nevertheless disrupted because it is linked in the network. In contrast to recent therapeutic trials, a different approach is proposed: modulating the brain circuit dysfunction to improve function. As DBS has been used to modulate the activity of motor circuits in Parkinson's disease and other disorders it may be possible to use this same approach to modulate activity in dysfunctional cognitive neural circuits in Alzheimer's disease.

Clinical Results

The effect of DBS was measured using ADAS-cog-13, CDR-SB, and brain glucose metabolism as measured by FDG-PET with SPM analysis method. Increasing evidence exists that neuronal glucose metabolism is a main player in the complex processes involved with memory formation and retrieval. ADAS-cog-13 is used to assess a patient's cognitive status and CDR-SB assesses both cognitive and functional performance. The subgroup of interest in this analysis is ADvance patients aged 65 or older with mild AD.  The subgroup includes 30 patients, with 15 in each arm.  The ADvance trial was not powered to achieve statistical significance in clinical measures.

On glucose metabolism, patients in the DBSf treatment arm increased in five pre-specified brain regions of interest at 12 months whereas patients in the placebo group declined. Treated patients increased between 20.4% and 22.5% in the five regions, while the placebo group declined by 0.2% to 1.4%.  This change was statistically significant at 6 months (p = 0.03), and the metabolism increase observed in the treatment group was maintained at 12 months.

On the ADAS Cog-13, patients in the placebo group worsened by an average of 7.8 at one year, whereas the worsening was 3.7 in the DBSf treatment arm.  The trend toward slowing of clinical decline was not statistically significant (p = 0.12).

On the CDR-SB, patients in the placebo group worsened by an average of 3.5 at one year.  In comparison, the worsening was 2.1 in the DBSf treatment arm.  The trend toward slowing of clinical decline was not statistically significant (p = 0.17).

Safety Results

DBSf demonstrated an acceptable safety and tolerability profile in the ADvance study analysis, as previously reported.  SAEs were consistent with what is typically observed in DBS of other study populations, including Parkinson's disease patients, the most common population treated with DBS.

About Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral disturbances that eventually result in a person's inability to perform daily activities.  In 2010, it was estimated that 25 million individuals were living with AD worldwide.

About Deep Brain Stimulation

Deep brain stimulation (DBS) uses a surgically implanted medical device, similar to a cardiac pacemaker, to deliver mild electrical pulses to precisely targeted areas of the brain. The therapy is currently licensed in the United States, Europe, Canada and other regions of the world for the treatment of the disabling symptoms of essential tremor and advanced Parkinson's disease. It is available under a Humanitarian Device Exemption (HDE)1 for primary dystonia in the United States. In Europe, Canada, Australia and Taiwan, DBS therapy is approved for the treatment of refractory epilepsy.  The therapy is also approved for the treatment of severe, treatment-resistant obsessive-compulsive disorder in the European Union, Australia and in the United States under an HDE2.  More than 100,000 people worldwide have received DBS therapy.

About Functional Neuromodulation, Ltd.

Functional Neuromodulation is a privately held medical device company dedicated to advancing the application of DBSf therapy to help improve the lives of people with Alzheimer's disease and other diseases of memory and cognition.  Founded in 2010 in Toronto by Dr. Andres Lozano, Functional Neuromodulation has recently announced 12-month results of the ADvance study of DBSf in mild Alzheimer's disease patients.  More information about the company can be found at www.fxneuromod.com.

1 Humanitarian Device in the U.S.: The effectiveness of this device for the treatment of dystonia has not been demonstrated.

2 Humanitarian Device in the U.S.:  The effectiveness of this device for the treatment of obsessive-compulsive disorder has not been demonstrated.

CAUTION — Investigational device. Limited by Federal law to investigational use.                 

SOURCE Functional Neuromodulation Ltd.



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