Vol. 8 No. 194
An FDA advisory committee has recommended approval of Schering-Plough’s PegIntron for melanoma and GlaxoSmithKline’s (GSK) Votrient to treat kidney cancer.
The agency’s Oncologic Drugs Advisory Committee voted 6–4 Monday to tell the agency the risks of adjuvant treatment with PegIntron (pegylated interferon alfa-2b) are outweighed by the benefits for patients with Stage III melanoma after a complete lymphadenectomy.
One advantage of PegIntron is that it can be self-administered at home. Bruce Redman, professor of medicine at the University of Michigan Medical Center, said Schering-Plough’s product is no more toxic than the currently available high-dose interferon.
A number of panel members agreed that PegIntron also might benefit patients because it is a less intense treatment regimen compared with high-dose interferon. The high-dose treatment is administered for one year, beginning with a month of induction therapy five times a week, compared with a once-weekly regimen for PegIntron.
The morning debate over PegIntron centered on toxicity and whether the drug improves survival. Ronald Richardson, consultant at the Department of Medical Oncology at the Mayo Clinic, called the toxicities of the drug formidable. He cited data from a randomized, controlled study of PegIntron in which 44 percent of subjects receiving the drug discontinued treatment early because of the drug’s side effects.
FDA staff said they were troubled by some of the safety and efficacy results. Schering-Plough based its sBLA for PegIntron on a randomized, controlled study in 1,256 melanoma patients, and only 13 percent of the 627 patients receiving the product completed the full five years of treatment, Charles Stimler, medical officer at the Division of Biologic Oncology Products, said during the agency’s presentation.
Stimler pointed to the higher number of serious adverse events in the PegIntron arm versus the observational arm — 503 events compared with 147 events. Thirteen patients in the PegIntron group experienced arrhythmias compared with two in the observational arm. A total of 361 PegIntron-treated patients (59 percent) experienced depression. This number compares with 153 subjects (24 percent) in the observational arm.
In addition, PegIntron only offers a modest benefit of relapse-free survival, the study’s primary endpoint, Stimler said. However, the product failed to show any benefit for overall survival, he added.
The committee voted unanimously to tell the FDA that GSK’s Votrient (pazopanib), a potential treatment for advanced renal cell carcinoma, has an acceptable risk-benefit profile.
The treatment demonstrated a statistically significant improvement in progression-free survival in a pivotal trial. Data show a five-month improvement in median progression-free survival in the Votrient-treated group compared with placebo — 9.2 months versus 4.2 months, respectively. The overall response rate for patients taking the drug in the pivotal trial was 30 percent compared with 3 percent for the placebo group.
The drug also is associated with liver toxicity that can be fatal, FDA staff say in briefing documents posted on the agency’s website before the meeting. Three deaths in the renal cell carcinoma program were associated with liver failure, according to the documents. One death was considered probably related to Votrient by GSK and the FDA. The other two deaths did not have adequate clinical evidence to rule out the drug’s effects.
The risk of severe and fatal hepatotoxicity is important because there are other products approved to treat advanced renal cell carcinoma, according to the FDA briefing documents. Since 2005, five products have received FDA approval for advanced renal cell carcinoma — Bayer HealthCare’s Nexavar (sorafenib tosylate), Pfizer’s Sutent (sunitinib malate), Wyeth’s Torisel (temsirolimus), Novartis’ Afinitor (everolimus) and Genentech’s Avastin (bevacizumab). Nexavar and Sutent are tyrosine kinase inhibitors, as is Votrient (DID, Oct. 2).
In the multinational, 435-patient, pivotal Phase III trial of Votrient compared with placebo, four of the 290 subjects receiving the drug died of hemorrhages. Two more died of arterial thrombotic events, and one succumbed to a perforation/fistula, according to the FDA presentation. Other common adverse events in Votrient-treated patients in the trial included diarrhea (52 percent) and hypertension (40 percent).
Many on the committee said the drug is effective but toxic. However, most agreed with Richardson that Votrient’s toxicity was similar to other drugs in the class and it would be a good addition to the armamentarium. The panel also urged the company to conduct rigorous postmarketing analysis. — Elizabeth Jones
Separate cancer drug clinical trials — of SciClone Pharmaceuticals’ drug for pancreatic cancer and Seattle Genetics’ treatment for diffuse large B-cell lymphoma (DLBCL) — are being halted based on the decisions of their data monitoring committees (DMCs).
SciClone’s study was a randomized, placebo-controlled, double-blind Phase II trial evaluating RP101 for late-stage pancreatic cancer, the company says in a statement. The primary endpoint was overall survival, according to ClinicalTrials.gov. The drug, a nucleoside analogue also known as BVDU, is designed to enhance sensitivity to chemotherapy.
The Foster City, Calif.-based company says it has notified investigators and regulatory authorities of the decision to stop its study and will conduct a detailed safety and efficacy analysis, once the data are unblinded, before deciding whether RP101 has any further potential.
SciClone’s statement does not say why the DMC advised it to stop dosing patients, and spokeswoman Ana Kapor told DID Monday that the company itself had not been given the reasons yet.
“The data are still blinded and we’ve asked them to give us more information, but we had to get the announcement [of the trial halt] out there,” Kapor said. The drug is not being studied for any other indication, she added.
Seattle Genetics’ randomized, double-blind Phase IIb clinical trial, known as the SeaGen MARINER study, was evaluating dacetuzumab for DLBCL. After conducting an interim analysis, the DMC determined that the study was unlikely to meet its primary endpoint of superior complete response rate in the active arm compared with the placebo arm.
Patients in both arms of the trial got Rituxan (rituximab), ifosfamide, carboplatin and etoposide, and one addition — dacetuzumab or placebo. About two-thirds of the planned 224 patients with relapsed or refractory DLBCL were enrolled. Those in the active arm will no longer get the study drug, Seattle Genetics says.
Bothell, Wash.-based Seattle Genetics is continuing four separate Phase Ib trials of dacetuzumab, a humanized monoclonal antibody, for non-Hodgkin’s lymphoma and multiple myeloma, President and CEO Clay Siegall says in the statement.
The company is developing dacetuzumab under a worldwide collaboration agreement with Genentech and is planning an oral presentation of one of the Phase Ib clinical trials Dec. 7. The presentation at the annual meeting of the American Society of Hematology will focus on a single-arm trial evaluating dacetuzumab in combination with Rituxan and Gemzar (gemcitabine) for patients with relapsed or refractory diffuse large B-cell lymphoma, Seattle Genetics spokeswoman Peggy Pinkston told DID.
SciClone is sponsoring or planning other trials including a Phase II study of SCV-07 in oral mucositis and hepatitis C virus, a Phase III trial of thymalfasin for Stage IV melanoma and a trial of thymalfasin for influenza A (H1N1) virus, the company’s president and CEO, Friedhelm Blobel, says in the statement. — Martin Berman-Gorvine
Impax Laboratories has received tentative approval from the FDA for its generic version of Boehringer Ingelheim Pharmaceuticals’ Flomax 0.4-mg capsules to treat the functional symptoms of benign prostatic hyperplasia.
Impax joins Ranbaxy Laboratories, Teva Pharmaceutical Industries, Wockhardt USA, Mylan Laboratories and Sandoz subsidiary Lek in gaining tentative approval for their generic versions of Flomax (tamsulosin HCl) capsules, according to the FDA website (DID, Feb. 4, 2008).
The FDA recently granted a six months of pediatric exclusivity on the ’579 patent covering Flomax that runs through April 2010, according to a Sept. 25 statement from Astellas Pharma, Boehringer Ingelheim’s promotional partner for the drug.
U.S. sales of Flomax capsules were about $1.9 billion for the 12 months that ended Aug. 31, Impax says in an Oct. 5 statement, citing Wolters Kluwer Health. — Elizabeth Jones
Depomed’s gabapentin extended-release (ER) drug reduced pain associated with postherpetic neuralgia (PHN) in a Phase III clinical trial, according to the company.
The placebo-controlled study enrolled 452 PHN patients, who got either 1,800 mg of the drug daily or a placebo, Depomed says in a statement Monday. The primary endpoint was pain scores measured from baseline to the end of a 10-week treatment period, using the numerical Likert pain scale. This measurement method, which the FDA required the company to use, is called “baseline observation carried forward.”
Secondary objectives of the study included assessing changes from baseline in sleep interference and other patient and clinician assessments of pain and quality of life. The drug’s most common side effects were dizziness, seen in 11.3 percent of the patients in the active arm compared with 1.7 percent for placebo, and somnolence (5.4 percent versus 3 percent).
The drug, which also is called DM-1796, is an extended-release, once-daily tablet formulation of gabapentin. Depomed has licensed the marketing rights to Solvay Pharmaceuticals in the U.S., Canada and Mexico.
Depomed expects to submit an NDA for DM-1796 for the treatment of PHN by the end of the first quarter of 2010.
Earlier this year the FDA issued a MedWatch alert about an increased risk of suicidal thoughts and behavior for anti-seizure drugs, including gabapentin (DID, May 6). Depomed did not respond to a request for comment by press time. — Martin Berman-Gorvine
Drugmaker marketing authorizations will be handled by three new divisions of the European Medicines Agency (EMEA) when it completes its internal reorganization in December.
The changes will not affect the marketing authorization application process or any other procedures used by drugmakers to correspond with the agency, Martin Harvey Allchurch, a spokesman for the EMEA, told DID Monday. Drugmakers also should not expect a change in the review times for marketing authorization applications, Allchurch said.
The new Human Medicines Development and Evaluation unit will manage medicines for human use — from providing advice during R&D to management of the review process and changes to products after they have been approved, the EMEA says in a statement Monday.
The reorganization will create a Patient Health Protection (PHP) unit to oversee pharmacovigilance measures, risk and crisis management, patient and healthcare professional information, inspections and appropriate regulatory compliance, the EMEA says. PHP also will be in charge of community procedures for both centrally and non-centrally authorized products.
The management of information related to applications will fall under the purview of the new Veterinary Medicines and Product Data Management unit, which will have sole responsibility for the management of product data and documentation related to applications for the whole agency. This unit also will be involved in the development of IT systems to support scientific business processes, the agency says.
“It’s an efficiency issue, really. The agency has a had a fairly static structure for many years, but during that time the number of staff has increased quite dramatically, the complexity of the procedures has increased and just the sheer volume of different responsibilities we have has increased,” Allchurch said. “It’s a way of managing those processes better.”
During the reorganization there will be minimal changes in staff responsible for product applications in order to avoid disruption of to the operation of upcoming scientific committee meetings, the EMEA says, and stakeholders will be notified of any changes to the teams or staff handling their applications.
“The primary purpose of this is not to speed drug reviews — we’ve already done an awful lot to address that,” Allchurch added. — David Belian
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