The Takeda and Lundbeck pharmaceutical companies announced October 1, 2012, that they had submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the investigational agent Brintellix (vortioxetine, also identified as Lu AA21004) for treatment of major depressive disorder (MDD) in adults. Brintellix is thought to work through a combination of two complementary mechanisms of action: receptor activity modulation and reuptake inhibition.

The NDA includes data from six short-term placebo-controlled studies, including one dedicated study in elderly patients. The studies were conducted in regions throughout the world and showed statistically significant efficacy of vortioxetine in a daily dosage range of 5 mg to 20 mg. The efficacy of vortioxetine was also demonstrated in a long-term relapse-prevention study in MDD, and the vortioxetine global clinical development program included more than 7,500 individuals who took the drug.

The most commonly observed adverse reactions in the studies were nausea, constipation, and vomiting. Overall, 6.5 percent of the patients who received vortioxetine discontinued treatment due to an adverse reaction, compared with 3.8 percent of placebo-treated patients.

The review of the NDA is expected to be completed by October.

Merck announced December 3, 2012, that it has started a phase 2/3 clinical trial to evaluate safety and efficacy of MK-8931 versus placebo in patients with mild to moderate Alzheimer’s disease. MK-8931 is Merck’s novel investigational oral β-amyloid precursor protein site-cleaving enzyme (BACE) inhibitor, and it is the first with this mechanism to advance to this stage of clinical research. The amyloid hypothesis asserts that the formation of amyloid peptides that lead to amyloid plaque deposits in the brain is the underlying cause of Alzheimer’s disease, and BACE is believed to be a key enzyme in the production of amyloid β peptide. Evidence suggests that inhibiting BACE decreases the production of amyloid β peptide and may therefore reduce amyloid plaque formation and modify disease progression.

A global, multicenter randomized placebo-controlled study, called EPOCH, will be used to initially evaluate the safety of MK-8931 in a cohort of 200 patients prior to advancing into a larger phase 3 study. The study is expected to enroll up to 1,700 patients in the main phase 3 cohort. The primary efficacy outcomes of the study are the change from baseline in Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) score and the change from baseline in the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score.

Eli Lilly announced December 12, 2012, that it plans to conduct an additional phase 3 study of solanezumab, the monoclonal antibody being studied as a potential therapy for patients with mild Alzheimer’s disease. Additional details, including study design and length, are still being determined.

Solanezumab is a monoclonal antibody that binds to soluble monomeric forms of β-amyloid after it is produced, allowing it to be cleared before it clumps together to form β-amyloid plaques. Last August, Lilly announced that its clinical trials in more than 2,000 people showed that the drug was unable to halt the disease’s progress on measures of cognition and functionality (Psychiatric News, December 7, 2012). But Lilly did note evidence of “statistically significant slowing of cognitive decline in subjects with mild to moderate Alzheimer’s who were taking the drug.”

Eric Siemers, M.D., senior medical director of Lilly’s Alzheimer’s disease team, said in a press release, “We believe the results demonstrating a slowing of cognitive decline in patients with mild Alzheimer’s disease treated with solanezumab are the first data from phase 3 clinical trials that support the amyloid hypothesis.”

Lilly expects to initiate this new study no later than the third quarter of 2013.

When the FDA first expressed concerns about the possible increased risk of cardiovascular adverse events associated with the smoking-cessation drug Chantix (varenicline) in a Drug Safety Communication (DSC) dated June 16, 2011, the agency said it would require Pfizer, the drug’s manufacturer, to conduct a meta-analysis of randomized, placebo-controlled trials of the drug. In a DSC issued December 12, 2012, the FDA presented that meta-analysis. Results indicated a higher occurrence of major adverse cardiovascular events (a combined outcome of cardiovascular-related death, nonfatal heart attack, and nonfatal stroke) observed in patients using Chantix compared with those on placebo. However, these events were uncommon in both the Chantix and placebo groups, and the increased risk was not statistically significant, which means it is uncertain whether the excess risk for the Chantix group was due to the drug or due to chance.

The FDA advised health care professionals to weigh the risks of Chantix against its benefits, while noting that smoking is a major risk factor for cardiovascular disease and that Chantix is effective in helping patients quit smoking and abstain from it for as long as one year. “The health benefits of quitting smoking are immediate and substantial,” the agency emphasized in the communication. The Warnings and Precautions section of the Chantix label has been updated to include the results of the meta-analysis.

The DSC is posted at http://www.fda.gov/Drugs/DrugSafety/ucm330367.htm.

The FDA’s Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) met December 7, 2012, to discuss the NDA submitted by Zogenix for Zohydro (hydrocodone bitartrate extended-release capsules), an opioid analgesic medication for management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period. Zohydro, which does not include other active pharmaceutical ingredients such as acetaminophen or ibuprofen, would represent the first single-entity hydrocodone-containing drug product on the market, if approved.

The committee voted 2-11 (with 1 abstention) against the approval of Zohydro, with committee members expressing concern about abuse potential and dependency.

“Zogenix recognizes and appreciates that prescription opioid misuse and abuse is a critical issue,” said Stephen Farr, Ph.D., president and CEO of Zogenix. “We remain confident in the measures we have proposed to support safe use of Zohydro ER and are committed to continuing to work with the FDA through the review process.”

The date for completion of FDA review of the application is March 1. The AADPAC provides the FDA with independent expert advice and recommendations, but the final decision about approval of a medication is made by the FDA. If approved, Zohydro will be classified by the Drug Enforcement Administration as a Schedule II drug, and the Risk Evaluation and Mitigation Strategy (REMS) for Zohydro ER will be consistent with the recently introduced FDA-approved REMS for extended-release and long-acting opioids. ■