Liposome battle for antifungal market
shifts into high gear

Around the world, the incidence of fungal infections, particularly in the immunocompromised, continues to climb. And as the number of AIDS and cancer patients shows no signs of diminishing, infectious disease specialists have expressed concern.

"Fungal infections are inherently difficult to treat, particularly in those most prone to opportunistic infections," said Thomas Walsh, MD, head of the pediatric branch of the section of infectious diseases, National Cancer Institute. "These diseases pose some of our most significant diagnostic and therapeutic challenges."

One reason for clinicians' unease is that the development of new treatment options has lagged, especially against the hard-to-treat Aspergillus and Candida strains. Mortality from these mycoses ranges from 30 to 40 percent in the least severe cases of candidiasis to 90 percent for aspergillosis-practically a death sentence. For lack of a better alternative, amphotericin B remains the treatment of choice. Despite its broad spectrum of activity, the compound has earned the epithet "Ampho the Terrible" because of the havoc it wreaks on patients' kidneys. Many physicians often shy from providing the optimal therapeutic dose, choosing instead to reduce drug levels or adopt an alternate-day regimen in the hopes of minimizing toxicity. However, during the past few years, three new and improved forms of amphotericin B, all based on various lipid formulations, have landed on hospital shelves, and the ensuing battle for market share tells us a great deal about how infectious diseases specialists will go about bringing these vexing conditions under control. While hard figures on the global incidence of fungal infections remain, like the microbes themselves, somewhat elusive, financial analysts suggest the world market for these lipid formulations of amphotericin B will be surprisingly large.

Using a number of different models, researchers have concluded that the current incidence of both suspected and confirmed fungal infections in immunosuppressed AIDS, cancer, and organ transplant patients is nearly 400,000. As this group is the target audience for amphotericin B, many analysts and clinicians suspect that over time the vast majority of patients will be shifted to the newer and safer lipid versions of the drug. Given the extended length of treatment the lipid formulations afford, a powerful global market is projected-estimated to be worth $400 million to nearly $1.2 billion. The critical question is, which of the new agents will doctors choose? Of the three, AmBisome (liposomal amphotericin B), developed by NexStar Pharmaceuticals, Inc., was the first to market, receiving clearance in Ireland in 1989 for the treatment of refractory fungal infections. The drug, the only true liposome of the three, currently is approved in 22 countries around the world and achieved nearly $60 million in sales in 1995. It was followed by Amphocil (amphotericin B colloidal dispersion), a product of Sequus Pharmaceuticals, Inc., which was approved for the same indication in the United Kingdom in 1994, and by The Liposome Company's Abelcet (amphotericin B lipid complex), which came to market in the UK in April 1995 as first-line therapy in the treatment of AIDS-related cryptoccocal meningitis and systemic cryptococcosis.

While sales of Amphocil to date have been lethargic, The Liposome Company has reported first-year sales of $6 million. More important, Abelcet became the first of the three drugs to receive approval in the United States: in November 1995, the FDA found the agent to be safe and effective in the treatment of aspergillosis in patients who cannot tolerate or are refractory to amphotericin B. (Sequus has since filed an FDA New Drug Application for the same indication for Amphotec, as Amphocil is known in the US, while NexStar is pursuing a phase III trial comparing AmBisome and amphotericin B in the treatment of fever of unknown origin. Analysts expect the FDA to grant approval for Amphotec by the end of 1996, with an AmBisome go-ahead to follow in 1997.)

Choosing among a liposomal amphotericin B, an amphotericin B lipid complex, and an amphotericin B colloidal dispersion may seem at first glance like choosing among three brands of tartar-preventing toothpastes: All fight plaque about the same; the difference is the taste. To some extent, the same logic applies to the lipid drugs: each transports higher doses of amphotericin B to the body while minimizing exposure to sensitive organs. Walsh, who has experience with all three drugs, spoke for many experts when he said, "While no head-to-head comparative studies have been conducted so far, I suspect that in the end, the drugs will turn out to be more similar than different." Edward Hurwitz, an analyst with Robertson, Stephens & Co., concurred, noting that "it is still too early to make the call. However, over the next couple of years, it seems that the three drugs will look more and more like each other. The differentiation that will take place will be a factor of market forces and price."

Yet there may be important differences between the drugs, argues analyst David Crossen of Montgomery Securities. For one thing, of the three agents, Abelcet may be removed more quickly from the blood and taken up directly at sites of infection. For another, the higher dosing level and more rapid infusion of Abelcet may prove to be more efficacious. (Indeed, both NexStar and Sequus now are testing higher dosing levels in their agents.) But most importantly, Crossen argues, the more extensive clinical data package for Abelcet, which includes data comparing Abelcet favorably to amphotericin B in the treatment of candidiasis, may provide to physicians an added margin of confidence.

And then there are the market forces. Abelcet is the least costly of the three drugs in Europe, and may well undercut the competition in the US, too. Moreover, it is first out of the gate in America and may win approval first in the key European markets of France and Germany as well. In the managed-care climate of the US, these advantages may prove critical. "Abelcet will be unchallenged in the United States at least until the end of 1996," Crossen said. "As the first, and least expensive, of the three lipid formulations, Abelcet has a powerful edge in leveraging the US market and ultimately may achieve the dominant position." Of course, it remains to be seen whether these differences will prove meaningful. In the end, Hurwitz probably is correct when he asserts that all three products likely will carve out some portion of what is a growing and profitable world market.

Despite the clear advantages afforded by the lipid preparations of amphotericin B, some clinicians wonder if patients with HIV/AIDS who develop a fungal infection would, or should, benefit from the novel agents. As William G. Powderly, MD, director of the clinical trials unit at Washington University in St. Louis, Missouri, pointed out, the most common mycoses seen in AIDS patients, cyptococcal meningitis and resistent esophogeal candidiasis, usually can be treated effectively with a short-course of conventional amphotericin B before switching to an oral antifungal agent. "Nephrotoxicity normally isn't a problem when amphotericin B is used for that length of time," Powderly said. "Physicians need to evaluate whether it is cost-effective to use the more expensive lipid preparations when a clear need has yet to be definitively established." Powderly did add that, in the case of aspergillosis, which requires a longer-and potentially toxic-three-to-five week course of amphotericin B treatment, the lipid drugs might provide "a significant advantage" and should be carefully considered by clinicians. Beside the three lipid formulations of amphotericin B, other new antifungal agents are in various stages of clinical testing. Nyotran, a liposomal form of nystatin under development by Aronex, is being compared with amphotericin B in immunocompromised cancer patients who fail to respond to bacterial treatment. In addition, many of the larger pharmaceutical companies, including Merck, Lilly, Pfizer, Bristol-Myers Squibb, Schering-Plough, and Abbott, are looking at a host of new approaches, including the second generation triazoles, and the echinocandins, pneumocandins, and pradimicins. However, the best of these compounds, which are in preclinical and early human testing, will not appear for many years. Until that time, the three new lipid agents appear to provide the best hope of stemming the serious threat of fungal infections in the immunocompromised patient.

Steven Marks is a Chicago-based medical and science writer.