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AAIC 2013 press room, July 13-18: 617.954.3414

New Alzheimer's Therapy Targets and Approaches Reported at Alzheimer's Association International Conference 2013
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BOSTON, July 14, 2013 – Results of four research trials investigating new targets for therapies in Alzheimer's disease, and incorporating novel approaches to participant identification and selection, were reported today at the Alzheimer's Association International Conference® 2013 (AAIC® 2013) in Boston.

The trials involve four compounds that target physical changes in the brain associated with the development and progression of Alzheimer's disease. Two drugs are intended to reduce brain inflammation, one is thought to inhibit the production of an abnormal protein in the brain known as beta-amyloid, and the fourth promotes brain cell regeneration.

"The Alzheimer's disease epidemic is here. It is vital that we accelerate the pursuit of novel ideas and strategies to treat and prevent Alzheimer's disease," said Maria Carrillo. Ph.D. Alzheimer's Association vice president of medical and scientific relations. "While many of the trials reported at AAIC 2013 are still in early stages, they represent a promising diversification of the Alzheimer's treatment pipeline and translate to new hope for a world without Alzheimer's disease in the future."

Microglial Modulator Reduces Inflammation and Improves Cognition in People with MCI

Inflammation in the brain has been implicated in the process and progression of Alzheimer's disease. Microglia are cells that act as the first and main form of active immune defense in the brain and spinal cord where they must react quickly to decrease inflammation and protect sensitive tissues. It has been recently suggested that amyloid plaques in the brains of people with Alzheimer's can stimulate microglia to produce compounds that cause brain cell damage. Thus, microglia have become a novel target for Alzheimer's disease therapies.

CHF5074 (Chiesi Pharmaceuticals Inc., Parma, Italy) is a microglial modulator that, in preliminary studies, has been shown to prevent brain plaque deposition and reduce deficits in transgenic mouse models of Alzheimer's disease.

At AAIC 2013, Joel Ross, M.D., FACP, AGSF, CMD, CPI, of the Memory Enhancement Center of America, and colleagues at Chiesi Pharmaceuticals reported the results of a 90-week (14-weeks double-blind, placebo-controlled study followed by a 76-week open label extension study) trial of CHF5074 at three different doses (200, 400 and 600 mg/day) in people with mild cognitive impairment (MCI). Participants received the same dose of the drug throughout the trial and were monitored for vital signs, cardiac activity, neuropsychological performance and safety.

Seventy-four (74) patients entered the open label part of the study: 26, 21 and 27 in the 200, 400 and 600 mg/day cohorts, respectively. At Study Week 40, 14 patients dropped out: four, two and eight in the 200, 400 and 600 mg/day cohorts, respectively. Three of dropouts were for adverse events: two in the 600 mg/day group (serum creatinine elevation and worsening of cognitive function) and one in the 400 mg/day group (pneumonia). The most frequent treatment-emergent adverse events were gastrointestinal disorders, with diarrhea being reported by 1.4 percent of patients on 200 mg/day, 6.3 percent of patients on 400 mg/day and 16.0 percent of patients on 600 mg/day.

An interim analysis of cognitive tests of 27 patients reaching Study Week 88 showed statistically significant, dose-dependent improvements in participants' cognitive abilities. Study participants who carried one or two copies of the ApoE4 gene, which increases the risk of Alzheimer's, performed significantly better than ApoE4 non-carriers on two of the cognitive tests.

"This is one of the first studies indicating that this neuroinflammatory inhibitor may be able to improve cognition in people with MCI who carry the ApoE4 gene," said Ross. "CHF5074 was well tolerated by people with MCI at doses up to and including 400 mg/day."

MK-8931 (BACE1 Inhibitor) Lowers Beta Amyloid in People with Mild to Moderate Alzheimer's

The presence of beta-amyloid plaques in the brain is a well-known manifestation of Alzheimer's disease. One hypothesis holds that the toxins produced by beta-amyloid initiate a cascade of events in the brain that cause Alzheimer's, but it is still unclear to many whether the plaques are a cause or a result of the disease.

Academic and industry researchers have investigated a variety of approaches to slow or stop the production of beta-amyloid and/or clear it from the brain. Yet, to date, some combination of safety concerns and lack of efficacy in slowing or stopping cognitive decline in people with Alzheimer's has plagued all of these attempts. While this has led to further questions about the validity of the amyloid cascade hypothesis, or the possibility of therapeutic intervention through this route, new approaches continue to be tested.

Mark S. Forman, M.D., Ph.D., and colleagues at Merck Research Laboratories conducted a randomized, double-blind, placebo-controlled, multiple-dose study of an experimental medication called MK-8931 in people with mild-to-moderate Alzheimer's. The drug acts by inhibition of beta-secretase (BACE1), one of two enzymes that produce beta-amyloid by breaking down its parent molecule, known as amyloid precursor protein (APP). Participants received 12, 40 or 60 mg of MK-8931 or placebo (n=8 per dose; n=6 for placebo) daily for seven days. Beta-amyloid levels were measured in cerebrospinal fluid (CSF, the fluid that surrounds the brain and spinal cord) obtained by lumbar puncture over 36 hours following the final dose.

The researchers found that the drug significantly lowered CSF beta amyloid in people with mild to moderate Alzheimer's in a dose-dependent fashion; at the highest dose, the average reduction from baseline was more than 80 percent. According to the researchers, MK-8931 was generally well-tolerated.

"This is the first demonstration of the lowering of beta-amyloid levels by a BACE1 inhibitor in people with Alzheimer's disease," Forman said. "We believe this candidate presents a unique opportunity to test the amyloid hypothesis."

Allopregnanolone Regenerative Therapy to Begin Phase 1 Trials

According to Roberta Brinton, Ph.D., of the University of Southern California, both aging and Alzheimer's disease are characterized by a decline in the ability of the body (including the brain) to self-renew and repair, but the capacity for regeneration is retained, albeit at a decreased level.

Allopregnanolone (also known as Allo) is a neurosteroid found in the brain and bloodstream. In previous studies, it has shown promise as a potential regenerative therapy to promote brain cell creation and improve cognitive function in older animals and animal models of Alzheimer's disease.

At AAIC 2013, Brinton reported the design of a Phase 1, multiple ascending dose, clinical trial of Allo in participants diagnosed with MCI due to Alzheimer's and mild Alzheimer's, with doses administered once-per-week for 12 weeks to establish a safe and tolerated dose. Because Allo is naturally expressed in the brain and reaches relatively high levels during the third trimester of pregnancy, the scientists were able to advance beyond the time limits of a typical first stage of safety testing.

Secondary goals of the trial include assessing potential short-term effects of Allo dosing on cognition and MRI indicators of AD and informing a subsequent Phase 2 proof of concept trial with MRI-based biomarkers of regenerative efficacy.

"Allopregnanolone is a well-characterized agent with a very promising track record of promoting neural stem cell generation and restoring cognitive function in animal models of Alzheimer's," said Brinton. "We consider Allopregnanolone a first in class regenerative therapeutic for MCI and Alzheimer's. Our hope is that, through further research, we will add Allo to the roster of Alzheimer's treatments.

"A critical issue to consider for potential regenerative therapies for Alzheimer's is the ongoing and progressive burden of brain cell death caused by the disease. It is not sufficient solely to generate new neurons and to promote their survival; it is necessary to reduce the ongoing burden of pathology for there to be long-term benefits for cognition and function," Brinton added. "We were very encouraged to discover that Allo reduced the burden of Alzheimer's pathology. Our latest findings are very exciting as they show that Allo increases the energy capacity of the brain. This is important because the generation of new neurons, new synaptic circuits and synaptic transmission all require substantial energy."

Phase 3 Trial of Pioglitazone to Delay Onset of MCI in Cognitively Normal Elderly (1) Uses Genetics to Enrich the Study Population and (2) Is Designed to Verify New Diagnostic Criteria

International trials to delay onset of MCI due to Alzheimer's disease are complex in design, requiring careful consideration of case definition, site characteristics, selection of primary outcome metrics and methods to ensure appropriate cultural and psychometric validation. They require innovations in approach to recruit the most appropriate study population, provide consistent MCI diagnoses across countries and to ensure the credibility of their results.

Kathleen A. Welsh-Bohmer, Ph.D., of the Joseph and Kathleen Bryan Alzheimer's Disease Research Center at Duke University Medical Center, and her colleagues at Zinfandel and Takeda Pharmaceuticals International, Inc., are currently initiating an international Phase 3 trial of low dose pioglitazone, a medication which at higher doses is approved for treatment of type 2 diabetes, as a therapy to delay onset of MCI due to Alzheimer's. The trial will begin enrollment in 2013. In earlier human studies, treatment with pioglitazone was associated with decreased markers of brain inflammation.

Study participants will be cognitively normal individuals who carry genetic risk variations in the APOE and TOMM40 genes that are associated with an increased risk of earlier onset of symptoms of Alzheimer's. By recruiting people with this genetic combination, the researchers believe they will enrich the study population so more participants will get MCI and/or Alzheimer's during the course of the trial.

In addition, the study includes applying and validating the new NIA/Alzheimer's Association diagnostic criteria for MCI due to Alzheimer's (Albert, et al., 2011; Alzheimer's & Dementia: The Journal of the Alzheimer's Association) and determining an appropriate set of cognitive tests that would work effectively in all study sites around the globe by taking into account, for example, language and cultural differences.

"Since this is an international trial, with sites in the U.S., Europe, Australia and Russia, it is vitally important that we apply standards that can be used and validated seamlessly around the world," said Welsh-Bohmer. "This study is meant to operationalize the NIA/Alzheimer's Association diagnostic criteria, which represent new standards."

"The new procedures under development for this trial may serve as useful tools for application in other global trials to prevent the onset of symptomatic Alzheimer's," she added.

About AAIC

The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association

The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800.272.3900.

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Proposal ID: 37712
Topic: Therapeutics
Subtopic: Clinical Trials
Presentation: Oral session, Tuesday, July 16, 2013, 2:45 p.m. ET

Sustained Cognitive Benefit in Patients with Mild Cognitive Impairment (MCI) Upon Prolonged Treatment with CHF5074

Presenting author: Joel Ross, MD, FACP, AGSF, CMD, CPI, Joel S Ross, Memory Enhancement Center of America, Inc.; Sanjiv K Sharma, Memory Enhancement Center of New Jersey; Abhijit Chatterjee, Memory Center of New Jersey; Jaron Winston, Senior Adults Specialty Research; Gabriella Bottini, Niguarda Cà Granda Hospital; Massimo Franceschi, IRCCS Multimedica; Mercedes Fernandez, University of Bologna; Luciana Giardino, University of Bologna; Laura Calzà, University of Bologna; Dottie Norris, Chiesi Pharmaceuticals Inc.; Helen Cicirello, Chiesi Pharmaceuticals Inc.; Bruno P Imbimbo, Chiesi Farmaceutici

Background: CHF5074 is a new microglial modulator that has been shown to prevent brain plaque deposition and attenuate memory deficits in transgenic mouse models of AD. In man, the drug dose-dependently lowers cerebrospinal fluid levels of two biomarkers of neuroinflammation (sCD40L and TNF-a). We monitored the safety and tolerability and cognitive effects of CHF5074 after prolonged treatment in MCI patients.

Methods: At the end of a 14-week double-blind, placebo-controlled study in 96 MCI patients evaluating three titrated dose regimens of CHF5074 (200, 400 and 600 mg/day), patients were given the option to enter a 76-week open label extension study. Patients received CHF5074 at the dose equal to that of their originally assigned double-blind study cohort. Patients were monitored for vital signs, cardiac activity, neuropsychological performance and safety laboratory parameters.

Results: Seventy-four patients entered the open label study: 26, 21 and 27 in the 200, 400 and 600 mg/day cohorts, respectively. At Study Week 40, 14 patients dropped out: four, two and eight in the 200, 400 and 600 mg/day cohorts, respectively. Three of dropouts were for adverse events: two in the 600 mg/day group (serum creatinine elevation and worsening of cognitive function) and one in the 400 mg/day group (pneumonia). The most frequent treatment-emergent adverse events were gastrointestinal disorders, with diarrhea being reported by 1.4 percent of patients on 200 mg/day, 6.3 percent of patients on 400 mg/day and 16.0 percent of patients on 600 mg/day. Interim analysis of cognitive tests of 32 patients reaching Study Week 64 showed statistically significant improvements compared to Baseline on Digit Symbol Substitution Test (+4.8±1.1 matches, p<0.001), Trail Making Test-A (-8.1±2.4 sec, p=0.002), Trail Making Test-B (-14.5±4.6 sec, p=0.004), Immediate Word Recall (+2.9±0.8 words, p=0.001) and Delayed Word Recall (+1.3±0.4 words, p=0.003). APOE4 carriers performed significantly better than APOE4 non-carriers on Immediate Word Recall (+5.4±1.2 vs +1.4±0.9 words, p=0.012) and Trail Making Test-A (-12.4±2.8 vs -5.6±3.3 sec, p=0.034) with improvements representing 25-38 percent of Baseline scores.

Conclusions: CHF5074 was well tolerated by MCI patients after prolonged treatment at doses up to and including 400 mg/day. Drug treatment was associated with sustained cognitive benefit in executive function and verbal memory for at least 64 weeks.

Proposal ID: 38061
Topic: Therapeutics
Subtopic: Clinical Trials, Amyloid-based
Presentation: Oral session, Sunday July 14, 2013, 2:15 p.m. ET

The Novel BACE Inhibitor MK-8931 Dramatically Lowers CSF Abeta in Patients with Mild to Moderate Alzheimer's Disease

Presenting author: Mark Forman , Mark Forman*1, Huub-Jan Kleijn1, Marissa Dockendorf1, John Palcza1, Jack Tseng1, Christina Canales1, Michael Egan1, Matthew Kennedy1, Omar Laterza1, Lei Ma1, Jack Scott1, Michael Tanen1, Jeffrey Apter2, Miroslav Backonja3, Larry Ereshefsky4, Hakop Gevorkyan5, Stanford Jhee4, Rebecca Rynders3, Arian Zari4, Ellie Bryan4, John Wagner1, Matthew Troyer1, Julie Stone1 1Merck, Whitehouse Station, New Jersey, United States; 2Princeton Medical Institute, Princeton, New Jersey, United States; 3CRI Lifetree Research, Salt Lake City, Utah, United States; 4Parexel International Early Phase, Glendale, California, United States; 5Parexel International, Glendale, California, United States

Background: Compelling evidence implicates the abnormal accumulation of Aß in the pathogenesis of Alzheimer's disease (AD). Inhibition of BACE1 to reduce Aß production is a promising approach to test the amyloid hypothesis. In prior studies in healthy volunteers, the BACE1 inhibitor MK-8931 was generally well-tolerated and resulted in a dose-dependent reduction of CSF Ab.1 Here we report the initial characterization of the pharmacodynamics of MK-8931 in AD patients.

Methods: Randomized, double-blind, placebo-controlled, multiple-dose study in mild-to-moderate AD patients. Subjects were administered 12, 40 or 60-mg MK-8931 or placebo (n=8 per dose; n=6 for placebo) daily for 7 days. CSF Aß40, Aß42 and sAPPß concentrations were determined over 36 hours postdose on Day 7 using samples collected via lumbar catheterization. A semi-mechanistic mathematical model was developed to describe Ab40, Ab42 and sAPPb modulation in CSF and used to generate dose-response profiles for AD patients.

Results: Following placebo administration, mean CSF concentrations of Aß40, Aß42 and sAPPb increased relative to baseline. By contrast, administration of MK-8931 resulted in a dose-dependent and sustained reduction in CSF Ab levels with mean percent reduction from baseline of up to: Aß40=84 percent, Aß42=81 percent, and sAPPß=88 percent. CSF modulation of Ab40, Ab42 and sAPPb was best described by a sigmoid Emax model and transit compartments accounted for the delay between brain and lumbar CSF Ab. Based on dose-response profiles generated using this model, targeted CSF Ab reductions between 50 to 75 percent and between 75 to 100 percent from baseline are predicted to be achieved in AD patients at dose levels of 12 and 40 mg MK-8931, respectively.

Conclusions: This study is the first demonstration of a pharmacodynamic effect of BACE1 inhibition in AD patients. Multiple doses of 12 to 60-mg MK-8931 resulted in a dose-dependent reduction in CSF Aß, similar to that observed in healthy volunteers and have enabled robust dose-response modeling. Dose-response profiles predict that 12 and 40 mg MK-8931 will inhibit Aß production by >50 percent and >75 percent, respectively, in the majority of AD patients. Thus, MK-8931 presents a unique opportunity to test the amyloid hypothesis of AD pathogenesis. (Ref 1: Forman et al. 2012 AAIC abstract.)

Proposal ID: 38062
Theme: Basic Translational Science; Molecular and Cell Biology; Stem cells, IPS cells
P4-012 -- Wednesday, July-17, 2013 Poster session (11:45 a.m.–2:15 p.m.)

Allopregnanolone as a Regenerative Therapeutic for Alzheimer's #1: From Discovery to Phase I Multiple Ascending Dose Clinical Trial

Presenting author: Roberta Brinton , Roberta Brinton*1, Ronald Irwin1, Wendy Mack1, Kathleen Rodgers1, Gerhard Bauer2, Michael Rogawski2, Lon Schneider1 1University of Southern California, Los Angeles, California, United States; 2University of California, Davis, Sacramento, California, United States.

Background: Regenerative therapeutics hold the promise of self-renewal and repair. Aging and Alzheimer's are marked by a decline in self-renewal and repair, but a capacity for regeneration is retained. Allopregnanolone (Allo) is a pleiotropic regenerative therapeutic that promotes neurogenesis and restores cognitive function in both a pre-clinical AD model and wild-type aged mice while also reducing AD pathology in AD mouse brain. Further, Allo promoted regeneration of human neural stem cells. Allo is a neurosteroid endogenous to the brain of low molecular weight and blood brain barrier penetrant with abundant existing safety data in animals and humans. Its mechanisms of neural stem cell proliferation, restoration of cognitive function and AD pathology reduction are well characterized and unlikely to induce amyloid related imaging abnormalities (ARIA).

Methods: Based on a foundation of pre-clinical discovery, translational research, clinical development with NIA USC ADRC and FDA assessment and IND approval, we designed a Phase 1 multiple ascending dose clinical trial of Allo doses administered in a regenerative regimen of once-per-week for 12 weeks to establish a safe and tolerated dose of Allo necessary to advance to a Phase 2 efficacy trial.

Results: A Phase 1 multiple ascending dose trial of Allo in participants diagnosed with MCI due to AD and early AD was designed. Primary safety objectives are to determine: maximally tolerated dose; incidence and severity of treatment emergent adverse events; designated medical events; clinically important changes in safety assessments including ARIA. Secondary objectives are to: assess potential short-term effects of Allo dosing on cognition and MRI indicators of AD; inform subsequent phase 2 proof of concept trial with MRI-based biomarkers of regenerative efficacy.

Conclusions: Allopregnanolone is a first in class regenerative therapeutic for MCI and AD that targets endogenous neural stem cells and disease modifying mechanisms. Trial outcomes will provide: 1) an estimated safe and well-tolerated dose of Allo; 2) parameter estimates for cognitive efficacy to advance to a Phase 2 proof of concept trial of Allo; and 3) parameter estimates for MRI-based biomarkers.

Supported by NIA-U01-AG031115, ADDF, CIRM-DR2-05410 to RDB & SC-CT < pSI NCATS-UL1 RR031986.

Proposal ID: 37072
Topic: Therapeutics: Clinical trials I
Presentation: O1-06-01, Oral session, Sunday, July 14, 2013, 2:15 p.m. ET

Challenges in International Clinical Trials to Delay Early Symptomatic Alzheimer's Disease

Presenting author: Kathleen Welsh-Bohmer, Kathleen Welsh-Bohmer*1, Heather Romero1, Kathleen Hayden2, Brenda Plassman1, Cassandra Germain1, Mary Sano3, Mark Espeland4, Suzanne Craft4, Andreas Monsch5, Lon Schneider6, Carl Chiang7, Stephen Haneline8, Janet Oneil9, Manoj Malholtra9, Stephen Brannan9, Daniel Burns8, Allen D Roses10 1Duke University Medical Center, Durham, North Carolina, United States; 2Bryan ADRC, Duke University Medical Center, Durham, North Carolina, United States; 3Mount Sinai School of Medicine & James J Peters VAMC, New York, New York, United States; 4Wake Forest School of Medicine, Winston-Salem, North Carolina, United States; 5University Hospital Basel, Oberwil, North Carolina, Switzerland; 6University of Southern California, Los Angeles, California, United States; 7Zinfandel Pharmaceuticals, Inc., Durham, North Carolina, United States; 8Zinfandel Pharmaceuticals, Inc., Research Triangle Park, North Carolina, United States; 9Takeda Pharmaceuticals International, Inc., Deerfield, Illinois, United States; 10Zinfandel Pharmaceutials, Inc., Research Triangle Park, North Carolina, United States.

Background: International trials to delay onset of mild cognitive impairment due to Alzheimer's disease (MCI-AD) are complex in design, requiring careful consideration of: case definition, site characteristics, selection of primary outcome metrics, and methods to ensure appropriate cultural and psychometric validation. We describe the methodological and instrumentation challenges faced in the initiation of an international, phase III randomized, controlled trial of low-dose pioglitazone to delay MCI-AD in a cognitively normal population enriched by a novel genetic marker, TOMM40.

Methods: A Phase III study to delay onset of MCI-AD is in process with sites in the United States, Europe, Australia, Russia and Israel. A group of international experts was assembled to operationalize the recent NIA/AA core clinical criteria for MCI-AD and to determine an appropriate neuropsychological outcome battery for the global context. A deliberative process spanning 18 months involved systematic reviews of the literature and databases followed by statistical modeling to determine methods with optimal performance characteristics. Also considered were 1) methods to secure normative data essential for diagnostic decisions and 2) approaches to establish linguistic and cultural validity as well as to measure equivalence across sites.

Results: We developed an MCI-AD diagnostic algorithm requiring: 1) a Clinical Dementia Rating Scale score of 0.5 based on structured interview; and 2) a specific profile of impairment on neuropsychological testing with an emphasis on episodic memory impairment and evidence of change from baseline. A clinical diagnosis of MCI-AD requires fulfillment of the criteria on two consecutive examinations, six months apart, which is supported by clinical, functional and medical data and ultimately adjudicated by a panel of clinical experts reviewing all cases. The design of the clinical trial and the development of normative and validation data to support the use of the neuropsychological battery in the international context will be discussed.

Conclusions: Operationalization of the new NIA/AA research criteria for MCI-AD rests heavily on empirically sound methods acceptable to the international research community and regulatory bodies. Establishing consistent MCI-AD diagnoses across countries is critical to study conduct and broad data acceptance. This trial will begin enrollment in 2013.

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Make history at AAIC 2013 • Boston, MA • July 13-18, 2013