And, Not-So-New Drugs
Three New Antivirals Trickle From the Pipeline, But Will They Provide Any Benefit for Those Who Need Them Most?
Whose needs served?
A group of new anti-HIV therapies are about to enter expanded access programs, but heavily pre-treated patients aren't out of the woods yet. Due to cross resistance, at least one of the new products isn't expected to work in people with extensive prior nucleoside experience, and it may be difficult to cobble together a regimen from the two remaining new agents that can reasonably be expected to produce sufficient virologic suppression.
1592 -- late for nearly everyone
Thanks to Glaxo-Welcome's crack marketing team (and a cynically delayed release designed so as not to cannibalize the recent launch of "Combivir"), perhaps the most hotly anticipated of the new therapies is Wellcome's 1592U89 (now known by the name "abacavir"). Early study results suggested as much as a 2 log reduction in plasma HIV RNA when treatment naïve patients were treated with 1592. Data recently presented by Dr. David Hardy to an investigator's meeting sponsored by Glaxo-Wellcome, however, suggests that heavily pre-treated patients may not benefit from 1592. While patients pre-treated with ddI or d4T experienced relatively normal reductions in plasma HIV RNA (about 1.5 log) after twelve weeks of 1592 treatment, patients with extensive AZT or AZT+3TC double nucleoside therapy were much less responsive: after twelve weeks of therapy, patients with more than a year of prior AZT treatment had only a .05 log reduction while patients with extensive AZT+3TC therapy had only a 0.05 log reduction. Since the lion's share of the traditional expanded access population will have received loads of prior AZT (and invariably 3TC too), it is unlikely that they will receive much benefit from 1592 -- at least based on the results from this study.
Due to community pressure, plans for expanded access to 1592 keep changing. The most recent plan was for 1592 to become available beginning September 15, with participating sites allowed to enroll 2 patients per week until the end of the year, some 16 weeks. Eligible patients would have a CD4+ T-cell count < 100 and a plasma viral load > 30,000. The program plans to enroll approximately 2,400 patients in North America and another 900 patients in Europe. Separate (and smaller) expanded access programs will make 1592 available for pediatrics as well as for adults with HIV dementia.
Sustiva, sustava, sustain me
In contrast to the disappointing cross-resistance news with 1592, DuPont-Merck's new non-nucleoside reverse transcriptase inhibitor (NNRTI) DMP-266 (now with the generic name "efavirenz" and trade name "Sustiva"), seems to be active against the most common resistance mutation (Y181) associated with use of nevirapine and delavirdine, the two commercially available NNRTIs. As long as only one mutation (181) is present, current dosing of DMP should be enough to suppress virus, however when two NNRTI resistance mutations (Y181 and K103) are present, DMP may not be enough to suppress replication. Early studies suggest that DMP may be taken once a day, and can reduce viral RNA counts by about 1.5 logs. The most common side effects are lightheadedness and rash.
DuPont-Merck recently announced an expanded access program for DMP that will be available to a limited number of patients (approximately 2,000) through the end of 1997, and will then broaden to include additional patients in early 1998. Patients with < 50 T-cells who are failing current therapeutic regimens are eligible for the program as it is currently designed. Participants, though, will be required to take DMP with a second new drug, such as 1592 or adefovir (see below). DuPont Merck expects to file its NDA for efavirenz in March of next year. For more information on the program, patients and physicians can call 1-800-998-6854.
Gilead Science's adefovir dipivoxil (formerly known as bis-POM PMEA) is a nucleotide analogue which will also be made available through an expanded access program said to be very similar to DuPont Merck's program for DMP-266. Adefovir, to be marketed under the trade name Preveon, is active against the hepatitis B virus and CMV as well as HIV. The drug has been reported to deplete the body's store of L-carnitine levels (which is made by the body to help supply energy to muscles), so supplementation (500 mg once daily) with this amino acid is recommended for people taking adefovir. Gilead's expanded access for adefovir is slated to begin mid-November. Eligible patients will be required to 1) have failed a regimen containing at least two commercially available nucleoside RTIs and one commercially available protease inhibitor; 2) have a CD4 cell count < 50 cells/mm3 3) a plasma HIV RNA copy number > 30,000 within the past 2 months; and 4) not qualify for other adefovir clinical trials. Participants in the adefovir program will also be advised, as in the DMP expanded access program, to add at least one new antiretroviral agent to the mix. Adefovir is administered as a 120 mg tablet once daily. For more information about the adefovir expanded access program, call Gilead at (800) GILEAD-5.
The bottom line...
While two new protease inhibitors, Glaxo-Welcome's GW-141 and Abbott Laboratories' ABT-378 are in the pipeline, there are not yet estimates on when these drugs will become available. Early reports suggest that GW-141 will be cross-resistant with indinavir and ritonavir, however in vitro studies suggest that ABT-378 may be effective against viral strains that are resistant to other protease inhibitors. (More critical on-lookers warn that the 84 mutation knocks ABT-378 on its back.)
Cross-resistance between anti-HIV therapies is continuing to baffle design of expanded access programs. Those patients for whom expanded access is intended -- patients with few other therapeutic options -- will often be the patients least likely to benefit from new therapies. This creates powerful disincentives for companies to make drug available -- just witness the incredibly shrinking expanded access programs over recent years.
On the flip side, companies such as Glaxo-Wellcome have also learned that expanded access schemes represent a powerful promotional tool for manipulating the HIV/AIDS communities. When Glaxo-Wellcome limited access to 3TC just prior to approval, it created strong pressure from AIDS activists to approve the drug despite serious limitations in the available knowledge regarding use of the product. That the company seems to be repeating this pattern with 1592 (Witness, for example, the relentless headline-making paeans from patients with advanced disease who dutifully propose that, "This product could save my life."), is testament to the manufacturer's marketing skills and the community's collective amnesia.
Programs like expanded access and accelerated approval were designed to make available therapies that were desperately needed by patients with few other treatment options. When new products are unlikely to be effective in these patients, AIDS activists will have to ask themselves if programs such as expanded access and accelerated approval are serving their needs, or are simply highly effective pre-approval marketing efforts by pharmaceutical manufacturers. These difficult questions are likely to haunt the AIDS communities for the foreseeable future.