Med Check

Regulatory Briefs

• The Food and Drug Administration (FDA) Division of Drug Marketing, Advertising, and Communications (DDMAC) sent a warning letter to Takeda Pharmaceuticals concerning “false and misleading” promotional materials for the sleep medicine ramelteon. The January 28 letter stated that a sell sheet for the drug made unsubstantiated claims for its superiority, omitted and minimized risks, and made a misleading claim. The sell sheet, a promotional brochure, claims that ramelteon has no abuse potential and implies that the drug has no toxicity compared with other sleep medications, which the FDA considers unsubstantiated and misleading.

The FDA warning letter to Takeda is posted at <www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM205265.pdf>.

• Eisai Medical Research Inc. was issued a warning letter on February 3 from the FDA's DDMAC for misleading TV advertisements for donepezil. The advertisements, according to the FDA, overstated the drug's efficacy by depicting dramatic changes in simulated patients' behaviors before and after taking the Alzheimer's drug and implying that patients' functioning and cognition can return to normal with the medication. Such claims are unsubstantiated by clinical-trial results and are thus considered misleading. The company was asked to cease distributing the advertisement.

The FDA warning letter to Eisai is posted at <www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM201238.pdf>.

• During a March 15 meeting, experts on the FDA's Neurological Devices Advisory Committee were divided over whether Medtronic's deep brain stimulation device should be approved for treating severe epilepsy. The device was previously approved for treating Parkinson's disease and for compassionate use in patients with severe obsessive-compulsive disorder. In a randomized, double-blind clinical trial conducted with patients refractory to multiple antiepileptic drugs, the deep brain stimulation failed to show significant efficacy over sham stimulation in which the device was implanted but not turned on. The panel voted 7-5 to approve the device, which leaves the FDA with no clear recommendation for the device's approval or rejection.

• The FDA granted fast-track review status to a treatment intended for autism, according to an announcement by Cure-mark LLC in February. The treatment, known as CM-AT, is an undisclosed proprietary formulation of enzymes developed by the company and is being tested in phase 3 clinical trials.

• The Physician Payments Sunshine Act of 2009 was signed into law on March 23 as a part of the sweeping health care reform legislation. It requires all U.S. manufacturers of drugs, devices, biologics, and medical supplies to report payments to physicians and teaching hospitals that exceed $100 annually to the Department of Health and Human Services (HHS). Effective January 1, 2012, all manufacturers are required to begin recording the physician's name, address, and national provider identifier; the amount of payments; and the purpose of the payment. These data will be transferred to HHS annually, and HHS will then post the data on a public Web site.

Certain categories are exempt from this reporting requirement, including educational materials given to benefit patients, rebates and discounts, and dividend or investment interest paid through a publicly traded stock or mutual fund. However, physician ownership or investment interest in manufacturers and group-purchasing organizations is required to be disclosed. Physicians who are employees of a company are also exempt. Companies can delay reporting the names of physicians who are paid to conduct clinical trials on developing new drugs or products for four years or until the product is approved for marketing, whichever comes first.

The text of this law is posted at <www.prescriptionproject.org/tools/sunshine_docs/files/Sunshine_Leg_Language.pdf>.

Industry Briefs

• A long-acting formulation of buprenorphine is being tested in a randomized, controlled, phase 3 clinical trial, its developer, Titan Pharmaceuticals, announced on March 30. This formulation, known as Probuphine, is a subcutaneous injection that purportedly delivers a continuous, therapeutic level of buprenorphine for six months with one administration. In this phase 3 trial, two groups of patients are being given the long-acting buprenorphine product or placebo in a double-blind manner and followed for 24 weeks. In addition, a second comparison group will receive Suboxone sublingual tablets in an open-label fashion for the same duration.

• The FDA approved low-dose formulations of the tricyclic antidepressant doxepin, at 3 mg and 6 mg, for treatment of transient or chronic insomnia due to sleep-maintenance difficulty, according to a March 18 announcement by Somaxon Pharmaceuticals. The effect of doxepin on sleep maintenance is believed to be derived from its antagonism of the histamine-H₁ receptor. Unlike other insomnia medications, doxepin is not a controlled substance.

• A drug candidate in late-stage clinical development for treating Alzheimer's disease failed two phase 3 trials, Pfizer and Medivation Inc. announced March 3. In the randomized, double-blind, placebo-controlled clinical trials, dimebon (also known as latrepirdine) did not meet the primary or secondary endpoints in nearly 600 patients with mild to moderate Alzheimer's after six months of treatment. Outcome endpoints included cognitive function, measured by the Alzheimer's Assessment Scale–cognition subscale (ADAS-cog); global functioning, based on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus); and activities of daily living, measured by the Alzheimer's Cooperative Study Activities of Daily Living Scale (ADCS-ADL). Dimebon was tested in two dosages, 5 mg or 20 mg three times daily, but neither dosage showed significant difference from placebo.

These results are a major disappointment for the two companies that are co-developing the drug, which showed some promise in phase 2 trials. Four other phase 3 clinical trials are still ongoing.

• Several phase 3 clinical trials will be conducted to test the efficacy and tolerability of two antidepressant candidate drugs being jointly developed by Lundbeck and Takeda, the two companies announced on March 3. Of the two investigational drugs, Lu AA21004 is an antagonist of the serotonin 5-HT₃, 5-HT₇, and 5HT_1B receptors and an agonist of the 5-HT_1A receptor. It also inhibits serotonin reuptake. Lu AA24530 inhibits the reuptake of multiple monoamines and inhibits the 5HT₃ and 5-HT_2C receptors.

Lu AA21004 is currently in phase 3 development for treating moderate to severe depression, and data have shown “encouraging results,” according to the companies' announcement. Lu AA24530 has passed phase 2 development and been deemed favorable for phase 3 trials, which are scheduled to begin this year.

• In January and March, Allon Therapeutics released promising results from clinical trials of its investigational drug davunetide, which is being studied for treatment of schizophrenia, amnestic mild cognitive impairment, and frontotemporal dementia. A phase 2a trial suggested that treatment with davunetide was associated with significantly increased levels of N-acetyl aspartate in the dorsolateral prefrontal cortex, a biomarker whose level is decreased in patients with schizophrenia and patients with brain injuries and dementia. A phase 1 trial validated the tolerability and pharmacokinetics of an intranasal formulation of the drug.

Davunetide, a molecule derived from an endogenous protein called activity-dependent neuroprotective protein, may improve cognitive function in a range of neurodegenerative diseases. The drug has already received orphan-drug designation from both the FDA and European regulatory authority for treatment of progressive supranuclear palsy, a neurodegenerative brain disease.

• AstraZeneca, the maker of quetiapine, will discontinue its research programs in schizophrenia, bipolar disorder, and depression as part of its corporate restructuring, according to a March 2 report by Reuters. Other diseases, including acid-reflux disease and thrombosis, will also be cut from its research portfolio as the company plans to eliminate 1,800 global research staff.