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Emerging HIV Therapies
Part 1: Emerging Therapies That Do Not Target HIV Reverse Transcriptase or HIV Protease

By Lucy Sannes, Ph.D.
Sannes & Associates, Inc.

October 4, 2006

Up to 20% of HIV-diagnosed individuals show resistance to at least one class of current anti-HIV drugs, making the market rife with opportunity for treatments that work differently.  Combined with the significant side effects associated with current therapies, there is an urgent need for new classes of anti-HIV drugs.  The potential payoff is tantalizing: HIV treatments netted over $7 billion in sales last year.  

HIV infection continues to be a major problem worldwide.  The Centers for Disease Control and Prevention estimates that over 1 million individuals were living with HIV/AIDS in the United States in 2003.  On a global basis, the World Health Organization (WHO) estimates that 39 million people worldwide were living with HIV in 2005.  

More than 20 compounds and an even greater number of formulations are available for the treatment of HIV-infected persons.  With one exception, all of the FDA-approved antiretroviral drugs are members of three classes of drugs: the nucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), or the protease inhibitors.  These drugs are typically given in regimens of three or more drugs, a practice which is referred to as highly active antiretroviral therapy (HAART).  While these drugs cannot cure patients with HIV infection, they can significantly suppress HIV replication.  Ongoing activities to develop new drugs that are members of these three classes of drugs will be discussed in Part 2 of this article.  

According to a recent Espicom report, the largest segment of the antiviral market is derived from the treatment of HIV, with reported sales of around $7 billion in 2005. The US market accounts for around 60%, equating to over $5 billion, while in Europe, France has the largest market value with revenues of around $600 million. HIV-reverse transcriptase inhibitors were among the top 20 leading therapeutic drug classes (based on 2005 US sales), generating global sales of $5 billion.  

While development of the currently available HIV therapies represented a significant advance for treatment of HIV-infected individuals, these drugs have limitations.  The two major ones are that they can cause significant side effects and HIV can develop resistance to these drugs. 
 

HIV Drug Resistance Is a Major Concern  

Last year, the WHO reported that wherever HIV therapy is available, drug resistance will occur to some degree. According to the WHO article, in industrialized countries, where antiretroviral treatment has been widely accessible for almost a decade, small studies have suggested that between 5% and 20% of individuals diagnosed with HIV have become resistant to at least one class of anti-HIV drugs.  

Results from a survey commissioned by the American Academy of HIV Medicine, released in July, highlight the major issue of HIV drug resistance in the US, reporting that more than 90% of physicians surveyed are “extremely” or “very” concerned about the issue. 
 

Fusion Inhibitors Are First New Class to Hit Market  

The newest class of drug to reach the market for the treatment of HIV is the fusion inhibitors.  The only marketed fusion inhibitor is Roche’s Fuzeon (enfuvirtide), which received FDA approval in March 2003.  Fuzeon was developed by Trimeris Pharmaceuticals and Roche.  Fuzeon is an injectable drug; hence, an oral, small-molecule fusion inhibitor would provide a new therapeutic option.  

Fuzeon inhibits the fusion of HIV to CD4-positive cells by binding to the gp41 subunit of the viral envelope protein, thus preventing conformational changes that are required for fusion of HIV and the cell membrane.  Fuzeon is FDA approved for treatment of HIV-1 infection in treatment-experienced patients who have exhibited evidence of HIV-1 replication despite their ongoing antiretroviral therapy.  Fuzeon is not used as part of the initial HAART therapy in treatment-naïve patients.  Fuzeon must be injected twice per day, and in Phase III clinical trials, 98% of patients had at least one local injection-site reaction.  Due to this problem, patients taking Fuzeon are told that each injection should be given at a different site than the previous one, and that injections should only be made at sites where there is no prior reaction.  

Another of Fuzeon’s limitations is that HIV can develop resistance to it, as it can to other available HIV drugs.  These limitations have served to limit Fuzeon’s sales.  For 2005, Roche reported Fuzeon sales of 259 million Swiss francs (approximately $210 million).  However, use of Fuzeon is increasing: Its 2005 sales represented a 53% increase over its 2004 sales.  

Fusion inhibitors such as Fuzeon are members of a broader group of emerging HIV therapies known as viral-entry inhibitors.  All viral-entry inhibitors act by blocking the entry of HIV into the cell, but they can work by a number of different mechanisms.  These include: blocking the attachment of HIV to the cell, blocking receptors (such as CCR5 or CXCR4) that are required for viral entry, or blocking fusion of HIV to the cell membrane.  Several viral-entry inhibitors are in clinical development (see accompanying table [below]), but this is proving to be a difficult field.   

For example, Trimeris and Roche were developing a second-generation HIV fusion inhibitor (T-1249) that binds to a different region of HIV than does Fuzeon.  As a result, T-1249 was expected to be effective against Fuzeon-resistant HIV.  However, in January 2004 the two companies put clinical development of T-1249 on hold, citing challenges in achieving the desired technical profile of the formulation. According to Trimeris’ Web site, T-1249’s safety, efficacy, and tolerability were in no way related to the decision. They are instead developing new HIV fusion inhibitors, which are still in preclinical development.   

Most viral-entry inhibitors in development today are in Phase II or earlier stages of development.  The most advanced viral-entry inhibitor is Pfizer’s maraviroc, a CCR5 receptor antagonist that is in Phase III development.  In July 2006, while reporting the company’s second-quarter results, Pfizer indicated that it is targeting an NDA submission for maraviroc for treatment of treatment-experienced, HIV-infected patients by the end of 2006.  

The HIV integrase inhibitors are another emerging class of HIV therapies.  An important step in the HIV life cycle is integration of viral DNA into the host cell’s DNA.  Integrase inhibitors block the enzyme responsible for this integration.  Several integrase inhibitors are in development (see table).  The most advanced integrase inhibitor is Merck’s MK-0518, which is in Phase III clinical development.  MK-0518 is being evaluated in both treatment-naïve patients as well as in patients who have failed current antiretroviral therapy. 
 

Merck’s Integrase Inhibitor Shows Highly Promising Efficacy  

In August 2006, promising interim (24-week) data was reported from an ongoing Phase II, dose-ranging trial of MK-0518 in treatment-naïve, HIV-infected patients.  In this study, patients received either 1) MK-0518 in combination with Viread (tenofovir) and Epivir (lamivudine), or 2) Sustiva (efavirenz) in combination with Viread and Epivir.  After 24 weeks, 85% to 95% of patients taking the MK-0518-based regimen had achieved reductions in HIV viral load to less than 50 copies/mL, while 92% of patients taking Sustiva had achieved this reduction.  Thus, MK-0518 appears to be equivalent to Sustiva in this treatment regimen.  In addition, MK-0518 was reportedly well tolerated.  If MK-0518 is eventually approved for both the treatment-naïve and treatment-experienced patient populations, its potential market opportunity will be significantly larger than for drugs (such as Fuzeon) that are approved only for treatment-experienced patients who are failing therapy.  In August 2006, Merck announced a worldwide, expanded early access program for patients who have either limited or no treatment options, making MK-0518 available to them.  

Another emerging class of HIV therapies is the HIV maturation inhibitors, which inhibit the final step in the processing of the HIV gag protein.  Only one maturation inhibitor is in clinical development at this time--Panacos Pharmaceuticals’ bevirimat (PA-457), which is in Phase II clinical trials.  Panacos has completed seven clinical studies of bevirimat in over 300 subjects, showing significant reductions in viral load in HIV-infected subjects and a promising safety profile.
 

Much Work Remains  

Many additional emerging HIV therapies have also reached clinical development, several examples of which are presented in the table below.  Many of these are based on either immunotherapy (i.e., stimulating the immune system) or gene therapy.  It appears that none of these other emerging HIV therapies have reached Phase III clinical development.  

There is a significant need for HIV therapies that operate by novel mechanisms of action, as more patients develop drug resistance and exhaust the current arsenal of anti-HIV treatments. The successful development of these novel therapies is proving to be a challenge and is taking considerable time.  Only two HIV therapies based on novel mechanisms of action appear to be in Phase III development at this time.  However, due to the limitations of currently available anti-HIV drugs, the potential opportunity for these emerging therapies is significant if they can successfully navigate the path to market. 

Selected Emerging HIV Therapies Based on New Mechanisms of Actions in Clinical Development^*

^* Agents that do not target HIV reverse transcriptase or HIV protease.  

Source: Lucy Sannes, Ph.D.

Copyright 2006, All Rights Reserved. Cambridge Healthtech Institute.