HIV Portfolio
Myrexis has advanced investigational HIV compounds through Phase 2 clinical trials and are actively seeking partnership opportunities for our HIV portfolio. If you are interested in learning more about our development candidates or collaborating with Myrexis, Inc., please contact our Business Development group:
Joshua T. Jones, Ph.D.
Manager, Business Development
(p) 801-214-7876
business.development@myrexis.com
HIV Maturation Inhibitor Program
MPC-4326 (bevirimat dimeglumine) is an investigational new drug being developed by Myrexis, Inc. for the oral treatment of human immunodeficiency virus 1 (HIV-1) infection. MPC-4326, MPC-9055 and MPI-461359 are potential first-in-class/best-in-class inhibitors of viral maturation.
About MPC-4326
MPC-4326 (bevirimat dimeglumine) is an investigational new drug being developed by Myrexis, Inc. for the oral treatment of human immunodeficiency virus 1 (HIV-1) infection. MPC-4326 has been granted Fast Track designation by the US Food and Drug Administration (FDA).
MPC-4326 (bevirimat dimeglumine) is an investigational new drug being developed for the oral treatment of human immunodeficiency virus 1 (HIV-1) infection. This potent small-molecule is a first-in-class drug candidate that acts as a viral maturation inhibitor. A compound with this novel mechanism of action would strengthen the armamentarium of approved drugs and preclinical studies have demonstrated that MPC-4326 exhibits potent activity against a broad range of HIV strains, including isolates that are resistant to currently approved HIV therapies.
Over 675 subjects, including over 180 HIV-infected patients, have been studied in clinical trials. Results from these trials have shown MPC-4326 to be well tolerated and have demonstrated significant and clinically relevant reductions in viral load in a subset of HIV-infected patients representing approximately 60% of HIV infected patients, who can be identified by a simple assay of the HIV virus. In a Phase 2 clinical trial completed in 2008, MPC-4326 met its primary objective by demonstrating drug plasma concentrations in HIV-infected patients to be in a target range for virologic reduction. In addition, MPC-4326’s safety profile was comparable to earlier studies where it had been similar to placebo.
MPC-4326 may become an important addition to the repository of HIV drugs currently used in combination to combat the continuing appearance of viral resistance to approved medications. MPC-4326 has been granted Fast Track designation by the U.S. Food and Drug Administration.
Myrexis' anti-viral drug discovery program began with the discovery of the interaction between the HIV Gag protein and the human host protein, TSG101, in the viral budding/maturation pathway of HIV. This research was first published on October 5, 2001 [1], and expanded upon in September, 2003 [2]. Both articles were featured as the cover article in the journal Cell. Myrexis scientists have made subsequent discoveries regarding the biology of HIV viral particle maturation, viral fusion with host cells and intra-cellular events in the life cycle of HIV which has enabled Myrexis to identify additional novel targets which may inhibit HIV infection.
Clinical Studies
MPC-4326 has been studied in over 675 subjects, including over 180 HIV-infected patients. Results from these clinical studies have shown MPC-4326 to be well tolerated.
MPC-4326 has demonstrated clinically relevant reductions in viral load in both anti-retroviral treatment experienced and treatment naïve patients [3,4]. Laboratory studies recently uncovered viral genetic predictors of response to MPC-4326 in HIV-infected patients [5]. HIV-infected patients whose virus lacks specific amino acid changes to the Gag protein, the target of MPC-4326, were much more likely to respond to MPC-4326. These amino acid variations in the Gag protein, known as polymorphisms, are easily determined by rapid and inexpensive genotype tests similar to those already being routinely performed by practicing HIV physicians throughout the course of a patient's treatment. Epidemiological data suggest 60% or greater of patients with HIV are infected with viral strains that are free of Gag polymorphisms [5].
Importantly, MPC-4326 has a low probability for certain types of drug-drug interactions that are common amongst some of the currently available therapies and laboratory experiments have shown no evidence of antagonism between MPC-4326 and other HIV therapies [6]. A solid tablet formulation has achieved 67% relative bioavailability in a Phase 1 study of 28 healthy individuals.
Mechanism of Action
MPC-4326 is the first in a new class of HIV drugs called Maturation Inhibitors. MPC-4326 blocks viral maturation by inhibiting the final step in the processing of the HIV Gag protein. MPC-4326 inhibits the ability of the virally-encoded protease to release the capsid protein and complete the viral maturation by binding to the Capsid/SP1 cleavage site on Gag [7]. The resulting immature virus particles are structurally defective and noninfectious. MPC-4326 is comparable to or more potent than currently marketed HIV therapies in in vitro anti-viral assays against laboratory strains of HIV-1 as well as HIV-1 viral strains obtained from patients with active disease.
MPC-4326 has potent anti-viral activity against HIV-1 isolates resistant to many of the approved HIV medications and acts synergistically with protease inhibitors (indinavir, nelfinavir, saquinavir and ritonovir) in vitro. There is no evidence of antagonism between MPC-4326 and other HIV therapies [8].
Viral isolates resistant to MPC-4326 were found to possess mutations in close proximity to the Capsid/SP1 cleavage site of the Gag protein, consistent with the compound’s mechanism of action [7]. Unlike other regions of the Gag protein, the Capsid/SP1 domain is highly conserved between different HIV isolates, suggesting there may be a high genetic barrier to the development of resistance to MPC-4326 in patients. In addition, in vitro experiments have shown that development of MPC-4326 resistance is significantly slower in HIV-1 strains that are already resistant to protease inhibitors [7].
About HIV and AIDS
Infection by HIV causes a slowly progressive deterioration of the immune system resulting in Acquired Immune Deficiency Syndrome, or AIDS. According to the United Nations UNAIDS program, approximately 33 million people worldwide are living with HIV. In North America, Central Europe and Western Europe, HIV infects approximately 2.1 million people. Approximately 475,000 patients are currently being treated for HIV with antiretroviral (ARV) drug therapy in the U.S [9]. With new HIV testing mandates from both governmental and academic groups, more people with HIV are expected to seek treatment.
Several major classes of ARV drugs are available for use by patients, including reverse transcriptase inhibitors (NRTIs, NTRTIs, NNRTIs), protease inhibitors, a fusion inhibitor (enfuvirtide), an integrase inhibitor (raltegravir) and a CCR5 antagonist (maraviroc). Up to 85% of treated patients harbor at least some drug-resistant HIV strains, as do up to approximately 25% of newly diagnosed patients, making drug resistance a major challenge in the treatment of HIV. As a result, current treatment guidelines recommend that patient treatment regimens include the use of three fully-active ARV drugs in combination and may require frequent readjustment. HIV drug treatment regimens can include multiple drugs from the same class, and increasingly include drugs available as co-formulations or fixed dosage combinations. Some recent data suggests that as many as one third of patients change their HIV treatment regimen each year [10], which often results from the development of treatment resistance in patients. These treatment changes, coupled with approximately 25,000 patients who start treatment for the first time each year, result in opportunities for new products to be incorporated into the new treatment regimens.
Because one of the most important challenges in treating HIV is the emergence of viral strains that are resistant to currently approved drugs, our primary aim is to develop small-molecule oral drugs that treat HIV via a novel mechanism of action. By focusing on this novel class of maturation inhibitors, we aim to meet the growing unmet need caused by viral resistance to current classes of ARVs.
Clinical Trials
Visit clinicaltrials.gov for more information: http://clinicaltrials.gov/ct2/show/NCT01026727
Recent Presentations on MPC-4326
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MPC-4326 (bevirimat dimeglumine) Drug-Drug Interaction Profile  17th Conference on Retroviruses and Opportunistic Infections (CROI) Feb 16-19, 2010 Moscone Center San Francisco, CA 360 KB |
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Efficacy, Safety and Pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 300mg BID Monotherapy Administered for 14 days in Subjects with HIV-1 Infection Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Sep 12-15, 2009 Moscone Center San Francisco, CA 580 KB |
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Pharmacokinetics and Safety of a Novel 100 mg Tablet Formulation of MPC-4326 in Subjects with HIV-1 Infection Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Sep 12-15, 2009 Moscone Center San Francisco, CA 137 KB |
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Susceptibility of Diverse HIV-1 Patient Isolates to the Maturation Inhibitor, Bevirimat (MPC-4326*), is Determined by Clade-Specific Polymorphisms in Gag CA-SP1 CROI: 16th Conference of Retroviruses and Opportunistic Infections Feb 8-11, 2009 Palaisdes Congres de Montreal Montreal, Canada 133 KB |
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HIV-1 Gag Polymorphisms Determine Treatment Response to Bevirimat |
References
- Garrus J.E., et al, Tsg101 and the Vacuolar Protein Sorting Pathway Are Essential for HIV-1 Budding. Cell 2001 107 : 55-65. PMID: 11595185: View Abstract
- von Schwedler , U.K. , et al, The Protein Network of HIV Budding. Cell 2003 114 : 701-713. PMID: 14505570: View Abstract
- Pharmacokinetic/Pharmacodynamic Effects of PA-457 In HIV-infected Patients Following A Single Oral Dose. 3rd IAS Conference, July 2005, Rio de Janeiro, Brazil: View PDF
- HIV-1 Gag Polymorphisms Determine Treatment Response to Bevirimat (PA-457). XVII International HIV Drug Resistance Workshop June 10-14, 2008 Sitges, Spain: View PDF
- Role of Gag Polymorphisms in HIV-1 Sensitivity to the Maturation Inhibitor Bevirimat. XVII International HIV Drug Resistance Workshop June 10-14, 2008 Sitges, Spain View PDF
- Li F., et al, PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. PNAS 2003 Nov 11;100(23):13555-60: View PDF
- Adamson CS, Waki K, Ablan SD, Salzwedel K, Freed EO. Impact of human immunodeficiency virus type 1 resistance to protease inhibitors on evolution of resistance to the maturation inhibitor bevirimat. J Virol. 2009 May;83(10):4884-94. Epub 2009 Mar 11. View Abstract
- The first in class maturation inhibitor, PA-457, is a potent inhibitor of HIV drug-resistant isolates and acts synergistically with approved HIV drugs in vitro. 13th Conference on Retroviruses and Opportunistic Infections, February 2006, Denver, CO: View PDF
- UNAIDS 2008 Global Report
- Lodwick RK et al. Stability of antiretroviral regimens in patients with viral suppression. AIDS 22: 1039 – 1046, 2008. View Abstract
About MPC-9055
MPC-9055 is another in our portfolio of small-molecule maturation inhibitors being developed for the oral treatment of HIV-1 infection. MPC-9055 has successfully completed dose escalation in a Phase 1 human clinical trial in healthy volunteers, and is proceeding to a Phase 2a, multiple ascending dose trial in treatment-naive HIV-infected individuals.
MPC-9055 is a potent small-molecule maturation inhibitor being developed for the oral treatment of HIV-1 infection. Like our other maturation inhibitors, MPC-9055 targets a unique cleavage event in the HIV life cycle, inhibiting the processing of a Capsid-Spacer 1 intermediate of the Gag protein. This results in a noninfectious virion, and prevents subsequent rounds of HIV infection.
The Phase 1 trial was designed as a single ascending dose study to assess the safety, tolerability and pharmacokinetic parameters of MPC-9055 in healthy volunteers. The overall safety profile was favorable with no serious adverse events or clinically significant changes in laboratory values or electrocardiograms. The observed pharmacokinetic profile and good oral bioavailability supports continued development.
MPC-9055 has been tested extensively in preclinical in vitro and in vivo studies to establish antiviral activity and assess safety. MPC-9055 was shown to be active against viral strains that are resistant to the currently marketed anti-HIV drugs, including nucleoside reverse transcriptase inhibitors such as AZT™, non-nucleoside reverse transcriptase inhibitors such as Efavirenz™, and protease inhibitors such as Ritonavir™. MPC-9055 has been well-tolerated and exhibits a favorable safety profile in a variety of preclinical studies.
Myrexis' anti-viral drug discovery program began with the discovery of the interaction between the HIV Gag protein and the human host protein, TSG101, in the viral budding/maturation pathway of HIV. This research was first published on October 5, 2001 [1], and expanded upon in September, 2003 [2]. Both articles were featured as the cover article in the journal Cell. Myrexis scientists have made subsequent discoveries regarding the biology of HIV viral particle maturation, viral fusion with host cells and intra-cellular events in the life cycle of HIV which has enabled Myrexis to identify additional novel targets which may inhibit HIV infection.
Recent Presentations
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Phase 1, Single Ascending Oral Dose Study of the Safety, Tolerability, and Pharmacokinetics of a Novel HIV-1 Maturation Inhibit
CROI: 16th Conference of Retroviruses and Opportunistic Infections Feb 8-11, 2009 Palaisdes Congres de Montreal 478 KB |
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Anti-viral Characterization in vitro of a Novel Maturation Inhibitor, MPC-9055
CROI: 16th Conference of Retroviruses and Opportunistic Infections Feb 8-11, 2009 Palaisdes Congres de Montreal |
References
1. Garrus J.E., et al, Tsg101 and the Vacuolar Protein Sorting Pathway Are Essential for HIV-1 Budding. Cell 2001 107 : 55-65. PMID: 115951852. von Schwedler , U.K. , et al, The Protein Network of HIV Budding. Cell 2003 114 : 701-713. PMID: 14505570
About MPI-461359
MPI-461359 is a potent, orally available maturation inhibitor being developed by Myrexis for the treatment of HIV-1 infection. MPI-461359 was discovered in a medicinal chemistry program as a highly potent, broadly acting, small molecule inhibitor of HIV-1 maturation. Pharmacokinetic studies in rodents demonstrate that MPI-46139 is highly orally bioavailable. Based upon its efficacy profile, novel mechanism of action and pharmacokinetic properties, we believe MPI-461359 has potential as a promising new HIV therapeutic.
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ACS Conference March 2010 San Francisco, CA 422 KB |
