Kaposi's sarcoma treatment approved
SEQUUS Pharmaceuticals, Inc. (formerly Liposome Technology, Inc.) has received FDA approval for DOXIL® (pegylated-liposomal doxorubicin HCI) injection as a treatment of AIDS-related Kaposi,s sarcoma (KS).
The current New Drug Application (NDA) for DOXIL is directed toward the treatment of AIDS-related Kaposi's sarcoma for people in whom prior systemic combination chemotherapy has failed either due to disease progression or unacceptable toxicity. SEQUUS is also conducting clinical trials directed toward the possible future filing of NDA supplements to gain approval of DOXIL as first-line therapy for KS and for the treatment of certain solid tumors.
Permission to market DOXIL will be granted following the company's satisfactory response to FDA questions posed in the approval letter regarding routine chemistry, manufacturing and control processes.
In February 1995, the FDA's Oncologic Drugs Advisory Committee (ODAC) recommended that the FDA approve DOXIL in accordance with the agency's accelerated approval regulations. Accelerated approval regulations require generally that an applicant (in this case SEQUUS) study an investigational drug following product launch to verify and describe the drug's clinical benefit. SEQUUS personnel are working with the FDA in designing a "post-marketing" clinical study to meet accelerated approval requirements.
DOXIL is a long-circulation STEALTH liposome formulation of the widely prescribed anti-cancer drug doxorubicin hydrochloride. SEQUUS is developing the drug for treating various forms of advanced cancer, including AIDS-related KS and solid tumors. The anticipated approval to use DOXIL for AIDS-related KS will be the first approved utilization of the drug.
expanded access for new CMV treatment
The Food and Drug Administra-tion (FDA) has authorized investigational new drug (IND) treatment status for intravenous cidofovir (Vistide) for HIV positive people with relapsing cytomegalovirus (CMV) retinitis that has progressed despite treatment. CMV retinitis is an eye infection that can lead to blindness in individuals with impaired immune systems, as is the case with AIDS.
FDA established the treatment IND mechanism for people suffering from serious or life-threatening conditions who have exhausted existing treatments or have no satisfactory treatments. The treatment IND process allows individuals to obtain promising experimental drugs that have undergone sufficient clinical testing to show that they may be safe and effective. In this case, the FDA granted expanded access, based on a controlled clinical trial that indicated that intravenous cidofovir may slow the progression of CMV retinitis.
FDA has already approved two drugs for treating CMV retinitis: foscarnet and ganciclovir. Neither drug cures CMV retinitis, but they can significantly delay disease progression.
Gilead Sciences Inc., of Foster City, CA, is making the drug available free of charge in this treatment IND program. Individuals and health care professionals can obtain more information about the treatment IND and its enrollment criteria by calling 1-800-GILEAD5. For more information on other AIDS clinical trials, call 1-800-TRIALS-A.
new clinical trial for cryptosporidium starts
Unimed Pharmeceuticals, Inc. has announced the beginning of a Phase II clinical trial to test the saftey and efficacy of its new product nitazoxanide (NTZ) for treating Cryptospordium in people with AIDS. Unimed received the FDA's approval this past September to proceed with the trial based on its investigational new drug (IND) application, filed in August. The clinical trial will be conducted at Cornell Medical Center in New York City under the direction of Dr. Rosemary Soave, Department of Infectious Disease, an internationally known Cryptosporidium expert.
Approximately 15 to 20 percent of people with AIDS suffer from Cryptosporidium parvum. While this gastrointestinal parasite causes temporary diarrhea in those with fully-functioning immune systems, it may result in profound chronic diarrhea in PWAs. There is currently no approved treatment for cryptosporidium.
clarithromycin reduces mortality in relation to MAC
The antibiotic clarithromycin has been proven to prolong life in people with advanced HIV infection by disseminated Mycobacterium avium complex (MAC), researchers reported at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy.
MAC, the most common systemic bacterial infection in people with advanced AIDS, has been confirmed post-mortem in more than 50 percent of PWAs. The Centers for Disease Control and Prevention estimate that one in every four people living with AIDS has disseminated MAC. Several retrospective studies have demonstrated that MAC increases morbidity and decreases survival in PWAs.
Mark Pierce, M.D., of the Vanderbilt University School of Medicine, Nashville, Tennessee, presented results from a prospective, randomized, double-blind, multi-center study, conducted in the United States and Europe. The study was designed to assess the ability of clarithromycin to prevent MAC infections and its effect on overall survival of patients.
A total of 682 patients were given either clarithromycin 500 mg or placebo twice daily. During the study and follow-up, only 5.9 percent (19/341) in the group receiving clarithromycin developed MAC compared to 19 percent (53/341) in the group receiving placebo. This represents a 69 percent reduction in the risk of developing disseminated MAC.
Median survival was greater than 700 days for the clarithromycin recipients compared to 573 days for placebo recipients. Placebo recipients who were MAC positive had a relative risk of death of 2.6 compared to those who were MAC negative. This prospective trial demonstrated that MAC is a predictor of mortality. The favorable effect of clarithromycin on survival in advanced AIDS is due primarily to the prevention of MAC.
"Patients with advanced AIDS who are severely immuno-compromised are at high risk for the onset of opportunistic infections, such as disseminated MAC,o/oo says Dr. Mark Pierce, lead investigator of the study. "When used as a preventive agent, clarithromycin can reduce the risk of disseminated MAC. More importantly, the study has shown that the prophylactic use of clarithromycin extends the lives of patients with advanced AIDS.o/oo
Resistance, which is a particular concern with monotherapy in the treatment of AIDS, is an important issue in MAC prophylaxis. Of the patients randomized to clarithromycin only three percent (11/341) developed resistant strains of MAC. Clarithromycin-resistant MAC was seen only in people with CD4 counts of 25 cells/mm3 or less and only after a time of 385 days of prophylaxis. This evidence suggests that clarithromycin-resistant MAC may represent treatment failure in patients who had non-bacterial MAC infections at the start of prophylaxis. Therefore, clarithromycin resistance should be minimized by reliably excluding MAC prior to initiation of prophylaxis, especially in patients with baseline CD4 counts 25 cells/mm3 or less.
In April 1995, Abbott Laboratories submitted a Supple-mental New Drug Application to the U.S. Food and Drug Administration seeking marketing approval for the use of clarithromycin for the prevention of MAC in people with advanced HIV infection. Clarithromycin is marketed in the U.S. under the brand name Biaxin®. Oral Cytovene Prophylaxis For CMV Disease Infrequently Associated with Viral Resistance
New data presented at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco suggest that prophylactic therapy with oral Cytovene® (ganciclovir capsules) is infrequently associated with the development of cytomegalovirus (CMV) resistance (one percent). The preliminary resistance data from this study are encouraging, especially when coupled with earlier study findings that preventative treatment with oral Cytovene® decreases the incidence of CMV disease by 49 percent.
"Taken as a whole, the available data from study 1654 indicates that in HIV infected persons, oral Cytovene® prophylaxis decreases the risk of developing CMV disease without increasing the risk of viral resistance,o/oo said Lawrence W. Drew, M.D., University of California, San Francisco, one of the principal investigators of the study. "The preliminary resistance data are quite reassuring.o/oo
CMV disease is the most common opportunistic infection in the late stages of AIDS. The most frequent manifestation of CMV disease is CMV retinitis, an infection of the retina of the eye which can be sight-threatening. (CMV retinitis is the most common ophthalmological complication of AIDS; up to 40 percent of patients eventually develop the condition.
Cytovene® (ganciclovir) inhibits the ability of the virus to replicate, thereby slowing the progression of the disease. Cytovene® capsules are currently indicated as an alternative to the intravenous (I.V.) formulation for maintenance treatment of CMV retinitis in people with impaired immune systems whose CMV retinitis is stable following appropriate I.V. therapy and only in those for whom the risk of more rapid disease progression is balanced by the benefit associated with avoiding daily I.V. infusions.
effective prevention
Study 1654 is a multicenter study of the efficacy and safety of oral ganciclovir for the prevention of CMV disease. The study comprises 725 persons with HIV (CD4 cells less than or equal to 100) ~ 486 subjects were randomized to oral ganciclovir and 239 to a placebo control. A planned interim analysis completed in July 1994 demonstrated the significant efficacy of ganciclovir over placebo, and an independent Data and Safety Monitoring Board recommended discontinuation of the placebo arm of the study. A delay of eight months in the onset of disease was seen in 20 percent of patients in whom this analysis was possible.
"Results of this study have demonstrated that CMV prophylaxis with oral Cytovene® is associated with a 49 percent risk reduction in the development of CMV disease compared with placebo,o/oo said Dr. Drew. "In addition prophylactic therapy was generally well-tolerated among these patients.o/oo
At the dosages used in the prevention study (3 grams daily), the most frequently reported adverse events were gastrointestinal. The incidences of anemia, neutropenia (a decrease in the number of neuutrophilic leukocytes in the blood), and elevated serum creatinine were higher in the group receiving oral Cytovene® compared to the group receiving placebo.
development of viral resistance rare
At ICAAC, Dr. Drew presented an analysis of isolates from patients who participated in the 1654 prevention study and received at least 90 days of treatment. The results indicate that prevalence of resistance was very low (one percent) after a mean of 10 months of preventive treatment. Resistant virus was associated with later treatment failure in one patient.
In May 1995, Syntex (now Roche Bioscience, a member of the Roche group) submitted a supplemental New Drug Application (NDA) to the FDA based on the results of study 1654. The company is requesting marketing clearance for the use of oral Cytovene® for prevention of CMV disease in HIV positive individuals at risk.
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