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New Drugs in the Pipeline

By John S. James
AIDS Treatment News

Here are some of the experimental antiretroviral treatments (not yet approved for general use) that were discussed at the Retroviruses conference, February 24-28, 2002, in Seattle. We organized them by drug class.

Non-Nucleoside Reverse
Transcriptase Inhibitors

  • TMC125

    This is a very active antiretroviral of the NNRTI class (non- nucleoside reverse transcriptase inhibitor -- the same class as efavirenz, nevirapine, and delavirdine, the three NNRTI drugs currently approved in the U.S.). But TMC125 was rationally designed to overcome the main problem of this class of drugs, the development of viral resistance. This was accomplished, in part, by making the molecule flexible, so that it can still fit in the "pocket" (the active site) of the reverse-transcriptase enzyme, even when HIV mutates to change the shape of that site.

    In patients, TMC125 caused a faster drop in HIV viral load than has been seen with any other single drug so far (in a small, 12 patient study) -- an almost 2-log drop in only one week from this drug alone, in treatment-na´ve patients.(1) In that week the median CD4 increase was 119. No one knows why the drug worked so well. [Note: short, small clinical trials like this are used to estimate the antiviral potency, by measuring how fast the virus disappears from the blood in the days after the drug is started. This kind of study gives an idea of the antiviral activity of the new drug by itself, without giving the virus much time to develop resistance to it.]

    TMC125 also works in patients who are highly resistant to other NNRTIs. Another small study tested the drug for one week in patients who were failing either efavirenz or nevirapine, who had resistant virus with at least 10-fold reduced sensitivity to the drug they were using (all of these patients were at least 35-fold less sensitive to nevirapine). After one week of using TMC125, the median viral load had decreased 0.9 logs, and was still going down.(2)

    These trials used an early phase I formulation of TMC125, which required the volunteers to take many pills per day. The formulation has been improved since then, though more work is needed. Drugs of this class tend to be difficult to dissolve because of their chemical nature (the molecule needs to bind to a pocket in the viral enzyme with non-polar bonds), but this problem can be overcome.

    TMC125 was developed by Tibotec-Virco, a company headquartered in Belgium that uses high-tech methods to develop new drugs, especially antivirals (including treatment for hepatitis C). It also offers HIV phenotypic resistance testing (the Antivirogram) under the name Virco. Many of the principals in the company have a background in tropical medicine. On March 22 it was reported that Johnson & Johnson had bought Tibotec-Virco -- probably good news, as it was widely believed that Tibotec-Virco did not have enough money to develop the drug quickly.

    But because of the slow pace of drug development generally, it is unlikely that the company will be able apply for approval for TM125 before 2004, even if everything works as well as possible.

  • DPC-083

    This NNRTI is related to efavirenz (Sustiva(R)), but is active against many viruses that are resistant to efavirenz and other approved NNRTIs.(3,4) It seems to cause less of a problem with the mental changes that trouble some patients when they start efavirenz.

    Protease Inhibitors

  • Tipranavir

    Tipranavir, developed by Boehringer Ingelheim Pharmaceuticals, is the first of a new class of "non- peptidic" protease inhibitors (PIs) -- giving it a different resistance profile from the approved PIs. It is active against HIV that is heavily resistant to the approved drugs. (As with the protease inhibitor Kaletra, a low dose of ritonavir has to be used with tipranavir to keep the body from rapidly destroying the drug.)

    Forty one patients who were failing their second protease- inhibitor regimen, were NNRTI na´ve, and had a viral load over 5,000 were given tipranavir along with other antiretrovirals (including the NNRTI efavirenz). They had average viral load reductions of more than 2 logs at 48 weeks and beyond. Most of them (35 of 41) remained fully susceptible to tipranavir at 48 weeks. One patient had been resistant to tipranavir at baseline.(5)

    The difference in the resistance profile of tipranavir can be seen by comparing how resistant these patients were to various protease inhibitors. For saquinavir, for example, the average resistance was 17.4 fold (meaning it took about 17 times as much of the drug to suppress this resistant HIV, compared to HIV that had not developed resistance. By this measure, the average resistance to saquinavir was 17.4, nelfinavir 27.8, indinavir 17.1, ritonavir 48.5, amprenavir 3.7, and tipranavir 1.5.

    The development of this drug has been seriously delayed in the past, and patient groups are starting to seek an expanded-access program as soon as possible for those who have no other viable option.

  • Atazanavir

    In 48-week data presented at the Retroviruses conference, this protease inhibitor did not increase blood cholesterol, LDL cholesterol, or triglycerides in treatment-naive patients(6) -- suggesting that it may be useful in developing HAART treatment regimens with fewer side effects.

    And in a study of patients who were failing therapy, the combination of atazanavir and saquinavir worked well at 48 weeks, both in blood lipid levels and in viral load reduction.(7)

    Atazanavir is now in phase III trials. It should soon be available on expanded access for patients who cannot construct viable treatment regimens otherwise. It will probably be the next protease inhibitor approved.

    Entry Inhibitors

    Note that there are three different mechanisms of inhibiting viral entry into cells -- mechanisms that are used by drugs being developed today. BMS-806 blocks the first step -- the binding of gp-120 of the virus with the CD4 receptor on the cell. A later step is the binding with a co-receptor on the cell (usually CCR5 or CXCR4); this step is the target of SCH- C, described below. Then the final step is fusion of the viral and cell membrane, which brings the viral genes into the cell; this step is targeted by T-20, a drug well advanced in clinical trials.

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  • BMS-806

    This compound blocks entry by binding to gp-120 on HIV -- preventing the virus from binding to CD4 and then entering cells.(8,9) It is new and has not yet been tested in patients.

  • SCH-C

    This drug blocks viral interaction with the CCR5 co-receptor on the cell. The low dose studied so far produced an average of about a 0.7 log viral load decline by day 10.(10) Higher doses will be studied next.

  • T-20

    We plan to cover this important drug in a later issue.

    Integrase Inhibitors

  • S-1360

    This integrase inhibitor was synthesized by Shionogi & Co. Ltd. in Japan, and is being developed in the U.S. in partnership with GlaxoSmithKline. It is a small molecule that is orally bioavailable(11) and is now being tested in patients. Activists and others at the conference were encouraged that an integrase inhibitor has finally progressed this far.

    Integrase inhibitors (like entry inhibitors) have a different viral target than any currently approved drug. Therefore all the viral resistance that has developed so far is unlikely to affect these new drugs. HIV will be able to become resistant to them, however, so the new drugs will have to be used carefully in appropriate combinations. Their importance will be in providing new kinds of treatment options -- as protease inhibitors did when they were introduced.

    1. Sankatsing S, Weverling G, van 't Klooster G, Prins J, and Lange J. TMC125 monotherapy for 1 week results in a similar initial rate of decline of HIV-1 RNA as therapy with a 5-drug regimen. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract # 5].

    2. Gazzard B, Pozniak A, Arasteh K and others. TMC125, a next-generation NNRTI, demonstrates high potency after 7 days therapy in treatment-experienced HIV-1-infected individuals with phenotypic NNRTI resistance. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract # 4].

    3. Ruiz N, Nusrat N, Lauenroth-Mai E and others. Study DPC 083-203, a phase II comparison of 100 and 200 mg once-daily DPC 083 and 2 NRTIs in patients failing a NNRTI containing regimen. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract #6].

    4. Ruiz N, Nusrat N, Lazzarin A and others. Study DPC 083- 201: A phase II double-blind (DB) comparison of 3 once daily doses of the NNRTI DPC 083 vs 600 mg efavirenz (EFV) in combination with 2 NRTIs in HIV antiretroviral (ARV) treatment-na´ve patients. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract # 7].

    5. Schwartz R, Kazanjian P, Slater L and others. Resistance to tipranavir is uncommon in a randomized trial of tipranavir/ritonavir (TPV/RTV) in multiple PI-failure patients (BI 1182.2). 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract # 562-T].

    6. Piliero PJ, Cahn P, Pantaleo G and others. Atazanavir: A once-daily protease inhibitor with a superior lipid profile - - results of clinical trials at week 48. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract # 706-T].

    7. Haas D, Zala C, Schrader S, Thiry A, McGovern R and Schnittman S. Atazanavir plus saquinavir once daily favorably affects total cholesterol (TC), fasting triglyceride (TG), and fasting LDL cholesterol (LDL) profiles in patients failing prior therapy (trial AI424-009, week 48). 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract # 42].

    8. Lin P-F, Robinson B, Gong Y-F and others. Identification and characterization of a novel inhibitor of HIV-1 entry -- I: Virology and resistance. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 22-28, 2002 [abstract #9].

    9. Lin P-F, Guo K, Fridell R, Ho H-T, Yamanaka G, and Colonno R. Identification and characterization of a novel inhibitor of HIV-1 entry -- II: Mechanism of action. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract # 10].

    10. Reynes J, Rouzier R, Kanouni T and others. SCH C: Safety and antiviral effects of a CCR5 receptor antagonist in HIV-1 infected subjects. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract # 1].

    11. Yoshinaga T, Sato A,, Fujishita T, and Fugiwara T. S- 1360: in vitro activity of a new HIV-1 integrase inhibitor in clinical development. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24-28, 2002 [abstract #8].

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