Roche’s valganciclovir for AIDS-related eye infections backed by FDA panel

An advisory panel to the US Food and Drug Administration (FDA) voted has voted to recommend approval of Roche’s valganciclovir hydrochloride tablets for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.

In a 12 to 1 vote, the Antiviral Drugs Advisory Committee agreed that valganciclovir is safe and effective as induction therapy for CMV. The panel voted unanimously that Roche’s data support use of valganciclovir for long term maintenance therapy to treat the AIDS-related infection.

If the FDA follows the panel’s recommendation, which it almost certainly will, valganciclovir will be the first orally-administered CMV therapy approved for both induction and maintenance therapy. Currently, patients newly-diagnosed with the disease are generally treated with injectable induction therapies – including Roche’s Cytovene-IV (ganciclovir) – requiring long infusions that can carry the risk of sepsis.

The FDA approved an oral formulation of ganciclovir in 1994 for maintenance therapy only. Valganciclovir, Roche’s new oral drug, is the pro-drug of ganciclovir and “is rapidly converted into ganciclovir in the body,” according to the company.

Roche’s Dr. James Thomas commented that the advent of HAART therapy for AIDS patients, while undeniably good news overall, has made it more difficult to develop drugs to treat AIDS-related infections.

HAART therapy, which combines a trio of AIDS drugs, has dramatically reduced the incidence of opportunistic infections, including CMV retinitis, making it harder to recruit patients for studies, he noted. In addition, proving long term efficacy has become challenging, since AIDS-related infections disappear relatively quickly in patients on HAART therapy, he said.

As a result, Roche relied on data from a 4-week, 370-patient induction therapy study to show that its oral therapy was comparable to injectable Cytovene. The time period was deemed long enough to show safety and efficacy, but short enough to prevent positive effects of HAART therapy from biasing the findings.

Some panellists were concerned that the company had not demonstrated valganciclovir’s long term efficacy versus a comparator drug, but Roche representative Dr. Mary Jean Stempien argued that the firm had crossed the “highest hurdle” by demonstrating efficacy at the induction phase.

Roche’s study, which involved a “direct comparison with the standard of care” plus pharmacokinetic data, was sufficient to support the drug’s efficacy for CMV maintenance therapy, she told the committee.

The issues that arose at Tuesday’s meeting regarding data sufficiency are likely to come up frequently in evaluating drugs for AIDS-related infections in the era of HAART therapy, panel members agreed. The therapy has triggered a “real paradigm change” in the way drugs for AIDS-related conditions are studied, noted panel chair Dr. Roger Pomerantz, professor at Philadelphia-based Thomas Jefferson University.

The panel recommended that Roche conduct phase IV studies of valganciclovir to evaluate the product’s efficacy in light of factors including age and gender: the vast majority of patients in Roche’s clinical studies so far have been male.

“I would like to see a phase IV trial [in which] HAART patients are segregated in some way to see if there truly is efficacy with valganciclovir in the HAART era,” maintained panellist Dr. Ram Yogev, of Chicago-based Children’s Memorial Hospital.

The panel also suggested that Roche’s post-marketing studies should address possible drug-drug interactions and assess optimal dosing for CMV maintenance therapy.

Comment

A long awaited expanded access programme for valganciclovir opened in France last month. No similar programme will be available in the UK until June 2001, by which time the drug may already approved by the EMEA.