MARY JEAN SLUGS IT OUT IN GAITHERSBURG:
ROCHE'S VALGANCICLOVIR IS RECOMMENDED FOR APPROVAL
by Michael Marco

On 27 February at the sad and lonely Gaithersburg Holiday Inn, the FDA's Antiviral Drug Advisory Committee (ADAC) held a hearing to discuss Hoffmann-La Roche's NDA for valganciclovir for the treatment of CMV retinitis in people with AIDS (see TAG's position paper). One would have thought that CMV - once the second leading cause of death in PWAs - was an infection on par with toe fungus by the meager audience turnout. It was, however, an historic day for CMV research: the first oral drug with real efficacy to treat CMV was about to be recommended for approved. One couldn't help but wonder, "Where was this drug ten tears ago when we really needed it?"

The ADAC committee was absent of some of its members, most notably Roy "Trip" Gulick, the acting-chair. Roger Pomerantz filled in nicely for Trip, and luckily old-time HIV experts Princy Kumar (Georgetown) and Chris Mathews (UCSD) were present for a reality check. The advisory committee was infused with some well-respected ophthalmologists who unfortunately got "stuck-on-stupid" during the question and answer period.

Roche's Mary Jean Stempien, who is considered the mother of IV ganciclovir from the late 1980s, was back at the helm presenting the valganciclovir safety and efficacy data. Emory's Dan Martin, the consummate over-accruer and good-natured ophthalmologist, was on-hand to answer the technical ophthalmologic questions.

I had wondered why the FDA's Antiviral Drug Products Division requested a public hearing on valganciclovir, the valine-ester prodrug of IV ganciclovir. The valganciclovir data are excellent and there are years of experience treating thousands of patients with IV ganciclovir. A source close to the Division told me the hearing was needed because: 1) only one trial of 160 patients was being used for efficacy analysis; and 2) the sponsor was requesting an indication for CMV induction and maintenance therapy but only had efficacy data from the 4-week randomized valganciclovir vs. IV ganciclovir induction phase.

Roche pointed out three reasons it deserved an indication for maintenance therapy:

1. Valganciclovir provides systemic exposure (AUC) comparable to IV ganciclovir;
2. Valganciclovir's efficacy in the induction phase - the most rigorous test of a CMV drug - was similar to IV ganciclovir;
3. Valganciclovir offers exposure 10-times to that of oral ganciclovir (and it's approved for maintenance), valganciclovir should be considered at least as effective for maintenance.

I wondered if some of the ophthalmologists really knew HIV clinical care and understood the entire HIV-positive patient, not just his or her eyes. One ophthalmologist did not like the rate of anemia attributed to valganciclovir during the open-label maintenance phase. He repeatedly wanted to know if Roche would consider lowering the maintenance dose. Mary Jean began answering his questions simply and calmly, but when he just wouldn't let up, she lost her polite and professional tone of voice and let him have it. I have paraphrased her comments below:

Anemia is not something new! Doctors have been using ganciclovir for years and they know full well that it causes anemia. They look for it and treat it appropriately. Epogen does just fine. And with regard to lowering the dose, no, we won't lower the dose! The most important thing is to get to the MTD for val- or IV ganciclovir. Mutations occur and people fail this drug after a period of time. Even though the time to failure is longer with valganciclovir than other CMV drugs, people still fail. Look at the study data. Patients need as much drug as they can get to prevent mutations. I was so pleased her gloves were off. I was wondering how long Mary Jean would last with such nonsense. Holding my tongue, I wanted to scream out, "Where were you all with your toxicity questions when cidofovir was being approved? You were needed then to warn people that cidofovir would blow out patient's kidneys and cause death in some on HAART."

I did get a chance to deliver TAG's policy statement regarding valganciclovir's approval. This was during the open public comment portion;

I was the only "public" to comment. Since the ADAC already had a straightforward TAG statement that recommended valganciclovir for approval, I decided to discuss the questions which were soon to be voted on. With regard to its efficacy, I said that valganciclovir was comparable to ganciclovir, and it's surprising that even one study was ever completed during the HAART era. I reminded them that after 20 years of AIDS, an effective oral CMV treatment is still not available. I also reminded them that Roche headquarters in Basel wanted to stop the development of valganciclovir because of fear that CMV had gone away and there would be no market. As for its safety, I said valganciclovir is IV ganciclovir in a pill and all good HIV doctors know how to manage ganciclovir's hematological toxicities. When it came to the question of valganciclovir's effectiveness as maintenance, I informed the ADAC that most CMV drugs were approved for induction and maintenance therapy using an immediate versus deferred trial design. Such studies only told us that the drug was better than nothing (deferring) and were stopped so early by a DSMB that no real maintenance data exist. Why was the bar being suddenly raised for valganciclovir?" I ended by asking Roche to please take oral ganciclovir off the market once valganciclovir was approved. I said the pill burden was too great to make it an option for maintenance and it is not effective as CMV prophylaxis. During ADAC's discussion of the questions, Chris Mathews, who had remained silent the entire day, spoke honestly and passionately. To paraphrase Mathews, he said, the data on this drug are fine... I've needed a drug like this for my patients for years...having an oral drug is a great advance...I'm glad it's here.

When it came time to vote on questions #1: Do the Data submitted in this NDA support the safety and efficacy of valganciclovir for induction therapy of CMV retinitis?, the ADAC voted 12 yes to 1 no. After question #2 was reworded to simply ask, "Do you feel comfortable with valganciclovir being used as CMV maintenance therapy, the ADAC vote 12 yes, 0 no, and 1 abstention.

For such a home run drug, this ADAC meeting was grueling. If I was that exhausted, I wonder how Mary Jean must have felt? I guess there are no easy days in Gaithersburg.

Related files
- Position paper regarding approval of Hoffmann-La Roche's valganciclovir