FDA’s Cardio-Renal Division Kicks Off August With Three Approvals

The Medicines Co.’s IV therapy Cleviprex plus Novartis’ drug-drug combos, Exforge and Diovan HCT, are approved.

In a flurry of activity, FDA's Cardio-Renal division beat back the dog days of summer, approving one new chemical entity and two combination pills for reducing blood pressure.

The Medicine Company's Cleviprex was one of a few languishing drugs with missed user fee dates in the division, including antiarrhythmics vernakalant (Cardiome/Astellas' Kynapid ) and tedisamil (Solvay's Pulzium ) (¹ (Also see "For Amgen’s Nplate, No News Is Good News" - Pink Sheet, 23 Jul, 2008.)).

The third-generation intravenous new chemical entity was approved Aug. 1 for the reduction of blood pressure when the use of oral therapy is not feasible or desirable.

TMC is positioning Cleviprex (clevidipine butyrate, injectable emulsion) as the first genuinely new therapeutic option in a decade, Robyn Brown, VP-Investor Relations, said in an interview. "Unlike many current antihypertensive treatments which are metabolized by the kidney and/or liver, Cleviprex is metabolized by esterases predominantly in the blood and does not accumulate in the body, even in patients with end-organ damage."

The drug was approved based on six Phase III clinical trials totaling 1,406 patients entering the emergency department, operating room and intensive care unit.

In two placebo-controlled trials in pre- and post-operative patients, subjects had at least a 15 percent reduction in blood pressure from baseline within 30 minutes of starting IV (p<0.00001). Cleviprex also achieved similar blood pressure control to three active comparators - nitroprusside, nitroglycerin and nicardipine - in patients undergoing cardiac surgery.

The drug was originally scheduled for a May user fee goal date, but additional pre-clinical data requested in April delayed approval by three months (² (Also see "The Medicines Company Aims For Mid-2008 Cleviprex Launch" - Pink Sheet, 14 Sep, 2007.)).

"We plan to launch Cleviprex in September," Brown said. "We have expanded our territories and our sales force in preparation for the launch of Cleviprex. We have increased the sales force from 123 representatives to 178 this summer in anticipation of marketing approval."

TMC and manufacturer Hospira anticipate a broad range of physicians using Cleviprex in the critical care setting. Approximately 3.4 million patients are treated annually in the U.S. with IV antihypertensives like nicardipine (EKR Therapeutics' Cardene and generics).

Cleviprex will face competition from EKR, whose ready-to-use Cardene IV received FDA approval Aug. 1.

TMC is targeting $5 million to $10 million in 2008 sales, and it believes Cleviprex could see up to $200 million or more of U.S. sales in five years.

Two approvals for Novartis "reinforce current guidelines"

Novartis' single-pill combination therapies Exforge and Diovan HCT are now indicated for first-line therapy in patients likely to need multiple drugs to achieve blood pressure goals.

The sNDA for Exforge, a combination of the calcium channel blocker amlodipine and angiotensin receptor blocker valsartan, was approved July 23. Novartis' blockbuster Diovan HCT (valsartan and the diuretic hydrochlorothiazide), was approved for the first-line indication July 28.

"Up to 80 percent of patients need multiple medications to help them reach blood pressure goals," Novartis said. Current National Heart, Lung, and Blood Institute JNC7 guidelines recommend initial combination therapy for certain patients as it may simplify the treatment regimen and cost less.

The first-line approvals were based on experience in over 5,000 patients with mild to severe high hypertension, in which both products showed efficacy and tolerability.

Novartis recently asked FDA to apply a class-wide inclusion of cardiovascular outcomes data in antihypertensive drug labeling to fixed-dose combination pills, allowing for expanded labels without doing additional studies. Novartis' fixed-dose combination portfolio also includes Tekturna HCT (aliskiren/HCT).

The utility of combination therapy was highlighted at the annual American College of Cardiology conference (³ (Also see "Vytorin, Zetia, Other Combos In Spotlight At ACC Conference" - Pink Sheet, 21 Mar, 2008.)). In particular, the Novartis-sponsored ACCOMPLISH trial, the first to look at fixed-dose as initial therapy, compared its recently turned generic Lotrel (amlodipine/benazepril) with benazepril/HCT in reducing cardiovascular morbidity and mortality in high-risk hypertensive patients.

-Becky Jungbauer ([email protected])