Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 2 - April, 1994
Kevin Robert Frost

No new drug can, or should, be evaluated for approval in a vacuum. The FDA must consider both the context of currently available therapies and the data on newly emerging therapies. If there are therapies within the experimental pipeline that may possibly prove more efficacious or simply improve the quality of patients' lives, applications for approval must take these things into consideration. It would be tragic if therapies for the treatment of opportunistic infections become mired in the same kind of morass that antiretrovirals are in today. The only possible way to avoid this morass is for the FDA to closely examine applications for approval and insist that companies look at questions such as resistance and the long-term effects of new drugs.

With this in mind, it is critically important to examine the analyses of these studies, as well as the questions that remain unaddressed. More extensive studies of oral ganciclovir, along with an expanded access program for those who need the drug, may ultimately provide us with a better idea of whether this drug should be used for CMV retinitis and, if so, in what way.

CMV Standard Care

CMV retinitis is a sight-threatening eye infection caused by a type of the herpes virus known as cytomegalovirus. CMV has always been a major complication of immune deficiency, historically affecting 20 percent of people with AIDS. This percentage is increasing as other opportunistic infections are better managed and individuals survive longer. (While most commonly infecting the retina, CMV may also attack other organs, principally the colon and esophagus.)

If left untreated, CMV retinitis progresses relentlessly in 90 percent of patients. Standard therapy is onerous, involving daily infusions of either ganciclovir or foscarnet - both very toxic drugs. Ganciclovir's main toxic affect is on the bone marrow whereas foscarnet can cause kidney dysfunction.

Treatment is broken down into two phases, induction and maintenance. Induction therapy is the phase that initially inhibits the infection. It lasts two to three weeks and consists of one-hour infusions two or three times a day. This phase is followed by life-long maintenance therapy, which is a single infusion per day.

Despite maintenance therapy, the CMV lesions on the retina eventually becomes active again. This new disease progression, which may arise because of patients' decreasing immunological competence, the advent of drug-resistant strains of CMV, or the difficulty in delivering sufficient drug to the eye, occurs within two or three months on average. The current response to renewed CMV growth is to restart induction therapy or switch to the alternative drug.

History

Does oral ganciclovir work? In the winter of 1992, Syntex undertook two clinical studies, 1653 and 1774, to find out if an oral formulation was as effective as the intravenous form in slowing the progression of CMV retinitis. The company was looking at patients who had completed the induction phase of treatment and had stable disease. In addition to these maintenance trials, activists urged the company to provide the oral compound for a head-to-head comparison study with valacyclovir, Burroughs Wellcome's new, improved version of acyclovir for the prevention of CMV disease. Syntex refused and went ahead with maintenance studies instead.

Many activists believe that the reason the company chose to push first for a treatment indication on this compound was that treatment or maintenance studies can generally be accomplished faster and with far fewer patients than prevention studies. It would thus be easier and faster to show that the drug worked and get it approved by the FDA. If it worked.

From the earliest interim analysis (the first presented was on study 1653 in a March, 1992 meeting), it was evident that there were problems. Participants given the oral ganciclovir were switched to a treatment dose of IV ganciclovir (reinduction) much sooner than those who originally received IV ganciclovir. While many people voiced their disappointment over these results, most physicians wanted to wait for the analysis presented by the Fundus Photography Reading Center, which was providing an independent analysis of the photographs of the patients' eyes as part of the study protocol.

One early lesson of CMV retinitis studies was the need to standardize clinical endpoints in a way that would allow investigators at different sites to conduct the same study and be sure that the data were comparable. Defining disease progression can be a very subjective decision on the part of investigators, especially when they know which treatment each patient receives. There is simply too much room for investigator bias. Photographs of the retina provide the necessary standardization. By having all investigators follow a single protocol for photographing trial participants' eyes (the term "fundus" simply refers to the back of the eye known as the retina), CMV lesions can be measured with great precision by an independent center unaware of which therapy patients are getting.

Syntex finally provided the independent analysis of the photographs (almost two years after it was requested). In addition, the company provided two sets of numbers used to evaluate the time to disease progression: mean - which is simply the average time of all patients to progression, and median - the midpoint of all patients' time to progression. Both numbers are important because they tend to serve as a check and balance for each other. A large discrepancy might indicate something unusual and worthy of further investigation.

Efficacy

Such a discrepancy was exactly the case in the analyses presented in Washington. In the first abstract presented, which was a study of oral ganciclovir maintenance therapy in newly diagnosed patients with CMV retinitis, the photographs indicated that the average time to progression was 62 days in the IV group and 57 days in the oral group. In contrast, the median time to progression differed considerably - 49 days in the IV group and 29 days in the oral group. While it is important to look at the average times to progression, these results must be tempered by the knowledge that "averages" can be adversely affected by anomalies within the data. Extreme numbers can significantly affect the average. Medians are not susceptible to this kind of distortion.

The significant difference between the median times to progression in the oral study (49 days vs. 29 days) cannot be dismissed out of hand. It deserves a much closer look. If in fact the median times are a more accurate reflection of the efficacy of oral ganciclovir, the drug may not be much better than no drug at all. In the peripheral retinitis study of foscarnet that was carried out by the National Eye Institute, patients who were randomized to no therapy (called the deferred therapy group) had a median time to progression of 29 days.[3] While it is difficult to compare the results of one study to the results of another study, one must wonder - if there had been a deferred therapy group in the Syntex study 1653, would the difference between times to progression in that group and the oral treatment group have been significantly different? It is at least possible, based on these results, that oral ganciclovir is no better than nothing when it comes to treating CMV retinitis.

The second study presented in Washington also was anomalous. In that study, Syntex 1774, participants were randomized to IV ganciclovir and two oral treatment groups (one receiving 500mg six times a day as in study 1653 and one receiving 1000mg three times a day). Individuals receiving 500 mg had a mean progression time of 53 days but a median time of only 32 days. Those in the 1000mg group, on the other hand, had a mean time to progression of 54 days and a median progression time of 53 days. It is only in the 1000mg group that any efficacy data comparable to IV therapy has emerged. Unfortunately, with only 76 patients in this arm, it forms a very flimsy foundation for FDA approval. Further, it is crucially important to consider that all patients in this study, as well as the Syntex 1653 study, had been administered their induction dose and had stable disease.

Historically, the efficacy of anti-CMV drugs has been measured from a baseline of no treatment, meaning patients with untreated, active disease. In both of the Syntex studies, the oral compounds were studied in patients with previously treated, stable disease, which arguably made the outcomes appear more favorable.

Dr. William Buhles, who directs Syntex's ganciclovir program, suggests that IV ganciclovir slows CMV progression by only one or two weeks more than the oral formulation. The company believes that patients may choose the oral drug because of "safety and quality of life considerations."[4]

Safety

There are certain advantages to an oral therapy when compared to intravenous therapy. Patients who receive intravenous infusions on a regular basis usually require the use of a central venous catheter. While a catheter can introduce drugs directly into the bloodstream without the need for constant needle sticks, it can also provide direct access to the blood for organisms that can cause serious infections. It is no surprise that the patients receiving intravenous ganciclovir had more instances of sepsis (blood infections) than the patients who were able to take the drug orally. In addition, patients receiving the drug orally had a lower incidence of neutropenia (suppression of certain white blood cells), though this was probably due to the fact that the oral drug is poorly absorbed into the bloodstream and therefore does not achieve the drug concentrations that intravenous administration does. Poor absorption may also have a lot to do with why the drug did not work as well as IV ganciclovir.

Quality of Life

In some ways, this is the most difficult part of the equation. An oral formulation of ganciclovir that was able to halt the spread of CMV retinitis would be a highly desirable product. Currently, patients receiving intravenous ganciclovir must have a central venous line inserted (usually a Hickman® catheter), and receive infusions everyday for the rest of their life. This is extremely burdensome to patients and consumes enormous time and money.

At some point, the quality-of-life difference must be included in the overall FDA equation that determines whether or not a compound should be approved. As Syntex suggests, some patients might be willing to trade off some of the efficacy of intravenous ganciclovir, if it means dramatically improved quality of life when receiving oral ganciclovir. The question is unanswerable at this time, because it is impossible to tell if there is any significant efficacy associated with oral ganciclovir.

Resistance

One question that will almost certainly surface in the very near future is that of viral resistance - that is when the patient's CMV mutates and is no longer as susceptible to ganciclovir. In one study of intravenous ganciclovir, resistance was found in 40 percent of the patient subgroup that had culturable CMV in their bodily fluids during treatment.[5] Furthermore, in an abstract presented at the Association for Research in Vision and Ophthalmology, Dr. William Freeman showed that the drug levels achieved in the eye were too low to sufficiently suppress most human strains of CMV when ganciclovir was given intravenously.[6] Virologists know that viral resistance will occur much faster when treated with insufficient doses of medication. While there have not been any comparable studies with oral ganciclovir published to date, Syntex's studies indicate that the amount of ganciclovir that actually makes it into the bloodstream, when the drug is delivered orally, is less than when the drug is delivered intravenously.[7] There is no reason to suspect that oral ganciclovir would be any better at getting drug to the eyes than the intravenous formulation. Thus, oral ganciclovir may induce viral resistance more quickly than intravenous ganciclovir.

Ganciclovir Implants

The problem of delivering enough ganciclovir to the retina may be overcome by the use of ganciclovir implants - a device that continuously releases small amounts of the drug directly into the infected eye. Data from on-going trials will be available soon. Two published papers on ganciclovir implants have reported impressive results in preliminary trials, including in people whose retinitis was progressing despite intravenous ganciclovir therapy. In the first paper, 90 percent of the eyes stabilized after placement of the implant. The mean (not median) time to progression was 133 days after treatment commenced.[8]

However, it is possible that localized treatment for CMV retinitis may allow the infection to spread to the other eye or to other parts of the body. The current trials should answer these questions. One way to avoid the pitfalls of localized treatment with ganciclovir implants may be to combine implant therapy with oral ganciclovir. The oral drug would act as a relatively benign and unintrusive systemic prophylaxis. A twenty-center trial of this combination should start in a few months.

Conclusion

Syntex has at least two other studies in the planning stages that could clarify the efficacy of oral ganciclovir. But even if the compound should turn out to be a poor treatment for CMV retinitis, it does not mean that the drug has no value. The compound may work as a preventive (prophylaxis) for CMV disease or as a treatment for either CMV colitis or CMV esophagitis. These three applications probably require lower blood levels of ganciclovir than does CMV retinitis. Oral ganciclovir may yet have a promising future - though probably not as treatment for CMV retinitis.

References ----------

1 Crumpacker C. Abstract 538. First National Conference on Human Retroviruses and Related Infections, Washington, DC. December 1993.

2 Squires KE, et al. Abstract 540. First National Conference on Human Retroviruses and Related Infections, Washington, DC. December 1993.

3 Personal communication. Robert Nussenblatt. March 11, 1994.

4 Personal communication. William Buhles. February 14, 1994.

5 Drew WL, et al. Journal of Infectious Diseases, 1991; 163(4):716-719.

6 Freeman W, et al. Abstract 288. Association for Research in Vision and Ophthalmology, Sarasota, Florida. May 1992.

7 Spector S, et al. Abstract 539. First National Conference on Human Retroviruses and Related Infections, Washington, DC. December 1993.

8 Anand R, et al. Archives of Ophthalmology, 1993; 111(2):223-7.

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