DID - April 3, 2008 Issue

Vol. 7 No. 66

No Placebo-Controlled Pneumonia Trials, Committee Says

Placebos can never be used in clinical trials of community-acquired pneumonia (CAP), even in patients who are “less severely ill,” the FDA’s Anti-Infective Drugs Advisory Committee said in a unanimous vote.

The committee vote mirrored views expressed at a January workshop sponsored by the FDA and the Infectious Diseases Society of America, which found that placebo trials are not practical or ethical in this field because patients with pneumonia need access to effective antibiotic treatments if they exist (DID, Jan. 22).

“Give people the best thing we can on the active control arm” of noninferiority CAP trials, Tom Fleming, professor of biostatistics at the University of Washington, urged.

CAP studies can be either noninferiority trials to prove the investigational drug is no worse than existing treatments or superiority trials to show the drug is better than the standard of care. Noninferiority trials may use historical data on mortality caused by the disease, the advisory committee unanimously agreed.

Historical data from observational studies of drug-treated patients with pneumococcal/lobar pneumonia suggest a reduction in mortality of 18 percent to 25 percent while controlled trials of the same disease show a reduction in mortality of 10 percent to 19 percent. Mortality rates for CAP have been stable for about half a century since antibiotics became readily available, committee members said.

The historical data can be used to select a noninferiority margin for CAP trials of intravenous drugs in hospitalized patients, the advisory committee said. The committee consensus was that a 10 percent margin is reasonable for moderate-to-severe pneumonia with a mortality endpoint.

A microbiological diagnosis is strongly recommended although not required when enrolling the primary analysis population in a CAP trial, the committee said. Trial sponsors are advised to enrich the population of patients with particular microbes such as S. pneumoniae.

The advisory committee also voted to recommend that noninferiority studies of CAP include patients with etiologies of CAP other than those involving S. pneumoniae if the available evidence for setting a noninferiority margin is primarily derived from studies of patients whose disease was caused by that microorganism.

If a drug is found to be effective in severe CAP, this fact can support the drug’s effectiveness in patients with less severe manifestations of the disease, even if the drug has not been directly studied in the latter group, the advisory committee said. However, members expressed some reservations on this score.

The advisory committee did not reach a consensus on whether a treatment effect can be reliably quantified for noninferiority studies of outpatient CAP. Ten members said yes, but three said no, and a drug industry representative abstained. Some of those who said yes expressed reservations about the idea. — Martin Gidron


Cell Genesys Inks Potential $320 Million Deal for Cancer Vaccine

Takeda Pharmaceutical will pay $50 million upfront and as much as $270 million in regulatory and commercial milestones for worldwide rights to Cell Genesys’ investigational prostate cancer vaccine.

The vaccine is based on Cell Genesys’ GVAX platform and works by training the body’s immune system to fight cancers, a process that does not occur naturally.

Under the terms of the agreement, Takeda will pay double-digit royalties on a tiered schedule based on net U.S. sales and a flat double-digit royalty for sales in all other regions. Takeda also will assume all development costs for the therapy but none of the internal costs Cell Genesys incurs.

Cell Genesys will manufacture the product and has rights to co-promote GVAX for prostate cancer in the U.S. The vaccine platform also is being tested in Phase II trials against leukemia and pancreatic cancer, indications the agreement does not cover.

Stephen Sherwin, CEO of Cell Genesys, said the company entered into the agreement now, instead of waiting until Phase III trial data were available, because Takeda would be a valuable resource to help navigate the approval process. In addition, Cell Genesys could not afford pre-commercialization costs.

GVAX for prostate cancer consists of two prostate tumor cell lines modified to secrete granulocyte-macrophage colony stimulating factor, a hormone that plays a key role in stimulating the body’s immune response, according to Cell Genesys.

The product is being tested in two Phase III trials in patients with advanced prostate cancer — VITAL 1 and VITAL 2. Both studies are being conducted under special protocol assessments agreed to by the FDA.

VITAL 1 completed enrollment in 2007 with 626 patients. The randomized trial is designed to compare the product with sanofi aventis’ chemotherapy Taxotere (docetaxel) plus prednisone to treat metastatic hormone refractory prostate cancer. The primary endpoint is improvement in survival.

An independent data-monitoring committee completed its pre-planned interim analysis of the trial in January and recommended that it continue. A final analysis of the data is expected during the second half of 2009.

VITAL 2 is expected to complete enrollment with 600 patients during the first half of 2009. — Christopher Hollis


Appeals Court Reverses Lexapro Declaratory Judgment Ruling

Even though Forest Laboratories pledged not to sue Caraco Pharmaceutical over Forest’s ’941 patent on Lexapro, Caraco should be able to pursue a declaratory judgment of noninfringement of the patent, a panel of judges has ruled.

The U.S. Court of Appeals for the Federal Circuit issued an order Tuesday reversing a lower court’s dismissal of Caraco’s declaratory judgment action, remanding the decision to the district court.

Forest and Caraco are involved in ongoing litigation over Forest’s ’712 patent on Lexapro (escitalopram oxalate) in the U.S. District Court for the Eastern District of Michigan. Although Caraco’s ANDA contained Paragraph IV certifications for both the ’712 and ’941 patents — which expire in 2012 and 2023, respectively — Forest only sued Caraco for infringement of the ’712 patent.

Ivax, later acquired by Teva Pharmaceutical Industries, was the first company to submit an ANDA for the antidepressant with Paragraph IV certifications and is therefore entitled to 180-day exclusivity, the circuit panel said. Forest also sued Ivax for infringement of the ’712 patent and prevailed.

Therefore, Ivax cannot market its generic Lexapro until the ’712 patent expires, which will begin the company’s exclusivity period, and subsequent filers cannot begin marketing their products until 180 days after Ivax, according to the court’s opinion. The only way Caraco can trigger Ivax’s exclusivity is to obtain a court judgment invalidating the ’712 patent, prompting Ivax to begin marketing, or to obtain a court judgment invalidating both patents, triggering the exclusivity period immediately.

After Caraco sued Forest for a declaratory judgment of noninfringement of the ’941 patent, Forest filed a motion to dismiss, the ruling says. But soon after, the Federal Circuit ruled in Teva Pharms. USA Inc. v. Novartis Pharms. Corp. that a district court erred when it dismissed Teva’s complaint seeking a declaratory judgment of noninfringement of Novartis’ Famvir (famciclovir) patents (DID, April 3, 2007).

The ruling was handed down in light of the Supreme Court’s decision last year in MedImmune Inc. v. Genentech Inc, which abolished the “reasonable-apprehension-of-suit test” for establishing controversy. These rulings led Forest to grant Caraco a covenant not to sue in order to establish a lack of controversy, according to the judge’s opinion.

The district court agreed with Forest that there was no controversy and dismissed Caraco’s declaratory judgment action. However, according to the circuit judge issuing the ruling, the district court did not consider the MedImmune or Novartis decisions.

While Caraco is not under threat of an infringement suit, under the “all-the-circumstances” test developed by the Supreme Court in MedImmune, controversy does exist because “Forest’s actions effectively prevent the FDA from approving Caraco’s ANDA and thus exclude Caraco from the drug market,” Circuit Judge Arthur Gajarsa wrote. “Forest’s covenant not to sue does not eliminate the controversy with Caraco, because the controversy can only be resolved by a judgment that determines whether Forest’s ’941 patent is infringed [on] by the drug described in Caraco’s ANDA.”

In a dissenting opinion, Senior Circuit Judge Daniel Friedman said he would affirm the lower court’s ruling because Caraco is not in danger of being sued or suffering financial harm. — Breda Lund


New Benefit Found for Lipitor

Lipitor brings an unexpected and sharp reduction in myocardial ischemia — insufficient blood and oxygen to the heart — in patients with chronic stable angina, a new study shows.

The cholesterol drug reduced the average number of ischemic events by nearly 70 percent, and the total duration of events dropped by more than 60 percent from baseline to week 18 of the study, Pfizer said. The effects held until the end of the 26-week trial, the results of which were presented Tuesday at the American College of Cardiology annual meeting.

In 60 percent of patients treated with 80-mg doses of Lipitor (atorvastatin calcium), all ischemic events were eliminated by the end of the study, resulting in a substantial decrease in angina attacks and the need for nitroglycerin treatment.

The findings are a “pleasant surprise, because statins are not part of the current standard of care for the treatment of angina,” lead investigator John Deanfield said.

The trial compared Lipitor, the company’s Norvasc (amlodipine besylate) and a combination of the drugs in patients with coronary artery disease and chronic stable angina. Patients also received beta-blockers, long-acting nitrates and aspirin.

The anti-ischemic results demonstrated by Lipitor were similar to those seen with Norvasc, Pfizer said. Norvasc, a high blood pressure and anti-angina medication, is part of the standard of care for this patient population. Patients given a combination of the drugs also showed a significant reduction in ischemic events, but there was no incremental benefit with the combination compared with either drug alone.

Lipitor also brought a significant reduction in C-reactive protein, a marker of inflammation that helps identify and stratify individuals at risk for cardiovascular disease. — April Astor


Sirtris Receives Orphan Status for SRT501

The FDA has granted orphan designation to Sirtris’ SRT501 for the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome.

MELAS is a fatal disorder caused by a mutation of DNA mitochondria that can lead to reduced exercise capacity and eventual muscle failure. Symptoms include fatigue, recurrent headaches and seizures.

The company is conducting a Phase Ib trial evaluating the safety and pharmacokinetics of SRT501 (resveratrol) in 20 MELAS patients. Secondary endpoints include exercise tolerance and fasting blood glucose and insulin levels. The company expects data from the trial in the first half of 2009.

Sirtris also is testing the drug in Type 2 diabetes patients. In January, the company reported results of a 28-day Phase Ib trial in which treatment-naive patients were given 2.5 or 5 g of SRT501. Both doses were found to be safe and well tolerated, and the drug significantly lowered glucose levels, according to the company.

Sirtris plans to seek orphan status for the drug in Europe. — Elizabeth Jones


GlaxoSmithKline Changes Relenza Labeling

GlaxoSmithKline is adding a new warning to labeling for Relenza, following reports of delirium and abnormal behavior in flu patients who took neuraminidase inhibitors including the drug.

Although Relenza’s (zanamivir) contribution to the events is not established, the company is adding a new subheading, “Neuropsychiatric Events,” to the drug’s warnings and precautions section. It says flu patients may experience seizures, hallucinations, delirium and abnormal behavior and that such events in patients receiving the drug have been reported primarily among pediatric patients and mostly in Japan.

The drug is approved to treat uncomplicated acute influenza caused by A and B viruses in adult and pediatric patients age 7 and older.

The drug did not have any reports of neuropsychiatric adverse events associated with it in the 2004-2005 and 2005-2006 flu seasons, but 75 events were reported in the 2006-2007 season. No deaths were reported with the drug (DID, Nov. 29, 2007). — Yuliya Melnyk

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Reporters: Martin Gidron, April Astor, Breda Lund, Christopher Hollis, Elizabeth Jones, Yuliya Melnyk

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