POSITION PAPER REGARDING APPROVAL OF HOFFMANN-LA ROCHE'S VALGANCICLOVIR FOR THE TREATMENT OF CYTOMEGALOVIRUS (CMV) RETINITIS IN PATIENT WITH AIDS
by Michael Marco

Treatment Action Group
27 February 2001

On 27 February 2001, the FDA's Antiviral Drugs Advisory Committee will consider an application for approval of Hoffmann-La Roche's valganciclovir for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.

BACKGROUND
Cytomegalovirus (CMV) retinitis — a viral disease affecting the eyes and causing loss of vision — was once a rare disease occurring only among individuals with primary immunodeficiency syndromes or autoimmune disorders, organ transplant patients and immunosuppressed cancer chemotherapy patients. In people with AIDS (PWAs), CMV retinitis is by far the most common manifestation, accounting for between 77 and 90% of all CMV end-organ disease. In bone marrow transplant patients, however, there is a much greater incidence of CMV pneumonitis than retinitis.

From the 1980s to 1996, the incidence of CMV end-organ disease among PWAs was estimated to range between 10 and 40%. In the new era of highly active antiretroviral therapy (HAART), the incidence rate of CMV — for those who have access to HAART — is down well-below 5%. CMV end-organ disease occurs late in the course of AIDS and is associated with extremely low CD4 counts. The average CD4 count in patients with newly diagnosed CMV retinitis is below 30 cells/m³. The main symptoms of CMV retinitis include floaters, blurred vision, missing portions of vision and flashing light/sparks. Even subtle changes, such as a minor loss of peripheral vision, can indicate the development of CMV retinitis.

Treatments for CMV retinitis are palliative rather than curative. Resistance to the FDA approved antivirals for CVM retininis — intravenous ganciclovir, focarnet and cidofovir — is common and no oral drug indicated for CMV induction therapy exists. In heavily immunosuppressed patients with CMV retinitis, lifelong maintenance therapy is recommended in order to the hold lesions at a quiescent state. Recently published USPHS/IDSA guidelines indicate that "discontinuation of [secondary CMV] prophylaxis may be considered in patients with a sustained (e.g., greater than 3-6 month) increase in CD4+ T_lymphocyte count to greater than 100_150 cells/:L on HAART."

VALGANCICLOVIR'S PIVOTAL CMV STUDY
Valganciclovir (Val-GCV) is the valine ester of ganciclovir (IV GCV). In 1997, the FDA would not approve Val-GCV solely on pharmacokinetic data demonstrating that a 900 mg daily dose of Val-GCV had comparable exposure (AUC) to that of standard daily IV GCV dose of 5mg/kg. Instead, the agency required the sponsor to conduct a randomized controlled clinical trial demonstrating equivalence between Val-GCV and IV GCV for induction therapy of CMV retinitis.

Roche WV 15376 was the sponsor's registrational study which evenly randomized 160 patients with CMV retinitis to receive Val-GCV (900 mg twice daily for 3 weeks followed by 900 mg daily for 1 week) or IV GCV (5 mg/kg twice daily for 3 weeks followed by 5 mg/kg daily for 1 week). After the four-week induction phase comparison, all patients received maintenance therapy with open-label valganciclovir (900 mg daily). The primary endpoint was CMV retinitis progression within 4 weeks of initiating treatment using fundus photographs. Progression was defined as movement > 750 :m (along a > 750 :m front) or new retinitis lesions > 750 :m diameter. Statistically, the study was not a traditional head-to-head comparison but a non-inferiority study powered to prove that Val-GCV was not 10% worse than IV GCV. Both arms were evenly balanced for baseline demographics and disease status: ~90% were men; ~70% were on HAART; median CD4 cell count was ~23 cells; median HIV RNA copies/mL was ~4,000; ~24% had zone 1 retinitis; and ~25% had bilateral retinitis.

Of 146 patients who completed the 4-week induction phase, 7 of 73 (~10%) patients in the Val-GCV arm progressed compared to 7 of 73 (~10%) in the IV GCV arm (95% CI, -0.097, 0.100). Sixty-four and 63 patients had no documented photographic progression in the Val-GCV and IV GCV arms, respectively.

SAFETY
In Roche WV 15376, safety data were available on 158 patient. Adverse events were similar for Val-GCV versus IV GCV diarrhea (16% vs. 10%); pyrexia (13% vs. 11%); nausea (8% vs. 14%); vomiting (11 vs. 6%). As expected, the IV GCV had significantly more catheter-related infection, 11% vs. 2%. There were no significant differences in hematological abnormalities between the Val-GCV and IV GCV arms: ANC <750 cells/:L (21% vs. 19%); hemoglobin 6.5 to <8.0 g/dL (5% vs. 3%); platelets 25,000 to <50,000 (0% vs. 1%).

safety

The sponsor also carried out an ~200 patient open-label randomized safety study, Roche WV 15705. No significant differences in adverse events or hematological toxicities were noted between the Val-GCV and IV GCV arms.

DISCUSSION
Pharmacokineticly, Val-GCV has shown to provide systemic exposure (AUC) comparable to IV GCV. The sponsor fulfilled the FDA Antiviral Drugs Division's approval requirements by carrying out a randomized controlled Phase III study of Val-GCV which documented that Val-GCV was non-inferior to GCV for induction therapy of AIDS-related CMV retinitis. The safety profile of Val-GCV is almost identical to well-characterized IV GCV. Its most serious toxicity is neutropenia in which ~20% experience a grade 3 or 4 event by week 4.

pk data

The sponsor should be commended for studying Val-GCV against the gold standard IV GCV. Other approved CMV antivirals were merely approved using the quick and easy (some say lazy) immediate vs. deferred trial design. Val-GCV is the first drug that has been tested against IV GCV for induction since SOCA tested foscarnet vs. IV GCV (FGCRT) in 1990.

It has been 12 years since IV GCV was approved by the FDA in 1989. It has taken far too long for industry to bring an orally formulated anti-CMV therapy to market. We needed one years ago. The incidence of AIDS-related CMV retinitis has dramatically decline to less than 5%. Nevertheless, Val-GCV will certainly change the clinical management of CMV therapy. With easier administration, adherence to Val-GCV should be better than IV GCV and result in less resistance.

Val-GCV may hold great promise as prophylaxis for CMV retinitis. Hoffmann-La Roche should continue its positive, collegial relationship with the Adult AIDS Clinical Trails Group (AACTG) and support them in accruing and completing AACTG a3050, Valganciclovir Pre-emptive [Prophylactic] Therapy for Cytomegalovirus. If international sites in Spain, Australia, or Canada are needed to help with accrual, Hoffmann-La Roche must help in funding these units.

Lastly, Hoffmann-La Roche should cease with its erroneous patient-directed ad campaign warning individuals not to discontinue their CMV maintenance therapy with oral ganciclovir even though they are on HAART and fit the discontinuation guidelines outlined by the USPHS/IDSA.

POSITION ON THE INDICATION
Treatment Action Group supports the approval of valganciclovir for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.

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