Notes on HIV Drugs in Development
Boehringer Ingelheim announced the start of two large Phase III trials of tipranavir, a new kind of protease inhibitor (PI) that binds to the enzyme in a different way than currently available PIs. The U.S. study, dubbed RESIST 1, is aimed at people who have developed resistance to existing protease inhibitors and is one leg of the largest clinical research program ever launched for this highly treatment-experienced population. In phenotypic assays and early clinical trials, Tipranavir has shown activity against HIV with multiple protease resistance mutations.
RESIST 1 will enroll more than 500 patients at more than 115 trial sites in the United States, Canada and Australia. A similar 800-person study, RESIST 2, will enroll in Europe and South America. Two companion trials (study 1182.51 and RESIST 3) will be available for individuals with extremely limited treatment options that do not meet entry criteria for the two main trials. Finally, a very small emergency access program should be available to supply drug to about 50 patients. Overall, the suite of tipranavir studies will involve about 1,500 people worldwide.
RESIST participants will be randomized to receive either tipranavir (boosted with low-dose ritonavir) or an approved ritonavir-boosted PI selected by the individual's physician on the basis of treatment history and baseline resistance testing. Resistance testing will also be used to help determine an optimal individualized background regimen to backup the study drugs. Participants will be allowed to use certain currently experimental drugs such as T-20 (enfuvirtide, Fuzeon) and atazanavir. Eligible patients must have received at least two PI regimens prior to the study. Patients also must have received drugs from the NRTI and NNRTI classes, and must have at least one primary PI mutation prior to enrollment. There is no CD4 cell count criteria for entering the study but viral load at study entry must be over 1,000 copies/mL. U.S. trial sites for RESIST 1 can be located through: www.clinicaltrials.gov.
Community representatives met with T-20 makers Roche and Trimeris in New York in January to get a briefing on plans to distribute the injectable fusion inhibitor as soon as it is approved (see Boulder Blues for an account of a meeting with state ADAP directors). Due to an initially limited supply and no reliable guess on how much demand there will be, Roche is setting up the framework for a system that would be able to fairly allocate supplies if required. They will contract with a third-party pharmacy service corporation that will deliver drug kits (either by mail or to selected pharmacies), staff a patient assistance hotline and handle prescriptions for patients unable to pay.
The patient support component of this system will be critical if patients are to have good outcomes when using T-20. It's becoming increasingly clear that T-20 is not an easy drug to take and the decision to begin enfuvirtide therapy should be made in consultation with a physician who has been trained in the correct preparation and administration techniques. Resistance to T-20 can develop fairly quickly if full doses are not taken on a consistent basis, so an individual's informed commitment to making the regimen work is a must.
If you believe you may be a candidate for T-20, be sure your doctor and his or her staff have received the training offered by Roche. It is especially important that Medicaid providers involved with HIV care receive training so that this large segment of the patient population has access to this potentially important new drug and can enjoy the best possible outcome from it.
Although no price has been announced for Fuzeon, it is expected to be a doozy. Roche has been spreading a PR cushion to soften the blow, but there are signs that initial projections of $12,000 per year may be far too low. People with private insurance will be covered, as eventually will Medicaid recipients. But this leaves a large gap in the middle, especially if state ADAP programs decide they cannot afford to add this budget buster to their formularies. Roche has promised to make Fuzeon available to any who cannot afford it through a program administered by their third-party distributor. Details of the plan are yet to come. Expect approval by the end of March.
T-1249, a follow-on compound to T-20 with activity against HIV resistant to T-20, is now apparently on a slow track. Two years ago Trimeris was saying that T-1249 was about two years behind T-20 in the pipeline. Now, the company says not to expect the next fusion inhibitor until 2008, putting it 5 years behind its sibling. It's not clear exactly why this is, although it's likely the company wants to see how T-20 pans out before they sink another $500 million into developing a similar product. The manufacturing process for T-20 is famously difficult and expensive and there has been speculation that Roche may want to explore producing their next long peptide as a biologic product through gene expression instead of by the step-by-step assembly process currently in use. Another theory holds that the company would like to first perfect a pegylated form of T-1249 that would allow weekly injections rather than multiple daily shots. An effective pegylated T-20 would surely be welcomed by people currently taking the drug who have been bothered by painful or troublesome injection site reactions.
Another reason to speed T-1249 along emerged at the Retrovirus Conference where data was shown that indicated while people failing T-20 after one or two years of poking themselves responded to T-1249 during an 11-day activity study, only about half those failing with more than two years of T-20 above their beltlines responded. This may mean that if resistance mutations to T-20 continually accumulate and begin to affect T-1249's activity, then, for the first wave of those starting T-20 in the next few months, 5 years will be too long to wait. Step it up, kids.
Bristol-Myers Squibb reported long-term efficacy and safety results on their experimental, once-a-day, protease inhibitor, atazanavir (ATV) during a poster session at the 10th Annual Retrovirus Conference held in Boston. The trial was a follow up study to an earlier Phase II trial that compared two doses of atazanavir with nelfinavir. Results from the previous study, BMS 008, established that atazanavir was able to produce viral suppression comparable to that of nelfinavir without raising blood levels of cholesterol and triglycerides.
The new trial, BMS 044, either continued patients at their originally assigned doses of atazanavir (400 mg vs. 600 mg, both once-daily) or switched those who had been receiving nelfinavir to atazanavir (400 mg once-daily). All participants also continued stavudine (40 mg twice-daily) and 3TC (150 mg twice-daily).
Results were presented on virologic response, lipid levels and side effects with experience now out to 108 weeks of atazanavir use. Virologic response, defined as the proportion of subjects having a viral load less than 400 copies/mL, was sustained in those originally assigned to atazanavir (80% on ATV 400 mg and 82% on ATV 600 mg). At 24 weeks following the switch from nelfinavir to atazanavir, 86 percent of those switched had a virologic response, up from 71 percent at study entry.
Lipid profiles remained unchanged among those continuing on atazanavir, but improved significantly in those originally assigned to receive nelfinavir. Patients switched experienced median reductions in total cholesterol from 202 mg/dL to 169 mg/dL; reduction in fasting LDL (bad cholesterol) from 132 mg/dL to 99 mg/dL and reduction in fasting triglycerides from 127 mg/dL to 102 mg/dL.
Adverse events were comparable among the study groups and the drug was generally well tolerated. Elevated unconjugated bilirubin was the most frequent laboratory abnormality and was associated with symptoms of jaundice and yellowing of the eyes in as many as 22% of patients. No association between elevated bilirubin and elevated hepatic transaminase levels was observed which supports descriptions of atazanavir-linked hyperbilrubemia as clinically benign. Bristol-Myers Squibb has filed for U.S. and European approval of atazanavir. (Abstract 555, 10th CROI)
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.