Med Check

On December 13, EnVivo Pharmaceuticals announced that data published online November 10, 2011, in Neuropharmacology confirmed the mechanism of action of EVP-6124, a potent and highly selective agonist of alpha-7 neuronal nicotinic acetylcholine receptors in the brain, and that treatment with EVP-6124 (both alone and in combination with donepezil) restored memory loss and improved memory function in preclinical models. EnVivo said these findings support their clinical development strategy for EVP-6124 as a long-term treatment to restore and improve cognitive function with sustained effect in schizophrenia and Alzheimer’s disease.

A South Carolina judge upheld a $327 million civil penalty against Johnson & Johnson, which in March 2011, was found guilty by a jury of overstating the safety and effectiveness of its antipsychotic drug, Risperdal (risperidone). The jury decided that a Johnson & Johnson unit violated consumer protection laws by sending doctors a misleading letter in 2003 about the safety and effectiveness of Risperdal. The jurors also determined that the warning-label information was deceptive. Jurors found that the company’s Ortho-McNeil-Janssen Pharmaceuticals unit engaged in “unfair and deceptive acts” by claiming in the letter that Risperdal was better than competing drugs.

The letter was sent to some 700,000 doctors nationwide, including 7,200 in South Carolina. The Food and Drug Administration (FDA) issued the company a warning letter about false and misleading claims that minimized risks such as diabetes and overstated the drug’s benefits. South Carolina’s unfair trade practices law allows a judge to decide whether the company can be fined as much as $5,000 for each Risperdal letter sent to South Carolina doctors.

On December 20, AstraZeneca and Targacept announced results from the second of four RENAISSANCE phase three studies investigating the efficacy and tolerability of TC-5214 as an adjunct therapy to an antidepressant in patients with major depressive disorder (MDD) who do not respond adequately to initial antidepressant treatment. The study, RENAISSANCE 2, did not meet its primary endpoint, change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score after eight weeks of adjunct treatment with TC-5214 as compared to placebo.

These results follow the recent announcement of results from RENAISSANCE study 3, which also did not meet its primary endpoint. Both RENAISSANCE 2 and RENAISSANCE 3 were flexible-dose trials. The two remaining efficacy studies in the RENAISSANCE program for TC-5214 are fixed-dose trials. Results for both fixed-dose trials, as well as for a long-term study designed primarily to evaluate safety, are expected to be available in the first half of 2012.

Regulatory filing targets will be reviewed following results of the remaining RENAISSANCE program studies. A potential New Drug Application filing in the United States is planned for the second half of 2012, with a potential EU Marketing Authorization Application filing targeted for 2015.

Health Canada announced December 16, 2011, that is has approved Abilify (aripiprazole) for the treatment of schizophrenia in teenagers aged 15 to 17. Abilify is licensed to Bristol-Myers Squibb Canada, a subsidiary of Bristol-Myers Squibb Co. Abilify is the only medication in Canada approved to treat schizophrenia in adolescents; it was first approved in 2009 for the treatment of schizophrenia and bipolar disorder in adults. The approval was based on the results of a six-week, double-blind randomized, placebo-controlled trial that determined Abilify treatment is generally safe and well tolerated. Abilify is also indicated for treatment of manic or mixed episodes in bipolar I disorder in adults as acute monotherapy or co-therapy with lithium or divalproex sodium when there is an insufficient acute response to these agents alone. Abilify as co-therapy with lithium or divalproex sodium has been shown to be more effective than placebo plus mood stabilizer in maintaining clinical improvement for up to one year in adult patients with manic or mixed episodes associated with bipolar I disorder.

The Psychopharmacologic Drugs Advisory Committee (PDAC) of the FDA voted narrowly (9-8) with one abstention) on December 12, 2011, to recommend that the FDA approve Alexza Pharmaceuticals’ application for Adasuve (staccato loxapine) as a fast-acting treatment for agitation among patients with schizophrenia and bipolar disorder, when given as a single dose in 24 hours and used with the FDA-recommended Risk Evaluation and Mitigation Strategy. The PDAC convened at the request of the FDA, which had expressed concerns that the drug can cause bronchial spasms that may be fatal in people with conditions such as asthma or chronic obstructive pulmonary disorder.

The FDA updated on September 27, 2011, the labeling for the antipsychotic drug Orap (pimozide), to include dosing recommendation information for patients who are poor metabolizers of the enzyme CYP2D6. Orap was approved by the FDA in 1984 for the suppression of motor and phonic tics in patients with Tourette’s disorder who have failed to respond satisfactorily to standard treatment. Pimozide has a narrow therapeutic index, and increased exposure may result in QT-prolongation and risk of arrhythmia.

In 2005, studies conducted with sertraline and paroxetine found that concomitant administration of these CYP2D6 inhibitors with pimozide increased exposure to pimozide. Administration of either drug with pimozide was consequently contraindicated. A subsequent single-dose pharmacogenomic study found that CYP2D6 poor metabolizers had similar increases in exposure to pimozide as subjects taking paroxetine. Further pharmacokinetic studies determined that CYP2D6 poor metabolizers should not receive doses higher than 4 mg daily (adults) or 0.05 mg/kg daily (children) compared with 10 mg daily and 0.2 mg/kg daily for adults and children who are extensive or intermediate metabolizers.

The label for pimozide also now recommends that CYP2D6 genotyping should be performed if patients require doses above 4 mg per day in adults or 0.05 mg/kg per day in children. For patients who are CYP2D6 poor metabolizers, in addition to the maximum doses, dose increases should not occur earlier than 14 days after the last increase in dose because of the longer time to steady-state in these individuals. This genotype-informed dosing strategy is intended to minimize the QT prolongation risk associated with excessive pimozide exposure. Pimozide is currently available as both 1 and 2 mg tablets.

Full prescribing information is posted at www.accessdata.fda.gov/drugsatfda_docs/label/2011/017473s046lbl.pdf.