International Approvals: Isentress, Rexin-G, Vectibix

Yael Waknine

January 07, 2008

January 7, 2008 — The European Commission (EC) has approved raltegravir tablets for use with other antiretroviral agents in the treatment of multidrug-resistant HIV infection; the Philippine Bureau of Food and Drugs has approved a tumor-targeted gene delivery product for the treatment of chemotherapy-resistant solid tumors; and the EC has approved panitumumab intravenous infusion for epidermal growth factor receptor–expressing metastatic colorectal cancer with nonmutated (wild-type) KRAS genes.

Raltegravir ( Isentress) for Multidrug-Resistant HIV in EU

On December 26, the European Commission approved raltegravir tablets (Isentress, Merck Sharp & Dohme) with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adults who have evidence of replication and multidrug-resistant viral strains. The approval applies to all 27 member states of the European Union (EU) and will serve as a basis for separate national licenses to be issued in European Economic Area member states Iceland and Norway.

Raltegravir is the first in a class of antiretroviral agents known as HIV-integrase strand transfer inhibitors, designed to slow HIV-1 progression by blocking the integrase enzyme required for viral insertion into human DNA. The recommended dose is 400 mg (1 tablet) taken twice daily either with or without food; no ritonavir boost is necessary for effect.

The approval was based on 24-week data from 2 ongoing double-blind, placebo-controlled studies (BENCHMRK 1 and BENCHMRK 2) of 699 highly antiretroviral treatment–experienced HIV-1-infected patients aged 16 years and older who had documented resistance to at least 1 nonnucleoside reverse transcriptase inhibitor, nucleotide reverse transcriptase inhibitor, and protease inhibitor.

A pooled analysis of results revealed that the addition of twice-daily raltegravir to optimized background therapy (OBT) yielded viral loads of fewer than 400 and 50 copies/mL in 75.5% and 62.6% of patients, respectively, compared with 39.3% and 33.3% of those receiving OBT alone.

In addition, patients experienced significant decreases from baseline in HIV-1 RNA viral load (−1.85 vs −0.84 log10 copies/mL) and significant increases in CD4+ cell counts (+89 vs +35 cells/mm3).

"Treatment-experienced HIV patients have limited options for therapies that are well-tolerated and can reduce viral loads while boosting CD4 counts," says Jürgen Rockstroh, professor of medicine and head of the HIV Outpatient Clinic, University of Bonn, Germany, in a company news release. "The approval of raltegravir in the EU represents a significant scientific advancement, but more importantly, it addresses a much-needed evolution in the treatment of HIV and AIDS."

The most commonly reported adverse effects included diarrhea (16.6% vs 19.5% for OBT alone), nausea (9.9% vs 14.2%), headache (9.7% vs 11.7%), and pyrexia (4.9% vs 10.3%).

Raltegravir previously was approved by the US Food and Drug Administration and Health Canada.

Tumor-Targeted Gene Delivery Product (Rexin-G) for Metastatic Cancer in Philippines

On December 18, the Philippine Bureau of Food and Drugs granted accelerated approval for a tumor-targeted gene delivery product (Rexin-G, Epeius Biotechnologies Corp) for the treatment of chemotherapy-resistant solid tumors.

The pathotropic, tumor-targeted, injectable retroviral vector carries a mutant form of the cyclin G1 gene, which selectively accumulates in metastatic sites to destroy tumor cells and their blood supply.

According to a company news release, it is among the first gene-based medicines to be approved anywhere in the world and has exhibited unprecedented single-agent efficacy where other agents (including targeted biologics) have failed.

In an effort to gain US Food and Drug Administration (FDA) approval, the company has opened advanced phase 1/2 trials in chemotherapy-resistant pancreatic cancer, breast cancer, and sarcoma. The FDA has also approved a phase 2 protocol for osteosarcoma that includes pediatric and adolescent patients.

The product previously was granted orphan drug status by the FDA in the treatment of pancreatic cancer.

Panitumumab Injection ( Vectibix) for Metastatic Colorectal Cancer in EU

On December 5, the European Commission approved panitumumab 100-mg/5-mL intravenous infusion (Vectibix, Amgen, Inc) as monotherapy for epidermal growth factor receptor (EGFR)–expressing metastatic colorectal cancer (mCRC) with nonmutated (wild-type) KRAS genes after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The conditional approval was based on a positive benefit/risk assessment in a patient population that currently has few treatment options, the company says in a news release.

A prospectively defined analysis of data from a randomized, controlled phase 3 clinical trial showed that the addition of panitumumab to best supportive care (BSC) significantly increased mean progression-free survival (PFS) relative to BSC alone (96 vs 60 days; P < .0001).

Further analysis revealed that the effect of panitumumab on PFS was confined exclusively to the approximately 60% of patients whose tumors harbor wild-type KRAS.

"The ability to predict the patient population more likely to respond to Vectibix could potentially reduce drug exposure in patients who we know will not respond," says Eric Van Cutsem, MD, PhD, from the Digestive Oncology Unit, University Hospital, Leuven, Belgium, and panitumumab investigator, in a company news release.

Anti-EGFR therapies such as panitumumab inhibit downstream events that lead to malignant signaling. However, mutated or activated KRAS leads to continued signaling regardless of whether EGFR has been activated or therapeutically inactivated.

Panitumumab previously was approved by the US Food and Drug Administration in September 2006 for the treatment of EGFR-expressing mCRC in patients with disease progression while receiving or following fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens.

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