Alzheimer's by Phase

ALZHEIMER'S BY PHASE

NDA

• The FDA has accepted for review Eisai's NDA for once daily 23 mg Aricept for the treatment of moderate-to-severe Alzheimer's. The higher dose formulation is in an extended release delivery system. The NDA is based on a study comparing the 23 mg Aricept extended release tablet to the currently marketed once daily 10 mg Aricept immediate release tablet. More than 1400 subjects with moderate-to-severe Alzheimer's disease were enrolled in this global study. Eisai and Pfizer copromote Aricept in the United States, Japan, and key European markets. The Clinicaltrials.gov identifier for this trial is NCT00478205.

Phase III

• Early last month, Pfizer and Medivation announced that the investigational drug dimebon (latrepirdine) for Alzheimer's disease did not meet co-primary or secondary efficacy endpoints compared to placebo. The co-primary endpoints were measures of cognition and global function. The Phase III CONNECTION study comprised 598 subjects with mild-to-moderate Alzheimer's at 63 sites in North America, Europe, and South America, of which more than 40% were enrolled in the United States. A separate tolerability study had positive results. The companies will be reviewing the data to determine next steps. The Clinicaltrials.gov identifiers are NCT00675623 and NCT00838110 respectively.

• Bayer HealthCare Pharmaceuticals late last year, enrolled the first patient in an international Phase III clinical trial to evaluate the efficacy and safety of florbetaben (BAY 94-9172) PET imaging in the detection of beta-Amyloid plaques in the brain, a pathological hallmark of Alzheimer's disease. The Phase III trial is an open-label, multicenter, nonrandomized single dose study enrolling 400 subjects with and without dementia. The Clinicaltrials.gov identifier is NCT01020838.

• Semagacestat, Lilly's gamma secretase inhibitor, is currently being studied in two large multinational pivotal Phase III trials—IDENTITY and IDENTITY-2—to assess its effect on the progression of Alzheimer's disease. Enrollment in the IDENTITY trial was completed in the third quarter of 2009 and includes over 1500 subjects in 20 countries. Enrollment in IDENTITY-2 is targeted at 1100 subjects and is expected to be completed in the first half of 2010. The study is planned to be completed in March 2012. The Clinicaltrials.gov identifiers are NCT01035138 and NCT00762411 respectively.

• Also in development for Lilly is its A-beta antibody solanezumab, a monoclonal antibody that may slow the progression of Alzheimer's disease. Enrollment began in May 2009 in two multinational Phase III registration studies—EXPEDITION and EXPEDITION 2. Each study will enroll 1000 subjects for an 18-month treatment duration. The Clinicaltrials.gov identifiers are NCT00905372 and NCT00904683 respectively.

Phase II

• AFFiRiS AG's Alzheimer's vaccine candidate AFFITOPE AD02 is planned to enter Phase II clinical trials early in 2010. The company based its decision on the first interim analysis of the secondary endpoints at the six-month time point. Based on this analysis, the AD02 patients from the completed Phase I study will be offered an AD02 booster vaccination. The Clinicaltrials.gov identifier is NCT00711321.

• This month, EnVivo Pharmaceuticals plans to begin enrollment of 300 subjects for its adaptive designed Phase II randomized, double-blind, placebo-controlled study of EVP-6124. This alpha-7 nicotinic acetylcholine receptor showed improvement in cognition, as well as good tolerability and safety. INC Research is listed as a study collaborator, which has a Clinicaltrials.gov identifier of NCT01073228.

Business News

• On the heals of Pfizer's acquisition of Wyeth, which included Wyeth's Alzheimer's drug in Phase I/II development with Elan Pharmaceuticals, Eisai and Pfizer restructured their copromotion agreement of Aricept. In that agreement, Pfizer will continue to exclusively sell with Eisai Aricept in all countries it currently sells until July 2022. At that point, it will give Aricept rights to Eisai in Japan only.

• Anavex Life Sciences Corp. selected Forenap Pharma as its CRO for Phase I clinical trials of ANAVEX 2-73, the company's lead Alzheimer's drug candidate. Forenap will perform study set-up, protocol review, site monitoring, and project management for the trials. All work will be performed under individual work orders that fall under a master services agreement executed by Forenap and Anavex, including pre-clinical, pharmaceutical, and clinical development of ANAVEX 2-73.

ALZHEIMER'S: TARGET UNMET NEEDS

Challenges in the development of drugs for Alzheimer's disease are evident in the latest clinical trial results released by Medivation and Pfizer on their investigational drug dimebon, which failed to prove efficacy in the Phase III trial. The co-primary endpoints were improvements to cognition and memory, as well as global function for subjects with mild-to-moderate Alzheimer's.

While Medivation and Pfizer are evaluating the data to determine their next steps, the Alzheimer's community was disappointed with the results. Said Alzheimer's Association Chief Medical and Scientific Officer William Thies, PhD, in a statement, "People with Alzheimer's, their families, and caregivers desperately need more and better treatment options for this devastating, fatal brain disease."

Meds in Development: Alzheimers Disease

Recent reports from the association show that African-Americans are two times more likely than Whites to have Alzheimer's and other dementias, and Hispanics are one and one-half more times more likely. While there is no definitive genetic reason for this difference among ethnic populations, researchers believe that risk factors for Alzheimer's are more prevalent in these populations. Those risk factors are socioeconomic, including lower levels of education and income, as well as a higher prevalence of high blood pressure and diabetes.

Other data available on the disease from the association includes:

• 5.3 million Americans are diagnosed with Alzheimer's.

• In 2006, it was the seventh leading cause of death.

• Total payments for health and long-term care services for Alzheimer's patients will total $172 billion in 2010.

Biomarkers importance

While dimebon has taken a major setback in its pursuit to approval, other drugs on the market are still viable and making headway. As noted on the previous page, Aricept 23 mg was accepted into review to be approved as an extended release tablet for moderate-to-severe Alzheimer's. Namenda, Forest Laboratories' approved therapy for the treatment of moderate-to-severe Alzheimer's, represented 34.2% of the total prescriptions as of March 2009. It is anticipated to go off-patent in April 2015.

While treatments for later stage Alzheimer's are important, therapies in development target the neurogenerative aspect of Alzheimer's, which requires identification before patients exhibit even mild cognitive symptoms. As Charles Albright, PhD, Group Director at BMS, pointed out in a session on biomarkers at the 22nd Annual DIA EuroMeeting in March, it is important that Alzheimer's be detected in the predementia stage. When Alzheimer's is detected, brain atrophy has already begun and the prognosis is about nine years to death.

To achieve predementia diagnosis, advanced biomarkers are needed. The potential biomarkers Albright discussed were neuroimaging (MRI structural: volumetric MRI and Amyloid PET); blood (ApoE4 and others in development); and cerebrospinal fluid (CSF) analytes (Amyloid beta 42). However, each currently have limitations. "MRI is not specific to Alzheimer's yet. Amyloid PET is used to detect plaques, however, the access to ligands is limited and costly," said Albright. "That should resolve in a few years."

As for the ApoE4 blood biomarker, it is simple and ApoE4 carriers do progress more rapidly from pre- to prodromal Alzheimer's, however, it also is not specific. Albright noted that 30% to 50% of predementia Alzheimer's patients are non-ApoE4 carriers and 10% to 30% of the ApoE4 carriers have normal CSF biomarkers, making them slow progressors.

Albright outlined BMS' Phase II clinical trial in predementia Alzheimer's subjects for BMS-708163, a y-secretase inhibitor, and how it identified subjects. Cognitive and caregiver scores were used, as well as an MRI, but it also incorporated a CSF profile. The challenge? The current CSF Assays are "research use only" and therefore not GCMP compliant.

"There is a significant amount of work to get an assay validated," noted Albright. And many groups are working toward this. It is clear that biomarkers are key to the future of Alzheimer's treatment and drug development.