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Looking Down the Drug Pipeline

March 1998

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Aside from the new antiretroviral compounds that will, in all likelihood, be FDA-approved this year (abacavir, amprenavir, efavirenz and adefovir -- for more information on these, see Treatment Issues, Winter 1997/98), there are some other anti-HIV agents in earlier stages of development. Some of these newer compounds will work best in people who have not yet used the commercially available drugs and so have not developed resistance mutations. For this group of people, with little or no treatment history, some of the new compounds may offer more potent and less resistance-prone options than those drugs that are now on the market. Some of the other new agents now in development may offer hope for people with fewer treatment choices -- those who are drug-experienced and have already developed mutations that may confer cross-resistance to all remaining FDA-approved drugs.

New Nucleoside Analogs

Information on two new nucleoside analogs was presented at the 5th Conference on Retroviruses and Opportunistic Infections held in Chicago in February. One of these drugs was FTC (late-breaker 3). FTC is structurally related to 3TC and is hindered by the same mutation at codon 184. FTC is not a drug that would be effective in people who have developed 3TC resistance. However, for 3TC-naïve patients, FTC is extremely potent. Its in vitro activity against HIV is approximately four-to-ten-fold greater than that seen with 3TC.

Results from a small phase I/II trial using FTC monotherapy in ten patients showed an impressive decrease in viral load in 3TC- and abacavir-naïve study subjects. FTC was given in two doses: 25 mg twice a day and 200 mg once a day for 14 days. The five participants in the twice-a-day dosing arm had a baseline viral load of 15,900 (by standard PCR) and experienced an average 1.4 log (96%) drop in viral load from baseline. Of the five participants in the once-daily dosing group, the baseline viral load was about 50,000 (4.7 logs) and all five experienced an average 2.1 log (99.2%) decrease in viral load. Based on this preliminary data, FTC could be a once-a-day agent. The drug's manufacturer, Triangle Pharmaceuticals, is designing pivotal trials for this summer.

The other nucleoside analog reported on at the Chicago Conference was F-ddA or lodenosine, a fluoridated compound that has a structure akin to ddI and a similar activity profile. F-ddA was originally synthesized at the National Cancer Institute (NCI) in the mid-1980s; but, unlike ddI, development of the compound stalled, and it was never commercially produced. F-ddA has good oral bioavailability with or without food (65% in non-fasting conditions and 75% in fasting conditions), a long intracellular half-life that allows for the potential of once-daily dosing, little or no bone marrow suppression, and is less likely to cause peripheral neuropathy than ddI or ddC. Unlike ddI, stomach acids do not degrade F-ddA, so it can be administered without an antacid, thereby avoiding side effects attributable to the use of a buffer. And, like ddI, F-ddA may work well with hydroxyurea.

Interest in the drug was rekindled when it was discovered that F-ddA's resistance profile was different from the other nucleoside analogs. A mutation at codon 119 of the reverse transcriptase gene confers resistance to F-ddA. From what is known to date, this mutation would not limit the efficacy of any other drug. In addition, as is seen with ddI, resistance to F-ddA is slow to emerge. The drug has shown in vitro activity against strains of HIV resistant to AZT, ddI and ddC. Multidrug-resistant strains of HIV are moderately resistant to F-ddA (three-to-four-fold decreased susceptibility). It is difficult, however, to predict clinical efficacy of a drug based on test-tube research.

Robert Yarchoan, M.D., of NCI, presented a poster in Chicago on the results of a small phase I dose-escalating study of F-ddA monotherapy (abstract 651). F-ddA was administered twice a day in doses ranging from 0.2 mg/kg to 3.2 mg/kg for 12 weeks to 22 pretreated symptomatic study subjects with an average baseline CD4 count of 164. Eighteen participants had received more than six months of prior antiretroviral treatment. On the highest two doses tested, 1.6 mg/kg and 3.2 mg/kg twice a day, the median decrease in viral load was 0.49 log (68%) at week six. Although the effect on HIV RNA was modest, Dr. Yarchoan stated, "I was actually pretty pleased with the results. One, because this is at a dose that's completely nontoxic as far as we could tell, at least over 12 weeks. The other is that these were all patients that had extensive therapy before this. I think to see that degree of viral suppression in a heavily pretreated population is pretty good." F-ddA is going on to further studies at NCI as a once-a-day agent at 3.2 mg/kg, 4.5 mg/kg and 6.4 mg/kg (roughly 225 mg-450mg). It will be given as monotherapy for four weeks, and then d4T and nelfinavir will be added. Anyone interested in enrolling can call 301/496-8959 for adult trials. The drug is also being tested as a liquid pediatric formulation. For information about this trial call 301/402-1391.

F-ddA will probably not reach the FDA for at least two more years. US Bioscience licensed the compound in 1995 and plans an initial phase II trial looking at two different doses of once-a-day F-ddA (300 mg and 400 mg) in combination with a protease inhibitor and a nucleoside analog in antiretroviral-naïve participants. This study should get started within the next few months. Assuming all goes well, the protocol could be expanded into a pivotal trial for FDA approval. Future plans also include looking at treatment-experienced participants. Anyone interested in information on the trials can call 800/200-8070.

Update on a New Nucleotide Analog

Gilead Sciences continues to work on a class of antiretroviral drugs called nucleotide analogs. These compounds contain a phosphate group not found in the nucleoside analogs. What this means is that the nucleotides only require two, rather than three, steps to become fully active once in the body. To date, cidofovir, for the treatment of CMV, and adefovir, for the treatment of HIV, have been developed by Gilead. A third nucleotide analog, the oral prodrug form of PMPA (known as bis-POC-PMPA), is currently under development as an anti-HIV therapy.

A poster at the Retrovirus Conference reported on in vitro research on PMPA's resistance profile (abstract 680). PMPA exposure selected for a mutation at codon 65 of the reverse transcriptase gene. HIV with this mutation had a three-to-four-fold decrease in susceptibility to PMPA and showed moderate cross-resistance to ddC, ddI, 3TC and adefovir in vitro. HIV with the 184 mutation associated with 3TC resistance had an increase in sensitivity (about two-fold) to PMPA, possibly making the drug an option for 3TC-experienced patients. HIV with the 215 mutation, usually found in AZT-experienced patients, showed less than two-fold decreased susceptibility to PMPA.

Steven Deeks, M.D., of the University of California at San Francisco, presented data from a phase I/II study of oral PMPA at the Chicago Conference (late-breaker 8). The double blind, placebo-controlled study used escalating doses of once-daily PMPA monotherapy in 36 study subjects with average baseline CD4 counts of 350 and viral loads of 31,700 copies/ml. More than half the participants were treatment-experienced. Median decreases in viral load after 28 days of dosing were 0.32 log (52%), 0.44 log (67%) and 1.22 log (94%) in the 75 mg, 150 mg and 300 mg groups respectively. (In a phase I/II study using IV PMPA for eight days, median viral load was reduced by 1.1 [92%] log in the high-dose group and sustained for one week after treatment ended. While the viral load decrease on the highest dose of oral PMPA was roughly equivalent, a better response had been hoped for because the oral formulation has much higher cellular permeation and in vitro antiretroviral activity than the IV formulation. Higher doses of the oral prodrug might improve its activity but Gilead wants to compile additional safety data before increasing the dose studied.)

One reason Gilead is playing it safe is that long-term activity studies of monkeys receiving subcutaneous PMPA at doses 10 to 30 times the amount tested in humans found some bone weakness and fractures after 12 months. This could be due to an effect the drug had on the cells involved in bone formation or it could be an indirect effect based upon changes in renal (kidney) function. The kidneys modulate calcium and phosphate metabolism and a loss of these substances could lead to bone weakness. Evidence of renal dysfunction has been seen as a long-term toxicity in a small percentage (4% to 6%) of adefovir users who have received the drug for over six months, a side effect that did not occur in shorter-term dosing studies.

Gilead is proposing phase II trials for oral PMPA consisting of two longer-term dosing studies. The trials are designed to evaluate the 150 mg and 300 mg doses in combination regimens for up to 48 weeks in treatment-naïve and treatment-experienced patients. These doses were well tolerated in the one-month phase I/II study mentioned above. If, after three to six months, the doses prove to be safe, Gilead will consider dose escalating to 600 mg. According to James Rooney, M.D., vice-president for clinical affairs at Gilead, "We're balancing short-term activity against long-term safety." Anyone interested in more information about these trials can call 800/GILEAD-5.

In addition, a phase I/II study is being undertaken by HIVNET (the NIH-funded HIV Network for Prevention Trials) to evaluate the safety and tolerability of a topical formulation of PMPA in HIV-positive and -negative women as a vaginal microbicide. A gel form of PMPA provided protection against SIV (the monkey version of HIV) when applied intravaginally in primates.

Protease Inhibitors: The Next Generation

At a community presentation at the Chicago Conference, Eugene Sun, M.D., of Abbott Laboratories, stated that the world doesn't need another "me too" protease inhibitor. To that end, the company has been working on a second-generation protease inhibitor for the past several years. Abbot has developed what they consider to be a substantially improved drug, ABT-378, which in the test tube is one of the most potent protease inhibitors discovered to date. Compared to ritonavir (Abbott's original protease inhibitor), the in vitro antiviral activity of ABT-378 is ten-fold greater. According to Dr. Sun, "If we can get the target drug levels we're shooting for, then we would expect 378 to have some activity in patients failing other protease inhibitors." High drug levels have been achieved and tolerated in HIV-negative volunteers. Although ABT-378 is more potent than the four protease inhibitors currently on the market, its basic structure is the same, and it is also vulnerable to the development of resistance.

ABT-378 is administered with small amounts of ritonavir and the two drugs will probably be combined in one pill. Ritonavir is only being used to increase ABT-378 levels in the blood and will not have any independent antiviral effect. Therefore, the two drugs together are not considered a dual protease inhibitor regimen. The exact ratio and amounts of ABT-378 and ritonavir have yet to be selected, but the doses that are currently being studied are 200 or 400 mg of ABT-378 and 100 or 200 mg of ritonavir twice a day. This dual compound is known as ABT-378/ritonavir.

There are several improvements in dosing with ABT-378/ritonavir. There are no food requirements, so it can be taken on a full or an empty stomach. In addition, the combination pill will probably not need refrigeration. Perhaps most importantly, the side effects seen to date seem to be less severe than those commonly experienced by ritonavir users. In dosing studies in healthy volunteers, ABT-378/ritonavir has been well tolerated. There was a very low incidence of nausea, vomiting and perioral parasthesia (tingling in the mouth). Cases of diarrhea generally resolved after a few days.

Several trials are in the works. Protocol FDA 285A (Abbott protocol number M97-720) is currently enrolling treatment-naïve participants in a dose-ranging phase II study using a twice-a-day regimen of ABT-378/ritonavir in combination with d4T and 3TC. Another trial, now in the final phases of planning, will look at protease inhibitor failures. Anyone interested in finding out more about these trials can call 800/TRIALS-A.

Immune-Based Therapy

Immune-based therapies have been proposed for some time now as potential novel anti-HIV treatments. GM-CSF (Leukine, sargramostim) is a hormone that stimulates the production of various blood cells in the bone marrow. It belongs to a family of cytokines called colony-stimulating factors that have been used to treat neutropenia (low levels of infection-fighting neutrophils in the blood) and counteract bone marrow toxicities due to medicinal drug use or bone marrow transplantation (see Treatment Issues, Jan. 1997).

In 1996, Immunex, the manufacturer of GM-CSF, initiated a large phase III trial to evaluate the compound in reducing opportunistic infections and deaths in patients with advanced AIDS. Participants were to be randomized to receive either GM-CSF or placebo in addition to standard of care antiretroviral therapies for a minimum of six months. Due to a low accrual rate, Immunex sought and received permission from the FDA to reduce the sample size from 500 to 300 participants. At the same time, additional endpoints were added to the study to evaluate the potential effect of GM-CSF, in combination with antiretroviral therapies, on viral load and CD4 counts. Enrollment has finally completed in the last few months and findings should be announced in 1999.

One of the misgivings about GM-CSF has always been that it may increase viral replication as well as stimulating blood cell proliferation. This may be less of a concern with the availability of highly active antiretroviral therapy (HAART) to suppress viral load. (Additionally, the ability of GM-CSF to increase macrophage replication may be exploited to aid in draining the viral reservoirs, see page 4).

A small safety and efficacy study was presented at this year's Retrovirus Conference (abstract 615). Twenty HIV-positive participants on stable protease inhibitor-containing regimens were randomized to receive either GM-CSF or placebo for eight weeks. At baseline, in the GM-CSF group, median CD4 count was 114 and median viral load was 100,000 copies/ml. In the placebo group, baseline median CD4 count was 240 and median viral load was 19,950 copies/ml. After eight weeks of the study and four weeks of follow-up, there was no significant difference observed for mean change from baseline in CD4 count and viral load. Although the number of participants was very small, eight of ten in the GM-CSF arm demonstrated a 30% increase in CD4 cells as opposed to three of ten in the placebo group. Beyond mild injection-site reactions, no significant toxicity was seen (GM-CSF must be administered by injection). Results from the larger phase III trial mentioned above will provide more information next year.

Fusion Inhibitors

GM-CSF also was presented in a new light, as a possible inhibitor of chemokine receptor sites. It has long been known that HIV enters a host cell by fusing to the protein structure on that cell's surface that acts as a CD4 receptor site. However, important discoveries over the last two years have demonstrated that HIV also uses chemokine receptor sites on the host cell's surface, such as CCR5 and CXCR4, in conjunction with CD4, to gain entry to the cell (see Treatment Issues, May 1996, and June/July 1996, page 28).

At a poster session, Immunex presented in vitro research showing that GM-CSF may inhibit the expression of the co-receptors CCR5 and CXCR4 on macrophages and monocytes (abstract 37). If these receptors are not displayed on the cell surface, then HIV cannot gain entry and infect new cells. In addition, chemokines secreted by GM-CSF-treated cells protected nearby uninfected cells from viral entry by binding to CCR5 and CXCR4 on those cells. GM-CSF-treated macrophages showed a 70- to 100-fold decreased entry of HIV. It remains to be seen whether HIV could adapt and infect new cells as effectively if the CCR5 and CXCR4 co-receptors were not readily available.

Bruce Dezube, M.D., of Beth Israel Deaconess Medical Center in Boston, reported on a compound that uses a different mechanism of action to block HIV from fusing with CXCR4 and CCR5. Instead of inhibiting the expression of the chemokine receptor sites on the cell surface, FP-21399 (FP) interferes with the ability of the HIV envelope glycoproteins to use CXCR4 and CCR5 as co-receptors when entering CD4 cells. FP concentrates in the lymph nodes, which are important viral reservoirs. In addition, the drug has demonstrated antiviral activity against many clinical and laboratory strains of HIV, including those that are AZT-resistant. FP is now being developed as a fusion inhibitor by Lexigen Pharmaceuticals in Lexington, Massachusetts.

Dr. Dezube reported on a small phase I dose escalation trial of intravenous FP in 21 participants with baseline CD4 cell counts between 50 and 400 (abstract 650). Concomitant antiretroviral therapy was permitted but not required. Thirteen participants in the repeated dosing regimen received infusions of various doses of FP once-weekly for four weeks. Nine of these 13 participants showed an increase in CD4 count of at least 15% over their baseline values. Two of the thirteen participants showed a decrease in viral load of 1 log (90%), and two additional patients went from low viral loads to below the limit of quantification. The most frequent adverse event was a transient, dose-dependent appearance of green urine, resulting from the drug's blue color mixing with urine's ordinary yellow hue. Some fair-skinned patients also experienced a grayish discoloration of the skin. No deleterious effects were associated with the discoloration. Dr. Dezube explained that lymph nodes apparently become saturated with FP before it shows up in the skin as a dusky hue. The dose could be adjusted so that the drug would accumulate only in the lymph nodes and not overflow into other tissues.

Lexigen is conducting a phase II study to explore the immunologic and virologic activity of the compound. A once-a-month dose has been selected as the best candidate for further investigation. (Not only is the once-a-month dosing schedule easier than the once-a-week regimen used in the phase I trial, but there have been no reports of skin discoloration and less frequent reports of green urine at the lower dose.) The phase II trial is basically a rescue protocol looking at 40 participants who are failing on protease inhibitor regimens. FP is added to their background antiretrovirals and, in some cases, study subjects have chosen to stop taking their other drugs due to their poor response. Either way, FP will be administered for 48 weeks with little support from concurrent drugs, easing the way for the possible emergence of resistance.

Tom Dahl, Ph.D., vice president of clinical products development at Lexigen, said that in a previous phase II study conducted by the company, researchers observed hints of a cellular immune response in a small subset of subjects at risk for disease progression or development of opportunistic infections. Although it is premature to make assumptions from one trial, Dr. Dahl suggested that, "By interfering with fusion between the virus and the cells, we may be able to preserve the macrophage function and, in general, provide a cellular immune response." The current study is designed to evaluate if there is a shift in participants' ability to mount a cellular immune response. Dr. Dahl also pointed out that resistance to the drug has been difficult to develop in a laboratory setting.

Several other posters at the Retrovirus Conference looked at possible chemokine receptor site inhibitors (abstracts 620 and 287). For the most part, this research is still at a preclinical stage, and many of the approaches being studied have not yet been developed into drug form. With more pharmaceutical companies jumping on the chemokine bandwagon, more progress is expected. To cite one example, Hoffman-La Roche recently announced a collaboration with the biotechnology firm Progenics to conduct drug discovery research on agents that would target HIV co-receptor sites.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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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.
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