DID - Nov. 12, 2008 Issue

Vol. 7 No. 222

FDA: More Data Needed on Tamper-Resistant Properties of Remoxy

Pain Therapeutics and King Pharmaceuticals did not provide enough data to determine whether their investigational Remoxy painkiller is tamper-resistant, an FDA briefing paper says.

A joint meeting of two FDA advisory committees — Anesthetic and Life Support Drugs and Drug Safety and Risk Management — is scheduled to review Remoxy (oxycodone) Thursday. The drug has novel excipients designed to make it resistant to tampering and misuse.

Oxycodone is prone to abuse. Users crush the pill, breaking its controlled-release matrix to obtain higher concentrations of the drug, often by inhalation, intranasal or intravenous administration.

In agency briefing documents for the meeting, pharmacologist James Tolliver says the extraction of oxycodone from Remoxy was evaluated when the capsules were exposed to solvents for up to one hour. Long-term exposure to solvents was not examined for effectiveness, and a conclusion about tamper-resistance cannot be made, Tolliver says.

In addition, Tolliver says there were no attempts to test whether the drug could be turned into a form that abusers could inject or inhale.

“The matrix formulation of Remoxy capsules, because of its high viscosity, may not be abuseable by intravenous or inhalation routes without further manipulation,” he says. “However, the sponsor did not report any attempts or tests to demonstrate the possible conversion of Remoxy to a product suitable for intravenous or inhalation use.”

The FDA action date for Remoxy is Dec. 10. Pain Therapeutics, which licensed the rights for the drug to King, is seeking approval for Remoxy to manage moderate-to-severe pain when a continuous, around-the-clock analgesic is needed for an extended time.

Remoxy is important to King. In 2005, the company licensed it from Pain Therapeutics for $150 million upfront plus $150 million in milestone payments and the assumption of development costs. King is trying to expand in the pain-management market with its bid to acquire Alpharma, whose abuse-resistant painkiller Embeda (morphine sulfate/naltrexone HCl) is under FDA review (DID, Oct. 14). The advisory committee will review Alpharma’s drug Friday. 

Embeda contains naltrexone, an opioid antagonist. The chemical passes through the body with no clinical effects when the pill is taken as directed. But when it is crushed, both ingredients are released, whereby naltrexone reduces the euphoric effect of morphine, Alpharma says.

Broader Committee Discussion

According to discussion points for the meeting, the FDA wants committee members to weigh in on whether a minimum standard for tamper-resistant controlled-release drugs can be determined.

In addition, the committee will be asked to discuss methods available for evaluating the impact of a tamper-resistant formulation on abuse and misuse once the product is approved for marketing, briefing documents state. — Christopher Hollis


AstraZeneca Gets Win in Seroquel Suit

A Florida judge has ruled against several union health and welfare benefit funds that had sued AstraZeneca and contract research organization Parexel for allegedly marketing and promoting the atypical antipsychotic drug Seroquel for off-label uses.

The plaintiffs say the companies’ unlawful conduct denied them the opportunity to pay for equally safe and effective and less expensive alternatives to Seroquel (quetiapine fumarate), according to the complaint. Judge Anne Conway of the U.S. District Court for the Middle District of Florida found the plaintiffs had “not established that their injuries were proximately caused by Defendants’ alleged scheme to defraud,” according to court documents.

The plaintiffs filed suit last December seeking damages under the federal Racketeer Influenced and Corrupt Organizations Act (RICO), state consumer protection laws and common laws for fraud, misrepresentation, civil conspiracy and unjust enrichment.

In their complaint, the plaintiffs contend AstraZeneca and Parexel “misrepresented the comparative safety, efficacy and superiority of Seroquel over other traditional/typical or atypical antipsychotics.”

Seroquel has been approved to treat schizophrenia and bipolar disorder, including mania and depression. The plaintiffs cited a January 2007 report by the Agency for Healthcare Research and Quality that stated Seroquel was being prescribed for such off-label uses as dementia, Tourette’s syndrome, Alzheimer’s and obsessive-compulsive disorder.

The plaintiffs also allege the defendants promoted the drug illegally by:

  • Concealing adverse clinical trial results;
  • Aggressively promoting the drug as safe and effective for unapproved uses;
  • Making substantial contributions to nonprofit mental health organizations;
  • Sponsoring events where doctors were paid to attend and speak favorably about the drug to their peers;
  • Employing ghostwriters to author “seemingly-independent medical publications” about the superior safety and effectiveness of the drug”; and
  • Distributing and marketing promotional materials to doctors that “concealed or misrepresented facts about the drug’s safety and effectiveness.”

Conway ruled that the plaintiffs did not present enough evidence to make their case. To prove the defendants’ misconduct had caused injury, she said, “each physician who prescribed Seroquel to an individual consumer or health and welfare fund member would have to be questioned as to whether his or her independent medical judgment was influenced by the Defendants’ misrepresentations, and to what extent.”

This sort of inquiry “would likely have to be conducted with regard to each consumer purchase transaction or third-party reimbursement payment made” roughly in the past 10 years, according to court documents.

Such an inquiry could go against the 1992 U.S. Supreme Court decision in Holmes v. Sec. Investor Protection Corporation et al., which found that “civil RICO claims must be supported by a showing that the alleged injury was proximately caused by the alleged unlawful act,” according to court documents. — Elizabeth Jones


Disappointing Results Released in Three Clinical Trials

Bristol-Myers Squibb and Sanofi-Aventis’ blood pressure drug Avapro did not reduce deaths and cardiovascular-related hospitalizations in a large international clinical trial.

In addition to failing the primary composite endpoint, Avapro (irbesartan) failed to offer a significant benefit for the secondary endpoints of all-cause and cardiovascular mortality, nonfatal heart attack or stroke and quality of life.

I-Preserve — the irbesartan in heart failure with preserved systolic function trial — enrolled 4,128 patients suffering from heart failure with preserved ejection fraction at 293 sites in 25 countries. The condition affects mainly women and the elderly.

The results, presented at the American Heart Association (AHA) meeting in New Orleans and given to DID by the AHA, are consistent with two previous trials in patients with the same type of heart failure that also did not demonstrate a positive effect.

I-Preserve is the largest of the three studies. “No treatment has been demonstrated to improve [these patients’] clinical outcomes in a large-scale clinical trial,” the investigators note in their paper.

Diabetes, Pain Drug Trials Also Miss Primary Endpoints

Separately at the meeting, Sangamo BioSciences and Anesiva released negative results from their respective trials. Sangamo found in one of three Phase II clinical studies of SB-509 to treat diabetic neuropathy that the drug was not significantly better than placebo in a number of measures of nerve function and health six months after treatment, according to a company statement.

Anesiva says its Phase III trial evaluating Adlea, a novel formulation of capsaicin — the ingredient that makes chili peppers hot — “narrowly missed its primary endpoint of reducing post-surgical pain versus placebo following bunionectomy surgery at four to 32 hours post-surgery.”

The therapy achieved the secondary endpoint of reducing opioid use for patients taking Adlea versus those on placebo over a 4- to 32-hour period. Results of a second Phase III trial of the product in total knee replacement surgery will be announced next month. — Martin Gidron


Ranexa Gets Expanded Label, Sees Market of 9 Million Patients

The FDA expanded the indications for CV Therapeutics’ Ranexa, approving it as a first-line treatment for chronic angina and adding a claim that the drug slightly reduces levels of hemoglobin A1c.

The updated label, approved last week, eliminates contraindications that say Ranexa (ranolazine) should not be used by patients taking potent and moderately potent drugs that inhibit CYP3A, including the calcium channel blocker diltiazem.

The new label lists patients taking “strong inhibitors of CYP3A” under contraindications and gives physicians instructions for limiting the dose of Ranexa in patients taking calcium channel blockers — including diltiazem and verapamil.  

“Ranexa may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors and angiotensin receptor blockers,” the new indication and usage section of the labeling states.

The old indications and usage section warned that “because Ranexa prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs.” That statement was removed in the new label.

The expanded label allows the company to target the entire 9 million-patient angina market, CV Therapeutics CEO Louis Lange said during the firm’s recent third-quarter earnings call.

Reduction in Hemoglobin A1c

One-third of the angina market consists of patients with diabetes, and the claim that the product can reduce levels of hemoglobin A1c will boost the drug’s position, especially for patients taking beta blockers. Beta blockers are known to increase hemoglobin A1c, Lange said.

“Ranexa produces small reductions in hemoglobin A1c. Ranexa is not a treatment for diabetes,” the new label states.

The new label provides information showing that Ranexa reduced heart arrhythmias, including ventricular arrhythmias, new onset atrial fibrillation and bradycardia, or potentially dangerous slow heartbeat — also associated with beta blocker drugs, CV Therapeutics says in a statement.

Lange said the company would target patients who take nitrates. One benefit of Ranexa is that it can be used with erectile dysfunction medications, unlike nitrates, he noted.

Ranexa was approved by the FDA two years ago to treat patients with chronic angina who did not respond adequately to other treatments (DID, Jan. 31, 2006). The FDA previously missed the July 27 user fee date for the new labeling updates.

According to Lange, the new label puts the company in a strong negotiating position for potential partners to market the product. The company will use 210 sales representatives to promote Ranexa, including 40 new staff to detail primary care doctors in the Northeast in the area from New York City to Washington, D.C., he said.

The company recently licensed the European rights for Ranexa to Menarini (DID, Sept. 15). — Christopher Hollis


TNFerade Gets Fast-Track Status for Pancreatic Cancer

The FDA has granted fast-track designation for GenVec’s TNFerade to treat locally advanced pancreatic cancer.

The designation is based on evidence of the drug’s potential to improve survival in patients with pancreatic cancer. The company reached an agreement with the FDA in January to change its Phase II/III PACT trial studying TNFerade to measure overall survival as the primary endpoint rather than 12-month survival (DID, Jan. 4).

Fast-track status could allow GenVec to submit a BLA for the product on a rolling basis, permitting the FDA to review sections of the application prior to receiving the complete submission, the company says in a statement.

TNFerade uses an adenovector that contains the gene for tumor necrosis factor-alpha, an immune system protein with anti-cancer effects, for direct injection into tumors.

GenVec has tested TNFerade in combination with radiation or chemotherapy for several indications, including the treatment of cancers of the skin, rectum, esophagus and head and neck. — Elizabeth Jones

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