Genomics News and Upcoming Events

Upcoming Events

• American Society for Clinical Pharmacology and Therapeutics (ASCPT) 2012 Annual Meeting, Washington, DC.
  March 14-17, 2012.  Information and Registration
   

News 

• Breakthrough therapy targeting mutation in the CFTR gene: FDA approves KalydecoTM (ivacaftor) tablets to treat rare form of cystic fibrosis  

On January 31, 2012, FDA approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. Kalydeco is an excellent example of the promise of personalized medicine.

Kalydeco is the first available treatment that targets the defective CFTR protein and improves its function, and as a result, improves lung function and other aspects of CF such as increasing weight gain. Kalydeco is not effective in CF patients with two copies of the F508del mutation in the CFTR gene, which is the most common mutation that results in CF.

Kalydeco is to be administered with fat-containing food at a dose of 150 mg twice-daily (every 12 hours). Selection of 150 mg twice-daily dose was supported by exposure-response analysis for efficacy endpoint.

Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of Kalydeco in CF patients with the G551D mutation. In both studies, treatment with Kalydeco resulted in significant improvement in lung function.
 

• Pharmacogenetic changes to the FDA-approved Platinol® (cisplatin) label include safety update pertaining to the association of variants in the thiopurine S-methyltransferase (TPMT) gene and cisplatin-induced hearing loss in children

FDA updated the Platinol® (cisplatin) product label on December 29, 2011, to include new safety information pertaining to the association of variants in the thiopurine S-methyltransferase (TPMT) gene and an increased risk of cisplatin-induced ototoxicity in children. Cisplatin was originally approved as Platinol® by FDA in 1978 and is currently indicated for the treatment of metastatic testicular tumors, metastatic ovarian tumors, and advanced bladder cancer.

A retrospective study (Ross, C.J., Katzov-Eckert H., et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving Cisplatin chemotherapy. Nat. Genet. 2009;41:1345-1349.) involving an initial cohort and a replicative cohort totaling 162 children who received conventional doses of cisplatin, revealed an association between variants in the TPMT gene (e.g., TPMT*3B and TPMT*3C) and an increased risk of cisplatin-induced hearing loss (Odds Ratio of 17.0 [95% CI 2.3-125.9]). Patients were administered a median cumulative cisplatin dose of 400 mg/m2 for a median treatment duration of 4-5 weeks.

Although only 26 of the 162 patients (16%) had one or more TPMT gene variants, 25 of the 26 (96%) developed severe ototoxicity. For Caucasians and African Americans, approximately 11% of the population inherit one or more of these TPMT variants. Children who do not have one of these TPMT gene variants remain at risk for ototoxicity. Other genetic factors may also contribute to cisplatin-induced ototoxicity.

The updated label is expected to inform healthcare providers about the association between genetic factors and cisplatin-induced ototoxicity in children and to stress the importance of monitoring and management strategies for hearing loss.
 

• Pharmacogenetic changes to the FDA-approved Orap (pimozide) label include adult and pediatric dosing recommendations for CYP2D6 poor metabolizers

FDA has updated the Orap (pimozide) labeling on September 27, 2011, to include dosing recommendation information in CYP2D6 poor metabolizers. The genotype-informed dosing strategy is intended to minimize the QT prolongation risk associated with excessive pimozide exposures. The label for pimozide also now recommends that CYP2D6 genotyping should be performed if patients require doses above 4 mg/day in adults or 0.05 mg/kg/day in children. For patients who are CYP2D6 poor metabolizers, in addition to the above 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. Pimozide is currently available as both 1 and 2 mg tablets.

Orap (pimozide) was approved by 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 is a narrow therapeutic index drug, with increased exposure resulting in QT-prolongation and risk of arrhythmia.

In 2005, evidence from drug-drug interaction studies conducted with sertraline and paroxetine found that concomitant administration of these CYP2D6 inhibitors with pimozide increased exposure 1.4- and 2.5-fold, respectively. 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.

FDA subsequently in 2011 performed pharmacokinetic modeling of multi-dose pimozide pharmacokinetics to determine what the "not-to-exceed" dose of pimozide should be in adults and children who are CYP2D6 poor metabolizers. The review identified 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, respectively.
 

• Targeted therapies for 'ALK-positive' lung cancer and for 'BRAFV600E' positive melanoma were recently approved with an accompanying approved FDA test

Two kinase inhibitors targeting specific molecular alterations in tumors were approved in August 2011.

Crizotinib (Xalkori) was approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Vemurafenib (Zelboraf) was approved for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. 
 

• IL28B information in recently approved antiviral HCV drugs, boceprevir and telaprevir

In May, 2011, FDA approved boceprevir (Victrelis) and telaprevir (Incivek) for the treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy. 

A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, C to T change) is a strong predictor of response to peginterferon alfa and ribavirin (PR). Retrospective analysis of the data from treatment-naïve patients with genotype information in either of the combination therapies (boceprevir /PR or telaprevir/PR), showed that the response rates tended to be higher in the C/C patients than in patients with C/T or T/T genotypes. Among previous treatment failures, subjects of all IL28B genotypes had higher SVR (sustained virologic response) rates with either boceprevir- or telaprevir-containing regimens. 

This retrospective subgroup analysis should be viewed with caution because of the small sample size and potential differences in demographic or clinical characteristics of the substudy population relative to the overall trial population.