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BURROUGHS WELLCOME’s MEPRON (ATOVAQUONE) IS A SECOND-LINE THERAPY FOR MILD TO MODERATE PCP IN PATIENTS "INTOLERANT" TO TMP/SMX, ADVISORY CMTE. CONCURS

Executive Summary

Burroughs Wellcome's Mepron (atovaquone, 566C80) should be approved as a second-line treatment for mild to moderate Pneumocystis carinii pneumonia (PCP) in patients who are intolerant to or have failed therapy with trimethoprim- sulfamethoxazole (TMP/SMX), FDA's Antiviral Drug Products Advisory Committee agreed on Sept. 23. "I think all of us who take care of a lot of patients with PCP find ourselves up against the wall frequently in terms of patients for whom we don't have therapies that they can either tolerate or they've already failed on, so I think we need this drug," acting Committee Chairman Deborah Cotton, MD, Harvard Medical School, commented. Cotton added, however, that she is "concerned that people understand what we know and what we don't know about the drug." Committee members specifically felt that more information was needed on the action of atovaquone in patients with chronic gastrointestinal disease, with severe PCP, or who have failed other PCP therapies; the action of atovaquone in children; and on interactions with other drugs. Chronic GI disease was felt to be a potential problem because in both animal and human studies atovaquone was found to be a highly insoluble and poorly absorbed compound, and because Burroughs Wellcome is seeking approval for atovaquone in an oral dosage form. Committee member John Modlin, MD, Dartmouth/Hitchcock Medical Center, suggested that FDA include "preliminary cautionary labeling" referring to patients with chronic GI disease. In one Burroughs Wellcome's clinical study (protocol 03), a correlation between baseline diarrhea and decreased drug efficacy was found in the patient group receiving atovaquone. However, the committee agreed this was not a conclusive finding because it was a post hoc analysis and no such correlation was found in protocol 05, a randomized trial comparing the efficacy of atovaquone and I.V. pentamidine. Given the inconclusive data, baseline diarrhea might be used as an indication of a need for early monitoring of blood levels of atovaquone, committee guest Christopher Mathews, MD, University of California-San Diego, suggested. Alvin Novick, MD, Yale University, said that data addressing why "there is such a challenging resistance to absorption" and how this affects atovaquone efficacy "is not yet fitting into a pattern." Burroughs Wellcome would "like to have a formula that's better absorbed and more reliably absorbed so there's less variability in plasma levels," Burrough's Senior Director, Infectious Diseases and Immunology Sandra Lehrman, MD, told the advisory committee. The firm is developing new formulations of atovaquone and hopes to file an IND for one by the end of the year. "An I.V. formulation and/or better and more consistently absorbed oral formulations have been a very high priority for us with this molecule," Lehrman noted, in part because in humans "steady state" levels of atovaquone in its current form are not achieved for five to seven days. The firm plans to study the new formulations for prophylactic as well as treatment applications. Burroughs conducted two major clinical efficacy studies comparing atovaquone to existing therapies. Protocol 03, a randomized, double-blind study, compared the efficacy of atovaquone to that of TMP/SMX. A total of 160 AIDS patients with mild to moderate PCP were treated with atovaquone and 162 with TMP/SMX. At four weeks following treatment cessation, lack of response was reported in 50 atovaquone patients and in 26 TMP/SMX patients; however, only 11 atovaquone patients experienced treatment-limiting adverse effects compared to 33 TMP/SMX patients. Both differences were statistically significant. Four deaths in the atovaquone group related to PCP and one death in the TMP/SMX group at four weeks after therapy cessation. Protocol 05 compared the effectiveness of atovaquone and I.V. pentamidine. Of 73 and 72 patients with mild to moderate PCP treated respectively with atovaquone and I.V. pentamidine in the randomized trial, five on atovaquone and 28 on I.V. pentamidine were discontinued from therapy due to adverse experiences. Among patients who did not experience dose-limiting adverse effects, therapeutic success (defined as no relapse for four weeks following therapy) rates were 67% and 68% in the atovaquone and I.V. pentamidine groups. Atovaquone dosage for both protocols 03 and 05 was three 250 mg tablets, three times a day. Doses were administered with food in the trials because early clinical studies showed that administration of atovaquone in combination with food yields increased bioavailability. The studies suggest that Burroughs Wellcome should explore further whether any relationship exists between blood plasma levels of atovaquone and drug efficacy, committee members said. "If we find out that drug levels [particularly at] day four of therapy are predictive of who will respond, then they might be useful as an adjunct in choosing those patients who get this therapy as opposed to another," Mark Smith, MD, Henry J. Kaiser Family Foundation, noted. "Labeling [for atovaquone] is going to be extremely important," Cotton stated. Physicians "often don't push people enough in terms of drug toxicity. This is a fatal disease if left untreated and yet we see people starting to switch therapy oftentimes very early even though we know the natural history of the disease is to get worse before you get better, even if you're on effective therapy." Use of atovaquone in its current form in combination with another PCP agent is one possible approach suggested by FDA Division of Antiviral Drug Products Director David Feigal, MD. "We appreciate there are a number of disincentives to doing combination studies," Feigal said. However "it seems at some point the rational way to develop drugs for treatment of PCP is to start combining the drugs that have different toxicities so that you can reduce the doses, that have different mechanisms of action [so that you can increase effectiveness]...There are ways of establishing the effectiveness of individual components short of trying to find the population that the monotherapy works for." He noted that the drawback to this combination approach is the number of different drugs with different toxicities to which people with AIDS are exposed. In addition, atovaquone's and other AIDS treatments' "interactions with other drugs simply have not been studied," Fred Valentine, MD, New York University Medical Center, noted. FDA noted that in protocol 03 when patients who were also treated with corticosteroids were looked at, the efficacy rate decreased in the atovaquone group. Committee member Donald Abrams, MD, San Francisco General Hospital, suggested this was "an indication patients have more severe disease" and that labeling include a warning that in patients with PCP severe enough to require corticosteriods, atovaquone "would not be appropriate." There is also no data on the effectiveness of atovaquone in children, Modlin pointed out. However, he added, "I find it hard to sit here and argue against its use in children." Modlin noted that "most children with HIV who get [PCP] are under 12 months of age." He added that for very young children the oral dosage form of atovaquone is not appropriate and the "pharmacokinetics of crushing a tablet and putting it in [a different vehicle] has not been studied at all." To date, two children, both with severe PCP, have been treated with atovaquone through an open-label protocol. Burroughs Wellcome also has completed a "small, pilot" Phase I pharmacokinetic study of atovaquone in children six months to 13 years old. As of July 1, 427 patients with mild to moderate PCP had been treated with atovaquone under Burroughs Wellcome's Treatment IND, which was granted on Nov. 8, 1991 ("The Pink Sheet" Nov. 18, 1991, T&G-13). A total of 87 patients with severe PCP had been treated through the company's open-label protocol. In protocol 05, two of the 23 study centers were located in Canada. The Canadian Health Protection Branch is reviewing atovaquone, and Burroughs Wellcome hopes to receive simultaneous review and approval of the compound in Canada and the U.S. Burroughs Wellcome's NDA for atovaquone (20-259) for treatment of PCP was filed on April 24. The company is also conducting a Phase II open-treatment study of the compound for treatment of patients with cerebral toxoplasmosis who have failed or are intolerant to current therapy.
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