Sponsored Links: Prescription Drug Addiction     STRATEGIC BRIEFINGS  Emerging HIV Therapies Part 2: Emerging Therapies That Are Members of Existing Classes   By Lucy Sannes, Ph.D. Sannes & Associates, Inc. October 11, 2006 Part 1 of our two-part series on emerging HIV therapies discussed the continuing problem of HIV infection and the efforts underway to develop new classes of HIV drugs.  It would be remiss, however, not to talk about the ongoing efforts to improve “traditional” anti-HIV drugs.  As we will explore in this second installment, pharmaceutical companies are continuing to develop new drugs that are members of the three original classes of antiretroviral drugs: the nucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the protease inhibitors.      This new development of traditional drugs comes with a good reason: HIV treatments have become a major pharmaceutical market, garnering over $7 billion in worldwide sales in 2005.  This is despite the fact that current HIV drugs can cause significant side effects, and HIV can develop resistance to them.  These limitations create an undeniable need for better HIV drugs. Yet even with these drawbacks, currently available therapies have set a high standard that must be met in terms of efficacy.  New members of these drug classes are thus tasked to demonstrate significant improvements over today’s choices.    There is a clear payoff for the investment in developing such new agents: Voluminous sales of existing HIV drugs, combined with their proven efficacy, demonstrate that the potential market for new and improved HIV therapies from the current classes is vast—and it becomes even more so when one considers that many of the patents on current HIV drugs are approaching expiry.   Medivir’s Rich Pact with Bristol-Myers   An example of this interest in the so-called “established” therapies for HIV infection is the September 2006 announcement of an agreement between Bristol-Myers Squibb and Medivir for the development and commercialization of MIV-170, an NNRTI which is in preclinical development by Medivir.  Under this agreement, Bristol-Myers Squibb is responsible for worldwide development and commercialization of MIV-170 except for in the Nordic region, where Medivir retained rights to this compound.  Bristol-Myers Squibb agreed to pay Medivir an up-front payment of $7.5 million, development and regulatory milestones that may total approximately $97 million, and royalties on sales of the product.  Medivir reports that MIV-170 is a member of a new structural class of NNRTIs, and that it has shown excellent potency and an improved barrier to resistance in preclinical studies.   Current HIV therapy typically involves treatment regimens with three or more drugs (NRTIs, NNRTIs, and/or protease inhibitors).  This approach is called highly active antiretroviral therapy (HAART).  Although HAART can be very effective in reducing HIV viral loads to undetectable levels, these drugs can cause significant side effects, and the HIV virus can develop resistance to these drugs.   Much of the progress in treatment of HIV infection in recent years has been the development of combination drugs.  This is important because combination drugs reduce the number of pills that a patient must take each day, thereby increasing patient convenience and likely also increasing compliance with treatment regimens.  The most recent combination drug to reach the market was Bristol-Myers Squibb’s/Gilead Sciences’ Atripla (efavirenz/emtricitabine/tenofovir), which was approved by the FDA in July 2006.  However, these combination drugs address neither the problem of HIV drug resistance, nor the need for drugs with improved potency and safety, and there remains a need for new therapies for treatment of HIV.  Several combination drugs that are on the market are included in Table 1, and such combination drugs have been highly successful in this market. Table 1:  FDA-Approved Drugs for Treatment of HIV Infection*   Company Brand Name(s) (Generic Name) Date of FDA Approval 2005 Sales ($ millions) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (Includes fixed-dose combinations of NRTIs) GlaxoSmithKline Retrovir (zidovudine) March 19, 1987 41 £ (About $75) Bristol-Myers Squibb Videx, Videx EC (didanosine) October 9, 1991 (Videx); October 31, 2000 (Videx EC) $174 Hoffmann-La Roche Hivid (zalcitabine) June 19, 1992 NA Bristol-Myers Squibb Zerit (stavudine) June 24, 1994 $216 GlaxoSmithKline Epivir (lamivudine) November 17, 1995 261 £ (About  $475) GlaxoSmithKline Combivir (lamivudine, zidovudine) September 27, 1997 583 £ (About $1,061) GlaxoSmithKline Ziagen (abacavir) December 17, 1998 136 £ (About $248) GlaxoSmithKline Trizivir (abacavir, lamivudine, zidovudine) November 14, 2000 303 £ (About $552) Gilead Sciences Viread (tenofovir) October 26, 2001 $779 Gilead Sciences Emtriva (emtricitabine) July 2, 2003 $47 Gilead Sciences Truvada (emtricitabine, tenofovir) August 2, 2004 $568 GlaxoSmithKline Epzicom/Kivexa (abacavir, lamivudine) August 2, 2004 118 £ (About $215) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Boehringer Ingelheim Viramune (nevirapine) June 21, 1996 NA Pfizer (Agouron Pharmaceuticals) Rescriptor (delavirdine) April 4, 1997 NA Bristol-Myers Squibb Sustiva (efavirenz) September 17, 1998 $680 Protease Inhibitors     Hoffmann-La Roche Invirase (saquinavir) December 6, 1995 NA Abbott Laboratories Norvir (ritonavir) March 1, 1996 NA Merck Crixivan (indinavir) March 13, 1996 NA Pfizer (Agouron Pharmaceuticals) Viracept (nelfinavir) March 14, 1997 NA GlaxoSmithKline, Vertex Pharmaceuticals Agenerase (amprenavir)   April 15, 1999 See Lexiva Abbott Laboratories Kaletra (lopinavir, ritonavir) September 15, 2000 $1,005 Bristol-Myers Squibb Reyataz (atazanavir) June 20, 2003 $696 GlaxoSmithKline, Vertex Pharmaceuticals Lexiva/Telzir (fosamprenavir) October 20, 2003 112 £ (About $204) for Agenerase/ Lexiva Boehringer Ingelheim Aptivus (tipranavir) June 22, 2005 NA Tibotec Prezista (darunavir) June 23, 2006   Fusion Inhibitors Hoffmann-La Roche Fuzeon (enfuvirtide) March 13, 2003 259 CHF (About $208) Fixed-Combination Drugs (with multiple drug classes) Bristol-Myers Squibb, Gilead Sciences Atripla (efavirenz, emtricitabine, tenofovir) July 12, 2006   * Sorted according to 1) drug class and 2) year approved by FDA. Source: Lucy Sannes, Ph.D.   Emerging NRTIs are in Early Stages of Development   NRTIs are analogs of naturally occurring nucleosides that are substrates of the HIV enzyme reverse transcriptase.  These nucleoside analogs inhibit this enzyme and viral replication by competing with the naturally occurring nucleosides.  The first antiretroviral drug to be approved by the FDA, GlaxoSmithKline’s Retrovir (zidovudine) or AZT, is an NRTI.  NRTIs are an important part of HAART, and interest continues in the development of improved NRTIs.    For example, Pharmasset is evaluating Racivir in a Phase II clinical trial as a substitute for Epivir (lamivudine) in treatment-experienced, HIV-infected patients in order to evaluate viral-load reduction with Racivir in patients who are failing their current treatment regimen and who have the HIV mutation referred to as M184V, which results from treatment with the NRTIs Epivir (lamivudine) or Emtriva (emtricitabine).  Although there is a need for new NRTIs with improved HIV-resistance profiles, development of these new agents is proving to be challenging.  The most recent novel NRTI compound to reach this market was Emtriva, which was approved by the FDA in 2003.  None of the emerging new NRTIs in the pipeline are in late-stage (Phase III) clinical trials at this time, and some formerly promising agents have encountered problems.  For example, earlier in 2006, Incyte discontinued development of dexelvucitabine (formerly called Reverset), and returned rights for this compound to Pharmasset.  Pharmasset reports that it will analyze clinical data generated by Incyte before deciding whether or not to further develop this compound.   NNRTIs Must Overcome Problem of HIV Resistance   NNRTIs also inhibit the HIV reverse-transcriptase enzyme, but they act by a completely different mechanism.  The NNRTIs bind directly to HIV reverse transcriptase and are non-competitive inhibitors of this enzyme.  Only three NNRTIs have reached the market, and the most recent NNRTI to be approved by the FDA was in 1998 (Table 1).  These are widely prescribed, and NNRTI-based treatment regimens (an NNRTI in combination with two NRTIs) are commonly used as the initial regimen for treatment-naïve, HIV-infected patients.  Advantages of NNRTIs include their good potency, their tolerability (compared to protease inhibitors, although severe side effects can occur with the NNRTIs), and the simplicity of dosing (because NNRTI-based regimens typically require fewer pills per day than regimens that include protease inhibitors).  Also, use of an NNRTI-based regimen as the initial therapy saves the protease inhibitors for use later on, as the HIV develops resistance to other drugs.  The major drawback of NNRTIs has been the ease with which HIV can develop resistance to these drugs.  A single mutation can result in viral resistance that is often effective against the entire class of drugs.   There is considerable interest in development of new NNRTIs that have the benefits of current NNRTIs but with a higher barrier to HIV resistance.  This has proven to be a difficult challenge.  At this time, one emerging NNRTI is in late-stage development: Tibotec’s TMC125.  TMC125 is a member of a new series of NNRTIs that are diarylpyrimidine (DAPY) derivatives.  Tibotec reports these derivatives are active against wild-type HIV-1 as well as against HIV strains that have resistance-inducing mutations.  TMC125 is being evaluated in two Phase III trials (called DUET 1 and DUET 2) in treatment-experienced, HIV-infected patients with at least three primary protease inhibitor mutations in addition to NNRTI resistance.  The protease inhibitor being used in these trials is Tibotec’s Prezista (darunavir), formerly called TMC114.  In earlier clinical trials, TMC125 has been shown to be active in both treatment-naïve and NNRTI-experienced patients.  Tibotec has a second NNRTI in clinical development (TMC278), which is also a DAPY derivative.   Protease Inhibitors Have Shown Significant Progress   More significant progress has been made in recent years with the introduction of new protease inhibitors (Table 2, see below).  The most recent protease inhibitor to reach the market is Tibotec’s Prezista (darunavir), which was approved by the FDA in June 2006.  Prezista will be commercialized in the US by Tibotec Therapeutics, a division of Ortho Biotech Products.  Prezista is administered in combination with the protease inhibitor retonavir and other antiretroviral agents.  Prezista is FDA approved for treatment of HIV infection in antiretroviral treatment-experienced adult patients, such as patients with HIV strains that are resistant to more than one protease inhibitor.  The most advanced protease inhibitor in clinical development is brecanavir, which is being developed by GlaxoSmithKline and Vertex Pharmaceuticals and has reached Phase II trials.  Brecanavir has been granted fast-track designation by the FDA.  Vertex reports that brecanavir appears to be effective against HIV, including strains of HIV that are resistant to multiple protease inhibitors.   The Bottom Line   The HIV market has become a major pharmaceutical market with over $7 billion in worldwide revenues in 2005 (see Table 1 for the breakdown).  Yet, after many years of rapid development and introduction of new anti-retroviral drugs for treatment of HIV infection, the introduction of new drugs to the market for treatment of HIV infection appears to be proceeding more slowly now.  As we mentioned earlier, currently available therapies--despite their limitations--have set a high standard that must be met in terms of efficacy.  But there is still a significant need for better HIV drugs, and, as demonstrated by the sales of current HIV drugs, the potential market for new HIV therapies is vast.   Also, patents are beginning to expire on early HIV drugs.  For example, zidovudine is already available as a generic drug, and other early HIV drugs will soon face such generic competition.  To maintain HIV-related revenues, as well as meet the needs of HIV-infected patients, pharmaceutical companies must develop new drugs with improved profiles, especially in terms of toxicity and increased barriers to development of viral resistance.  As a result, the medical and commercial needs are fueling continued interest in the development of new NRTIs, NNRTIs, and protease inhibitors for treatment of HIV infection. Table 2:  Selected Emerging HIV Therapies That Target HIV Reverse Transcriptase or HIV Protease, and that were FDA Approved in 2006 or are in Clinical Development (Does not include drugs that are combinations of currently therapies.) Company Product or Technology Status Comments Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Achillion Pharmaceuticals Elvucitabine (ACH-126,443) (Beta-L-FD4C) Phase II -- Avexa ( Australia ) AVX754 (apricatabine) Phase II •Licensed from Shire Pharmaceuticals.  It was called SPD754 while being developed by Shire. Heidelberg Pharma Fozivudine Phase II •Carrier molecule coupled to AZT Heidelberg Pharma HDP 99.0003 Phase I •Carrier molecule coupled to fluorothymidine Koronis Pharmaceuticals KP-1461 Phase I -- Medivir Alovudine (MIV-310) Phase IIb completed •Was being developed in partnership with Boehringer Ingelheim.   In 3/05, Boehringer Ingelheim discontinued its development of alovudine and terminated the agreement. •Listed as a drug that Medivir will outlicense on the Medivir web site. Medivir MIV-210 Phase IIa ongoing •Listed as a drug that Medivir will outlicense on the Medivir web site. •MIV-210 was licensed to GlaxoSmithKline.  In 12/04, GlaxoSmithKline returned terminated that partnership and returned rights to MIV-210 to Medivir.