Alzheimer's Association International Conference: Round Up

Data Suggest Fewer New Cases of Alzheimer's in the US and Europe. Worldwide prevalence of Alzheimer's disease is projected to increase in the decades ahead as the planet's population ages, but recently published studies from the United States, the Netherlands, Sweden, and England suggest a decline in incidence or prevalence of dementia (or both) in those countries, according to a review of recent research conducted by Kenneth Langa, MD, PhD, of the University of Michigan and the VA Ann Arbor Center for Clinical Management Research, and reported at a plenary session at AAIC 2014.

Dr. Langa observed from the studies that a number of factors, especially rising levels of education and more aggressive treatment of cardiovascular risk factors such as hypertension and high cholesterol, may be leading to improved brain health and consequent decline of numbers of new cases of Alzheimer's disease and dementia in certain countries or regions of the world.

Alzheimer's Drug Crenezumab Fails Main Goals. The experimental drug crenezumab failed to improve thinking and memory in people with Alzheimer's disease, but the results from two Phase II studies leave the possibility that it might help those who don't show symptoms.

Data presented at the AAIC showed Roche Holding AG's drug did not meet its primary endpoints for cognition and activities of daily living, yet the authors saw a positive finding in a subgroup of the study population with mild AD who received the drug by intravenous infusion.

Crenezumab is an investigational, fully humanized, monoclonal antibody designed to target all forms of beta amyloid.

In the ABBY study, crenezumab treatment in people with mild-to-moderate AD “demonstrated a trend toward slowing the decline of cognitive abilities, measured by the 12-item cognitive subscale of the ADAS-cog12, but no effect on global functioning, measured by Clinical Dementia Rating-Sum of Boxes (CDR-SOB), the co-primary endpoints,” according to the company.

In an exploratory analysis of people with milder disease treated with intravenous (IV) crenezumab, there was a positive trend toward increasing reduction in cognitive decline in progressively milder subsets, relative to placebo.

In the BLAZE study, which enrolled people who tested positive for an amyloid imaging biomarker, the primary endpoint was a change in brain amyloid load. In a secondary endpoint analysis, treatment with IV crenezumab was associated with a trend towards slowing cognitive decline in those with mild disease (as measured by ADAS-cog12). Biomarker results from the ABBY and BLAZE studies will be presented at an upcoming medical meeting.

Carole Ho, head of early clinical development in neurology at Roche's Genentech unit, said the data were encouraging but the company hasn't decided whether to move forward with Phase III trials.

Drugmakers typically don't take a compound into the final phase of trials without a 60 percent to 70 percent chance of success, according to Tim Anderson, a New York-based analyst for Sanford C. Bernstein & Co., in a note to investors. Crenezumab and its ilk fall far short of that, Anderson wrote.

“What drives this?” he wrote. “The tremendous size of commercial opportunity. As we have shown previously, a drug that successfully modifies Alzheimer's disease progression could make Lipitor (sales peaked around $12 bil- lion) look like a mid-sized product.”

Nosing Into The Conversation: AD and Smell. There is growing evidence that the decreased ability to correctly identify odors is a predictor of cognitive impairment and an early clinical feature of Alzheimer's. As the disease begins to kill brain cells, this often includes cells that are important to the sense of smell.

Matthew E. Growdon, MD, MPH candidate at Harvard Medical School and Harvard School of Public Health, and colleagues investigated the associations between sense of smell, memory performance, biomarkers of loss of brain cell function, and amyloid deposition in 215 clinically normal elderly individuals enrolled in the Harvard Aging Brain Study at the Massachusetts General Hospital. The researchers administered the 40-item University of Pennsylvania Smell Identification Test (UPSIT) and a comprehensive battery of cognitive tests. They also measured the size of two brain structures deep in the temporal lobes—the entorhinal cortex and the hippocampus (which are important for memory)—and amyloid deposits in the brain.

At AAIC 2014, Growdon reported that, in this study population, a smaller hippocampus and a thinner entorhinal cortex were associated with worse smell identification and worse memory. The scientists also found that, in a subgroup of study participants with elevated levels of amyloid in their brains, greater brain cell death, as indicated by a thinner entorhinal cortex, was significantly associated with worse olfactory function—after adjusting for variables including age, gender, and an estimate of the subject's cognitive reserve.

“Our research suggests that there may be a role for smell identification testing in clinically normal, older individuals who are at risk for Alzheimer's disease,” said Growdon. “For example, it may prove useful to identify proper candidates for more expensive or invasive tests. Our findings are promising but must be interpreted with caution. These results reflect a snapshot in time; research conducted over time will give us a better idea of the utility of olfactory testing for early detection of Alzheimer's.”

Odor Deficits Linked to MCI Transition. In another smell study, researchers investigated a multi-ethnic (34 percent White, 30 percent African-American, 36 percent Hispanic) sample of 1,037 non-demented elderly people in New York City, with an average age of 80.7, and assessed them in a variety of ways at three time periods—from 2004-2006, 2006-2008, and 2008-2010. UPSIT was administered in English and Spanish between 2004 and 2006. During follow-up 109 people transitioned to dementia (101=Alzheimer's); there were 270 deaths.

At AAIC, Davangere Devanand, MD reported that, in 757 subjects who were followed, lower odor identification scores on UPSIT were significantly associated with the transition to dementia and Alzheimer's disease, after controlling for demographic, cognitive, and functional measures, language of administration, and apolipoprotein E genotype. For each point lower that a person scored on the UPSIT, the risk of Alzheimer's increased by about 10 percent. Further, lower baseline UPSIT scores, but not measures of verbal memory, were significantly associated with cognitive decline in participants without baseline cognitive impairment.

“Odor identification deficits were associated with the transition to dementia and Alzheimer's disease, and with cognitive decline in cognitively intact participants, in our community sample. The test was effective in both English and Spanish,” said Dr. Devanand. “If further large-scale studies reproduce these results, a relatively inexpensive test such as odor identification might be able to identify subjects at increased risk of dementia and Alzheimer's disease at a very early stage, and may be useful in identifying people at increased risk of cognitive decline more broadly.”

Dietary Fatty Acids May Reduce ALS Risk

Consumption of foods high in ω-3 PUFAs (omega-3 fatty acids) may help prevent or delay the onset of ALS, according to a new study in JAMA Neurology. Diet was assessed via a food frequency questionnaire developed or modified for each cohort. Participants were categorized into cohort-specific quintiles of intake of energy-adjusted dietary variables.

A total of 995 ALS cases were documented during the follow-up. A greater ω-3 PUFA intake was associated with a reduced risk for ALS. The pooled, multivariable-adjusted RR for the highest to the lowest quintile was 0.66 (95 percent CI, 0.53-0.81; P < .001 for trend). Consumption of both α-linolenic acid and marine ω-3 PUFAs contributed to this inverse association. Intakes of ω-6 PUFA were not associated with ALS risk.

Longitudinal analyses were based on five prospective cohorts: the National Institutes of Health–AARP Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Health Professionals Follow-up Study, the Multiethnic Cohort Study, and the Nurses' Health Study. Foods high in omega-3 fatty acids include: flax Seeds, walnuts, sardines, salmon soybeans, and tofu.

Stroke Incidence, Mortality Down Over 20+ Years

In a multicenter cohort of black and white adults in US communities, stroke incidence and mortality rates decreased from 1987 to 2011. The decreases varied across age groups, but were similar across sex and race, showing that improvements in stroke incidence and outcome continued to 2011. The report, in the Journal of the American Medical Association, found that 1,051 participants (seven percent) had incident stroke, including 929 with incident ischemic stroke and 140 with incident hemorrhagic stroke. Stroke incidence decreased over time in white and black participants (age-adjusted incidence rate ratio per 10-year period, 0.76).

The decrease in age-adjusted incidence was evident in participants age 65 years and older but not evident in participants younger than 65 years.

“Overall, mortality after stroke decreased over time. The decrease in mortality was mostly accounted for by the decrease at younger than age 65 years, but was similar across race and sex,” the authors wrote.

Parkinson's Drug Commences Phase II

Phase II clinical studies for APL-130277 will commence immediately, according to Cynapsus Therapeutics. APL- 130277 “is an easy-to-administer, fast-acting reformula- tion of apomorphine, which is the only approved drug in the United States, Europe, Japan and other countries, to rescue patients from ‘off' episodes experienced with Parkinson's disease,” according to the company.

CTH-105 is a Phase II clinical study and will be studied with 16 patients with Parkinson's disease who are naive to the use of apomorphine and who experience at least one daily “off” episode, with a total duration of “off” in any 24-hour period of at least two hours. The first patients are expected to enter the screening phase by August. This open-label study will examine the effect of APL-130277 on relieving “off” episodes over a single day, with dose-titration used to determine dose strengths necessary for future clinical development. In particular, the dose strength information is necessary in order to conduct the larger CTH-300a efficacy study in apomorphine naive patients, which is expected to commence in Q4 2014.

CTH-300a is a double-blind, placebo-controlled, parallel- design study with Parkinson's patients who have at least one “off” episode every 24 hours, with total “off” time of at least two hours. The primary end point will be the change in the UPDRS III score.

Practical Neurology Board Member Randolph W. Evans, MD Receives Achievement Award

Randolph W. Evans, MD, received the Texas Neurological Society Lifetime Achievement Award for 2014. Dr. Evans is board certified in Neurology and subspecialty certified in Headache Medicine and a fellow of the American Academy of Neurology, the American Headache Society, and the Texas Neurological Society. He is on the staff of Park Plaza Hospital, Houston Methodist Hospital, and St. Luke's Medical Center.

The TNS Lifetime Achievement Award is a peer-recognition award honoring members in the state for out- standing service to patients and the profession. There are many neurologists in the state of Texas who have played enormous roles in the development of the practice of Neurology.

This award will continue throughout the years to honor those physicians who have had great vision and have worked selflessly to advance our specialty on behalf of our patients and our colleagues, TNS says.

Pipeline Update: New MS Drug Enters Phase I

A Phase I clinical study of ALKS 8700, a novel monomethyl fumarate (MMF) molecule in development for the treatment of multiple sclerosis, is underway. The randomized, double-blind study will evaluate the safety, tolerability and pharmacokinetics of several oral formulations of ALKS 8700 compared to both placebo and active control groups in approximately 125 healthy volunteers. ALKS 8700 is designed to rapidly and efficiently convert to MMF in the body and offer differentiated features as compared to the currently marketed dimethyl fumarate, Tecfidera.

The Phase I study by Alkermes, announced July 17, will investigate the pharmacokinetics and pharmacodynamics of multiple formulations and doses of ALKS 8700, and is designed to determine those suitable to progress into advanced clinical testing.

Clarificaton: In the June 2014 edition of Practical Neurology®, in the story, “Non-invasive Tool Monitors Cerebral Blood Flow in Real Time,” comments were misattributed. The interview was conducted with Israel Schreiber, Chief Executive Officer of Ornim Medical.