Twelve Years in Coming
On February 27th the FDA’s Antiviral Drugs Advisory Committee met to consider an application for approval of Hoffmann-La Roche’s valganciclovir for the treatment of CMV retinitis in people with AIDS. Michael Marco prepared this position paper on behalf of TAG. A decision on the application is expected later this month.
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 recipients and immunosuppressed cancer chemotherapy patients. In people with AIDS, 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 recipients, 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 people with AIDS 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 persons with newly diagnosed CMV retinitis is below 30 cells/mm3. 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 CMV retinitis, intravenous ganciclovir, foscarnet and cidofovir, is common and no oral drug indicated for CMV induction therapy exists.
In heavily immunosuppressed individuals 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/mm3 on HAART.”
Valganciclovir’s Pivotal CMV Study
Valganciclovir is the valine ester of intravenous ganciclovir. Were the year 1997, the FDA would approve valganciclovir solely on pharmacokinetic data demonstrating that a 900mg daily (oral) dose of valganciclovir produced comparable drug exposure (area under the curve/AUC) to that of the standard daily intravenous ganciclovir dose of 5mg/kg. Instead, the agency required the sponsor to conduct a randomized controlled clinical trial demonstrating equivalence between valganciclovir and IV ganciclovir for induction therapy of CMV retinitis.
Roche WV 15376 was the sponsor’s registrational study which evenly randomized 160 individuals with CMV retinitis to receive valganciclovir (900mg, orally, twice daily for 3 weeks followed by 900mg daily for 1 week) or IV ganciclovir (5mg/kg twice daily for 3 weeks followed by 5mg/kg daily for 1 week). After the four-week induction phase comparison, all study volunteers received maintenance therapy with open-label valganciclovir (900mg daily). The primary endpoint was CMV retinitis progression within 4 weeks of initiating treatment using fundus photographs. Progression was defined as movement >750 µm (along a >750 µm front) or new retinitis lesions >750 µm diameter. Statistically, the study was not a traditional head-to-head comparison but a non-inferiority study powered to prove that valganciclovir was not 10% worse than IV ganciclovir. 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 individuals who completed the 4-week induction phase, 7 of 73 (~10%) individuals in the valganciclovir arm progressed compared to 7 of 73 (~10%) in the IV ganciclovir arm (95% CI, -0.097, 0.100). Sixty-four and 63 individuals had no documented photographic progression in the valganciclovir and IV ganciclovir arms, respectively.
In Roche WV 15376, safety data were available on 158 individuals. Adverse events were similar for valganciclovir versus IV ganciclovir diarrhea (16% vs. 10%); pyrexia (13% vs. 11%); nausea (8% vs. 14%); vomiting (11% vs. 6%). As expected, the IV ganciclovir had significantly more catheter-related infection, 11% vs. 2%. There were no significant differences in hematological abnormalities between the valganciclovir and IV ganciclovir arms: absolute neutrophil count <750 cells/mL (21% vs. 19%); hemoglobin 6.5 to <8.0 g/dL (5% vs. 3%); platelets 25,000 to <50,000 (0% vs. 1%).
The sponsor also carried out a 200 person open-label randomized safety study, Roche WV 15705. No significant differences in adverse events or hematological toxicities were noted between the valganciclovir and IV ganciclovir arms.
Pharmacokinetically, valganciclovir has shown to provide systemic exposure (AUC) comparable to IV ganciclovir. The sponsor fulfilled the FDA Antiviral Drugs Division’s approval requirements by carrying out a randomized controlled Phase III study of valganciclovir which documented that valganciclovir was non-inferior to ganciclovir for induction therapy of AIDS-related CMV retinitis. The safety profile of valganciclovir is almost identical to well-characterized IV ganciclovir. Its most serious toxicity is neutropenia in which ~20% experience a grade 3 or 4 event by week 4.
The sponsor should be commended for studying valganciclovir against the gold standard IV ganciclovir. Other approved CMV antivirals were merely approved using the quick and easy (some say lazy) immediate vs. deferred trial design. Valganciclovir is the first drug that has been tested against IV ganciclovir for induction since SOCA tested foscarnet vs. IV ganciclovir in 1990.
It has been 12 years since IV ganciclovir 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 declined to less than 5%; nevertheless, valganciclovir will certainly change the clinical management of CMV therapy. With easier administration, adherence to valganciclovir should be better than IV ganciclovir and result in less resistance.
Valganciclovir may hold great promise as prophylaxis for CMV retinitis. Hoffmann-La Roche should continue its positive, collegial relationship with the Adult AIDS Clinical Trials Group (AACTG) and support it 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.