Contents
ANTI-HIV DRUGS IN DEVELOPMENT
By Marshall J. Glesby, MD, PhD
The past two years have been productive from the standpoint of antiretroviral drug development, with approval by the Food and Drug Administration (FDA) of six new drugs to fight HIV infection. Four protease inhibitors and two nonnucleoside reverse transcriptase inhibitors (NNRTIs) were added to the five approved nucleoside analog drugs. Although these 11 drugs can be combined in a large number of ways, due to cross-resistance among drugs in the same class (see page 4), many persons living with HIV/AIDS have exhausted all available options. Furthermore, most of the combination drug regimens are extremely difficult to take and may have considerable side-effects. Given the obvious need for new and improved antiretrovirals, what candidates are in the drug development pipeline?
Instead of addressing this question by compiling an exhaustive listing of drugs in development, this article will focus on the drugs whose new drug applications are closest to being submitted to the FDA for approval. Since very limited clinical data are available on drugs which are earlier on in the development process, some of these drugs will be discussed only briefly.
Efavirenz (DMP 266)
Efavirenz (Sustiva®), also known as DMP 266, is an investigational NNRTI under development by DuPont Merck. Early clinical studies have generated considerable enthusiasm for this once-daily drug for several reasons.
Combinations of efavirenz with and without protease inhibitors have shown significant HIV viral load reductions. In two small studies of efavirenz in combination with indinavir (CrixivanJ), 94% and 88% of patients achieved viral loads below the level of quantitation (less than 400 copies/ml) at 24 and 48 weeks, respectively. The combination of AZT + 3TC + efavirenz is also being studied, and early results have shown that 22 of 25 (88%) of patients achieved viral loads below 400 copies/ml at 16 weeks. Some experts consider the combination of an NNRTI with two nucleoside analogs (here, efavirenz with AZT and 3TC) to be an attractive approach for initial HIV therapy since patients who fail such a regimen could receive a protease inhibitor subsequently. Others argue for using the best possible combination up front, that is a regimen containing a protease inhibitor. Studies to compare these two approaches are needed.
Preliminary laboratory data suggest that efavirenz may retain potent activity against strains of HIV that have mutations associated with resistance to other NNRTIs (nevirapine and delavirdine). It remains to be seen, however, if the drug can be beneficial clinically in patients who have developed resistance to other NNRTIs.
The side effect profile of efavirenz to date has been favorable. Some patients have experienced lightheadedness, dizziness, and feeling "out of sorts"; these side effects occur less frequently if the drug is taken at bedtime and tend to diminish after a few weeks of treatment. Rash, which occurs in about 20% of patients taking nevirapine or delavirdine, has also been reported with efavirenz. In one study, the same number of rashes were seen in patients taking the combination of efavirenz and indinavir versus indinavir alone. Although there have been cases of severe rash requiring hospitalization, most patients with rashes are able to continue taking efavirenz. Other reported side effects include nausea, vomiting and headache.
Efavirenz is currently in phase III studies, and DuPont Merck will likely seek accelerated approval by the FDA in the first quarter of 1998. An expanded access program for efavirenz was launched in late September 1997. The main eligibility criteria for this program are: age 13 years or older, T cell count of less than or equal to 50 in the last 90 days, and failure or intolerance of the current drug regimen with no other appropriate treatment options. In addition, efavirenz must be used with at least one antiretroviral which the patient has not taken previously. More information about the program can be obtained by calling 800-998-6854.
In addition to one of the phase III trials, CRIA is participating in an open label safety study of efavirenz in combination with one or more investigational antiretrovirals for patients with no other treatment options. To be eligible for this salavage protocol, patients must be failing their current drug regimen based on viral load, CD4 count or clinical deterioration (as specified in the U.S. Public Health Service Guidelines draft) and be able to obtain another investigational agent through expanded access. At this time, adefovir dipivoxil and abacavir (1592U89) are the only other drugs available by this mechanism (see below).
Adefovir Dipivoxil
Adefovir dipivoxil (Preveon™), also known as bis-POM PMEA, is an investigational nucleotide analog under development by Gilead Sciences. Nucleotide analogs differ chemically from nucleoside analogs (the class that includes AZT, ddI, ddC, d4T, and 3TC). In order for nucleoside analogs to be active, they must have phosphate molecules added to their chemical structures by an enzyme inside of the body's cells. This activation step is bypassed for the nucleotide analogs as they already contain the phosphate groups. This property confers a theoretical advantage to the nucleotide class of drugs as they are active in resting cells — including monocytes and macrophages, which are an important reservoir for HIV — and may prime uninfected cells to resist viral replication when subsequently infected by HIV.
Adefovir dipivoxil given alone (monotherapy) demonstrated modest anti-HIV activity in an early study, with an average reduction in HIV viral load of about 0.5 log (70% reduction). This is about the same magnitude of reduction that is seen with AZT monotherapy. Of course, no antiretroviral drug should be given as monotherapy, and adefovir dipivoxil is being studied in a number of different combinations . Like efavirenz, adefovir dipivoxil is taken once daily.
Adefovir dipivoxil appears to be active in the test tube against a variety of viruses that HIV-infected persons are prone to acquire, such as herpesviruses, CMV, and hepatitis B. Studies are underway to test whether adefovir dipivoxil can prevent CMV disease in patients with advanced HIV disease and whether it is effective against hepatitis B.
Another potentially important feature of adefovir dipivoxil is its resistance profile, which appears to be unique thus far. Resistance to adefovir dipivoxil appears to develop slowly, and there appears to be little or no cross-resistance with available antiretroviral drugs. If this resistance profile is verified in clinical trials, the drug may be an important option for persons with extensive antiretroviral drug experience.
The most common side effects seen in early studies of adefovir dipivoxil include nausea,vomiting, diarrhea, elevation of serum creatinine (a measurement of kidney function), protein in the urine, and liver inflammation. Because the drug may deplete the body’s supply of carnitine — a natural substance used by the body in energy production — L-carnitine supplements must also be taken once a day.
Adefovir dipivoxil is currently in phase III studies, and Gilead will likely seek accelerated approval by the FDA in 1998. An expanded access program was launched in December 1997 for patients with less than 50 T-cells, viral load greater than 30,000 copies/ml, and no other effective treatment options. More information on this program can be obtained by calling 800-GILEAD-5. CRIA will be participating in this program.
Abacavir (1592U89)
Abacavir, commonly referred to as "1592", is an investigational nucleoside analog under development by Glaxo Wellcome. It appears to be the most potent drug of this class studied to date. Data from small numbers of patients with less than 12 weeks of prior AZT use who received abacavir alone or in combination with AZT had average reductions in viral load of 1.7 to 2.1 logs (98-99% reduction) at 12 weeks. Abacavir has high penetration into the cerebrospinal fluid, the fluid around the brain, and is also being studied as a treatment for HIV-related dementia. Dosing is twice a day.
Preliminary studies of the resistance profile of abacavir suggest that there may be some degree of cross-resistance between it and the available nucleoside analogs. Of particular concern is a mutation in HIV (at position 184) that is associated with resistance to the commonly used drug 3TC (Epivir®). This mutation results in about a three-fold reduction in sensitivity to abacavir in the test tube. It remains to be seen, however, what clinical implications these laboratory findings will have. Preliminary evidence suggests that patients with the 184 mutation may still respond somewhat to abacavir but not to the same degree as those without the mutation.
Side effects seen in early studies of abacavir include nausea, headache, diarrhea, rash with or without fever, insomnia, dizziness, and abdominal pain.
The development of abacavir has generated considerable controversy in the HIV community. Activists have protested what they perceive to be the slow development of a drug that may be a potential option for many who have failed existing therapies and have asserted that Glaxo Wellcome has deliberately dragged its feet to prevent cutting into the market for their leading combination of AZT and 3TC. To explain the delay in broadening access to abacavir, Glaxo cited a lack of safety data in sufficient patients and inadequate supply of drug.
A compassionate use program for abacavir started in July 1997 through approximately 65 clinical trials sites nationwide. Enrollment has been limited to about 100 patients per week, with the demand for the drug far exceeding what Glaxo is supplying, which has led to further protests. To be eligible for enrollment, patients must have a T cell count less than 100, a viral load greater than 30,000 copies/ml, and a history of treatment with two nucleoside analogs and a protease inhibitor or intolerance to combination therapy. Information about study sites can be obtained by calling 800-501-4672. Compassionate use programs also exist for children failing antiretrovirals and adults with dementia. Abacavir is currently in phase III trials, and Glaxo Wellcome will likely seek accelerated approval by the FDA in 1998. A larger expanded access program is planned for March 1998.
141W94 (VX-478)
141W94 is an investigational protease inhibitor under development by Glaxo Wellcome. It is sometimes to referred to as the Vertex protease inhibitor because it was discovered by Vertex Pharmaceuticals and licensed to Glaxo. In animal studies, 141W94 has shown good penetration into the brain.
In an early clinical study, 141W94 taken as monotherapy caused, on average, about a 1.7 log (98%) reduction in viral load. The drug, which is taken twice a day, has been well tolerated in early studies. Side effects to date have included nausea, loose stools, diarrhea, abdominal pain, and headache. Rashes have also been seen, several of which have been severe enough to mandate discontinuation of the drug.
141W94 is currently in phase III trials, and Glaxo Wellcome will likely seek accelerated approval by the FDA some time in 1998. CRIA is participating in one of the phase III trials comparing 141W94 to indinavir (CrixivanJ) in patients with at least 12 weeks of nucleoside analog experience, no prior protease inhibitor therapy, and viral loads greater than 400 copies/ml.
Drugs in Early Development
Several nucleoside analog drugs are in the early stages of clinical testing, including the following: Lobucavir (Bristol-Myers Squibb) has activity in the test tube against CMV, other herpesviruses, hepatitis B and HIV, and is in phase I testing. F-ddA (US Bioscience) is chemically related to ddI but does not have to be administered with buffers for stomach acid, which may make it easier to tolerate. It is being studied at the National Cancer Institute in Bethesda, MD. FTC (Triangle Pharmaceuticals), a drug with activity in the test tube against HIV and hepatitis B, is in phase I testing.
MKC-442 (Triangle Pharmaceuticals) is a nucleoside analog that functions as an NNRTI. Preliminary data have shown about a 1 log (90%) reduction in viral load at the highest dose studied to date, with headache and loose stools as the most common side effects. Loviride (Jannsen Pharmaceutica) is an NNRTI that has been studied outside of the U.S. in several large studies. Little benefit was seen in one study when the addition of loviride plus 3TC was compared to adding 3TC alone to background therapy with other nucleoside analogs. Loviride is apparently not going to be studied in the U.S. at this time. HBY 097 (Hoechst/Bayer) is an NNRTI with a unique chemical structure that has caused reductions in viral load of about 1.5 logs (97%) as monotherapy in an early study. Phase II studies are underway.
There are a handful of second generation protease inhibitors in preclinical and early clinical development. ABT-378 (Abbott Laboratories) appears to be a very potent drug that is chemically similar to ritonavir (Norvir®) but ten times more active against HIV in the test tube. It has been studied only in healthy, HIV-negative volunteers to date but should be entering early clinical trials for HIV-infected patients soon. PNU-140690 (Pharmacia & Upjohn) is one of the more exciting drugs in early clinical development. Unlike the available protease inhibitors, it has a completely different type of chemical structure, and laboratory studies suggest that it may have activity against HIV strains that are resistant to protease inhibitors such as ritonavir and indinavir. It remains to be seen whether this will hold up in clinical studies. Bristol-Myers Squibb recently acquired two protease inhibitors that were originally being developed by Ciba-Geigy (Novartis). One of these drugs, BMS-234475 (formerly CGP-73547), is in phase I testing. Other protease inhibitors with chemical structures that differ from the currently available drugs — and thus have the potential to be active against resistant HIV strains —are in preclinical development.
Two nucleotide analogs are in early clinical development by Gilead Sciences: PMPA is given intravenously and the prodrug, bis-poc PMPA, is an oral form of PMPA which gets converted into active drug in the body. A small phase I study of PMPA demonstrated about a 1 log (90%) reduction in viral load at the highest dose tested, though this may not be the highest dose that can be given.
Fusion inhibitors are drugs which are designed to interfere with the attachment of HIV to cells. Several fusion inhibitors are in early clinical development. Pentafuside (T-20) (Trimeris, Inc.) is given intravenously, and a phase I study showed about a 1.5 log (97%) reduction in viral load at two weeks. FP-21399 (Fuji) works by a similar mechanism.
Integrase inhibitors are designed to inhibit HIV’s integrase enzyme, which, like reverse transcriptase and protease, is essential for its replication. The function of integrase is to bind to HIV DNA, which reverse transcriptase copies from the viral RNA, and integrate it into the cell’s genetic material. Zintevir (AR 177; Aronex Pharmaceuticals) works by inhibiting the binding of integrase to the HIV DNA, rather than inhibiting the enzyme’s activity per se. It is given intravenously and is being studied in a phase I/II trial at NY Hospital-Cornell Medical Center. Zinc fingers are structures that help package HIV genetic material into newly created viruses and appear to play a role in an earlier stage of the viral life cycle. CI-1012 (Parke Davis) is a zinc finger inhibitor in phase I development at the National Cancer Institute. A Dutch company (Van de Velde) is developing a similar type of drug called ADA (azodicarbonamide) in Europe.
Antisense drugs are small molecules, usually short pieces of DNA, that are designed to enter HIV-infected cells and inhibit the action of viral genes. GEM 91 (Hybridon, Inc.) is an antisense compound in phase II development. Based on studies in the test tube, it appears to inhibit several stages of the HIV life cycle, including the absorption of HIV into cells, the reverse transcription of viral RNA into DNA, and the production of proteins needed in the latter stages of virus production. Given intravenously, it has resulted in short term reductions in virus levels within cells of up to 90%. An intramuscular formulation of the drug is also under development.
Some of these drugs in the early stages of development offer the hope of increasing the treatment options of those who are exhausting the currently available drugs. In particular, drugs in new classes that attack different stages of the HIV life cycle may circumvent the problem of cross-resistance within existing classes of drugs. More data are certainly needed on the safety and efficacy of these investigational drugs before we can even begin to speculate what impact they might have on treating HIV infection. Information about participating in clinical trials of many of the drugs mentioned in this article can be obtained by calling 800-TRIALS-A or by contacting the AIDS Treatment Data Network (800-734-7104). For more information about CRIA's clinical trials, call 212-924-3934. Dr. Marshall J. Glesby is the Medical Director of CRIA.
Dr. Marshall J. Glesby is the Medical Director of CRIA.
