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Anti-HIV Drugs in Early Development

Winter 1998/1999

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated.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!

The anti-HIV drug development pipeline is like a crystal ball: it is filled with an abundance of hope, surprises, and disappointments. Unfortunately, we are still very much dependent on the predictions of the crystal ball. All of the currently available anti-HIV drugs are far from ideal; we still face problems of side effects (both short- and long-term), adherence issues, drug resistance, cost, and potency. Alas, hopes of long-term management and eradication both depend on an ever-growing number of therapeutic options.

Luckily, there are a number of promising drugs in the early stages of development. While it may be some time before these drugs are ready for approval, we can expect some of these to enter large clinical trials over the next year. Here's a look at what the crystal ball has in store:


Nucleoside Analogues (NRTIs)

Nucleoside analogue reverse transcriptase inhibitors ( NRTIs) -- the class of drugs that includes AZT, 3TC, ddI, d4T and abacavir -- are still being developed for the treatment of HIV. Three newer compounds are currently in the drug development pipeline and may prove to be effective anti-HIV therapies.

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Currently in phase I/II studies is lodenosine (also known as F-ddA), an NRTI being developed by U.S. Bioscience. A particular advantage of lodenosine is that, unlike ddI, it can be digested and metabolized in the stomach without an antacid buffer. The antacid buffer in ddI requires that it be be taken on an empty stomach and has been suggested to be the root cause of ddI's side effects. According to one preliminary study, lodenosine results in a half-log drop in viral load when taken alone, which is similar to that of other NRTIs. In test tube studies, lodenosine appeared to be active against HIV strains already resistant to AZT, ddC, and ddI, as well as non-nucleoside reverse transcriptase inhibitors (NNRTIs) -- good news for patients resistant to these drugs.

Another NRTI in development is FTC. The drug is manufactured by Triangle Pharmaceuticals and, at least in test tube studies, appears to be active against both HIV and hepatitis B virus (HBV). At the present time, the drug is being developed using a once-daily formulation (200 mg) and was associated with a 1.4 log drop in viral load after 14 days of use. Unfortunately, individuals already resistant to 3TC may not benefit from taking FTC as one of the most common mutations that confers resistance to 3TC also confers resistance to FTC.

A third NRTI in development is dOTC (also known as BCH-10652). BiochemPharma is the manufacturer and it is currently in Phase I, dose-finding studies. According to the manufacturer, laboratory tests have shown dOTC to be active against HIV strains resistant to 3TC, ddC, adefovir dipivoxil (a nucleotide analogue being developed by Gilead Sciences), and AZT.


Non-Nucleoside Analogues (NNRTIs)

Currently in phase II studies is MKC-442, an NNRTI being developed by Triangle Pharmaceuticals. It is expected that this drug will be used at doses between 750 mg and 1000 mg twice daily. According to results from one preliminary study involving 35 patients, the drug reduced viral loads by more than 1 log during the first week of therapy.

Drugs in Development

NUCLEOSIDE ANALOGUES

  • lodenosine (F-ddA)
  • FTC
  • dOTC (BCH-10652)


NON-NUCLEOSIDE ANALOGUES

  • MKC-442
  • S-1153


PROTEASE INHIBITORS (PI's)

  • ABT-378
  • tipranavir (PNU-140690)
  • DMP-450
  • BMS-232, 632
  • PD-178390


OTHER ANTIVIRALS

  • CI-1012
  • Pentafuside (T-20)
  • Zintevir
MKC-442 is very similar to today's already approved NNRTIs. For starters, it is associated with rapid resistance, a common occurrence among patients who took either nevirapine or delavirdine as monotherapy in earlier clinical trials; patients who took MKC-442 as monotherapy in a clinical trial began to see their viral loads head back upwards after one week of use. MKC-442 is also associated with rash, a common side effect reported by patients taking nevirapine, delavirdine, and efavirenz. While more data from resistance studies are needed, at least one team of researchers has suggested that MKC-442 is active against HIV strains already resistant to nevirapine. MKC-442 also poses a problem for people looking to avoid drug interactions. Given that the drug is metabolized by the cytochrome P450 enzyme system, interactions with oral contraceptives, protease inhibitors, rifampin, and rifabutin are likely to be discovered. The drug has also been shown to increase AZT levels in the blood by 90%, which will probably require a dose reduction of AZT.

Coming from a biotech group in Japan via Agouron Pharmaceuticals is S-1153. The drug is currently in Phase II studies; Phase I study results were presented at the 12th World AIDS Conference in Geneva last summer. According to test tube studies conducted as part of the Phase I trial, the drug may prove to be active against strains of HIV that are cross-resistant to nevirapine, delavirdine, and efavirenz. Like the currently approved NNRTIs, however, resistance is quick to occur with S-1153, at least when taken as monotherapy.

Other NNRTIs in the early stages of development are carbaxanilide analogues, calanolide A analogues, and the compound PNU-242721. Data regarding these drugs are limited, as they are just now entering human studies.


Protease Inhibitors

Without a doubt, the rapid development of new protease inhibitors (PIs) is one of the most pressing concerns on the minds of both patients and doctors. For all HIV-infected patients, there is a demand for new PIs that are powerful and easier to use (ie., patient-friendly dosing schedules and fewer side effects); for patients who are resistant to the available PIs, there is an urgent need for newer compounds with unique resistance profiles. In turn, the true test of the newest PIs will be their efficacy in patients with prior protease inhibitor experience.

Currently in Phase II clinical trials is ABT-378, a protease inhibitor being developed by Abbott Laboratories, the company that produces ritonavir. In test tube studies, ABT-378 has been shown to be 10 times more powerful than ritonavir. When used in combination with small amounts of ritonavir, ABT-378's activity in the blood is prolonged, allowing a twice-daily dosing schedule. In a presentation at the 12th World AIDS Conference, one team of researchers reported some preliminary data from a study comparing two doses of ABT-378 in combination with low-dose ritonavir (100 mg). Thirty-two patients who had never taken a protease inhibitor before were enrolled in the study. After three weeks of ABT-378/ritonavir therapy, the patients' viral loads had dropped by 2 logs; the majority of those treated for 20 weeks had viral loads below the level of detection of the first-generation test (<400 copies).

"For all HIV-infected patients, there is a demand for new protease inhibitors that are powerful and easier to use... The true test of the newest protease inhibitors will be their efficacy in patients with prior protease inhibitor experience."

At the present time, very little is known about ABT-378's resistance profile. However, both the manufacturer and a handful of independent researchers have suggested that it is effective against strains of HIV resistant to ritonavir, indinavir, and saquinavir; data from clinical trials involving patients with a history of protease inhibitor failure are anxiously awaited.

Situated further back in the pipeline is tipranavir (also known as PNU-140690). According to its manufacturer, Pharmacia & Upjohn, tipranavir also appears to be active against several protease inhibitor-resistant strains of HIV, including those resistant to indinavir and ritonavir. At the 12th World AIDS Conference, interim data from a preliminary study of the drug were reported. All patients were hospitalized for the initial 11 days of therapy and then discharged and asked to continue taking the drug under their own supervision. According to the results, tipranavir was well tolerated with no serious adverse events reported during the twelve-week study period. The 24 patients enrolled were taking a double NRTI combination (i.e., d4T and 3TC) at the time of entry into the study. After the 11-day hospital phase of the study, most patients saw their viral loads decrease an additional 1.0 - 1.3 logs after eleven days of therapy. Unfortunately, viral load levels began to increase again after twelve weeks of therapy, which the researchers attributed to poor adherence during the outpatient phase of the study.

Other protease inhibitors, most of which seem active against HIV -- including both "wild type" and protease inhibitor-resistant strains of HIV -- are now in phase I studies. These include DMP-450 (Triangle Pharmaceuticals), BMS-232,632 (Bristol Myers-Squibb), and PD-178390, a protease inhibitor being developed by Parke Davis.


Novel Therapeutics

There are several anti-HIV drugs being developed that do not readily fit within any of the above mentioned classes of drugs. These drugs are unique in the way they block HIV replication and may prove to be of substantial benefit when used in combination with standard anti-HIV compounds.

One of the most closely watched compounds in development is pentafuside (also known as T-20), a fusion inhibitor being developed by Trimeris Pharmaceuticals. Unlike reverse transcriptase inhibitors and protease inhibitors which interfere with viral reproduction once HIV is inside the cell, pentafuside prevents HIV from successfully docking with T-cells, protecting the cell from infection. In phase I studies of the drug -- with patients not taking other anti-HIV therapies -- pentafuside therapy resulted in a 1.5 log reduction in viral load when taken for 14 days; a significant increase in T-cells was also reported.

Another unique approach is the development of zinc finger inhibitors. Zinc fingers are part of the protein responsible for protecting and repackaging HIV-RNA on its way in and out of a cell's nucleus. In the absence of functional zinc fingers, HIV-RNA cannot successfully complete its task of infection and re-assembly. In the early stages of development is CI-1012, a drug that acts as a zinc finger inhibitor. Resistance may not be a big problem with this drug, as it interferes with a viral protein that does not readily mutate (as opposed to the reverse transcriptase and protease enzymes).

Last but not least is zintevir (also known as AR-177), a drug being developed by Aronex Pharmaceuticals. Zintevir is an inhibitor of integrase, the third of three retroviral enzymes long considered by researchers to be an ideal therapeutic target (the other two are reverse transcriptase and protease). Integrase is the enzyme responsible for integrating viral RNA into a host cell's DNA. Because zintevir effectively disrupts the integrase process, HIV cannot effectively take over the cell's nucleus, thereby preventing infection. Phase I studies of the drug suggest that it is safe. However, the drug is currently being studied in an intravenous (IV) formulation; it is still not clear if an oral version of the drug will be made available.


Conclusion

While the drug-development crystal ball seems to be filled with hopeful prospects, it is also filled with a great number of uncertainties. Of course, these uncertainties are to be expected; very few of the compounds discussed above have entered large-scale clinical trials. As a result, data regarding efficacy -- in both antiretroviral-naïve and experienced patients -- are still hard to come by, as is information about the safety and resistance profiles of these drugs.


Tim Horn is the Executive Editor of The PRN Notebook, published by Physicians' Research Network in New York


Back to the CRIA Update Winter 98/99 Contents Page.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. 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 AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 
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