Product

Xenazine


Approval Date

8/15/08

 

Release Date

Fourthquarter 08

 

Company

Ovation

 

Class

Centrallyacting dopamine-depleting drug

 

Indication

Treatmentof chorea associated with Huntington’s disease.

 

Active Ingredient

Tetrabenazine12.5mg; 25mg+ (+scored); tabs.

 

Agency Roster

S&R Communications Group

 

Marketing Strategy/Execution

Prestwick Pharmaceuticals, which owns the North Americancommercial rights to Xenazine, is seeding the market in preparation for theorphan drug’s USlaunch, which is expected by year end. The firm has a head start in reachingthe estimated 30,000 Americans with Huntington’s disease (HD); it sponsored acontrolled trial of 54 HD patients in 2006. To sign up additional patients, Prestwick’s sales force is expected to target neurologistsand CNS specialists. It also continues to work with the patient and advocacycommunity, which played a significant role in getting the FDA to act onXenazine. The Hereditary Disease Foundation, Huntington’s Disease Society of Americaand the National Organization for Rare Disorders provide Xenazine informationon their websites. Xenazine is already available in several European countries,including the UK, Germany, Franceand Italy. Ovation Pharmaceuticals has acquired the US marketing rights to the drug fromPrestwick.

 

Also in the Pipeline(courtesy of Adis R&D Insight)

No competitors in the USat Phase III/PreReg, but editorial identified the compounds below that are inphase II development for Huntington’s disease in the US but appear set toenter phase III trials in the near future. 

 

ACR 16 is a dopamine stabilizer in phase IIdevelopment with NeuroSearch in the US for Huntington’s disease. Aphase III trial is underway in Europe. Thisagent is both a dopamine D2 receptor antagonist and a dopamine receptoragonist.

 

Creatine monohydrate is a mitochondrial functionenhancer in phase II development with Avicena Group in the US for the treatment ofHuntington’s disease. Avicena has met with the US FDA to discuss a phase IIItrial and intends to submit a Special Protocol Assessment (SPA) to expedite thereview process.

 

Recent MM&M Coverage

TheTop 60: S&R Communications Group

S&RCommunications Group

 

Pharmacology

Huntington’s disease is a progressive neurodegenerativedisorder characterized by chorea (involuntary movements), rigidity, and changesin mood, cognition, and functional capacity over time.

Tetrabenazine is a reversible depletor of monoamines (eg, dopamine,serotonin, norepinephrine) from nerve terminals. It works by inhibiting theactivity of human vesicular monoamine transporter type 2, reducing the uptakeof these neurotransmitters into synaptic vesicles and depleting monoaminestores. It has been shown to improve chorea associated with Huntington’sdisease, but it may worsen the emotional and mood aspects, particularlydepression.

Tetrabenazine is metabolized by the liver into two majormetabolites which also have activity as monoamine depletors.

 

Clinical Trials

A randomized, double-blind, placebo-controlled trial wasconducted in 84 ambulatory patients with Huntington’s chorea. The trialincluded a 7-week dose titration period followed by a 5-week maintenance periodand a 1-week washout period. The primary endpoint was the Total Chorea Score,which rates the chorea on a scale from 0 to 4 in seven different parts of thebody. Total scores range from 0 to 28. During maintenance therapy, the TotalChorea Scores in the drug treatment group declined by about 5 units compared to1.5 units in the placebo group, a significant effect. One week afterdiscontinuing the study medication, the Total Chorea Scores returned tobaseline. Patients given tetrabenazine were more likely to experience animprovement in chorea scores. A Physician-rated Global Impression favoredtetrabenazine statistically. In general, measures of functional capacity andcognition showed no difference between tetrabenazine and placebo.

 

Adverse reactions

Sedation, fatigue, insomnia, depression, dysphagia,akathisia, nausea, parkinsonism, QTc prolongation, orthostatic hypotension,elevated serum prolactin; rarely: neuroleptic malignant syndrome, tardivedyskinesia, extrapyramidal effects.

 

Adults

Individualize. Initially 12.5mg once daily in the AM, then12.5mg twice daily after one week. Titrate slowly at weekly intervals by12.5mg. Doses of 37.5–50mg/day should be given in a 3 times/day regimen, max25mg/dose. Do not exceed 50mg/day before genotyping for CYP2D6 activity; seeliterature. Poor metabolizers (CYP2D6): max 25mg/dose and 50mg/day; extensivemetabolizers: max 37.5mg/dose and 100mg/day. Concomitant strong CYP2D6inhibitors (eg, paroxetine, fluoxetine, quinidine): reduce tetrabenazine doseby 1/2; moderate to weak CYP2D6 inhibitors: not evaluated. Retitrate if therapyinterrupted for more than 5 days.

 

Children

Not recommended.

 

Contraindications

Depression. Suicidal ideation. Hepatic impairment.Concomitant monoamine oxidase inhibitors (MAOIs). During or within 20 days ofstopping reserpine.

 

Precautions

Avoid in congenital long QT syndrome or history of cardiacarrhythmias. Bradycardia. Hypokalemia. Hypomagnesemia. Recent MI. Unstableheart disease. Cardiovascular disease. History of depression, suicidalideation, or breast cancer. Monitor for depression, emotional lability,akathisia. Poor metabolizers (CYP2D6). Reevaluate periodically. Pregnancy(Cat.C). Nursing mothers: not recommended.

 

Interactions

See Contraindications. Avoid other drugs that can cause QTprolongation (eg, chlorpromazine, thioridazine, ziprasidone, moxifloxacin,quinidine, procainamide, amiodarone, sotalol). Potentiated by CYP2D6 inhibitors(eg, paroxetine, fluoxetine). Increased risk of neuroleptic malignant syndrome,extrapyramidal syndrome with neuroleptics, dopamine antagonists. Additive CNSdepression with alcohol, other CNS depressants.