New Entry Inhibitor AMD-070 Shows Promise in Early Human Testing

AMD-070 is a small molecule drug candidate that belongs to a new investigational class of anti-HIV drugs known as entry (fusion) inhibitors. Currently there is only one FDA-approved entry inhibitor, enfuvirtide (Fuzeon), that is available for the treatment of HIV infection. Several experimental entry inhibitors are now in early stage testing, including AMD-070, which targets the CXCR4 receptor on HIV and prevents the virus from entering and infecting healthy cells. Other entry inhibitors target the CCR5 receptor of HIV.These new agents are widely viewed as next generation anti-HIV drugs with the potential to significantly advance HIV therapeutics.

AMD-070 Mechanism of Action

Chemokine receptors expressed on the surface of immune cells are known to play a critical role in virus infection and transmission. CXCR4, and another chemokine receptor CCR5, are involved in HIV infection.

See an animation showing AMD-070's mechanism of action.

The process of HIV entry begins with binding of the viral envelope glycoprotein to both the CD4 receptor and one of only two chemokine receptors, and ends with fusion of viral and cell membranes. Viral entry provides novel therapeutic targets against HIV. To date, at least 3 sub classes of HIV viral entry/fusion inhibitors have emerged:

  1. CD4 binding or attachment - targets initial recognition and binding of the viral glycoprotein gp120 to the cell-surface CD4 antigen.
  2. Chemokine co-receptor binding - targets binding of virus to the CCR5 or CXCR4 co-receptor.
  3. Fusion Inhibition - targets the viral glycoprotein gp41 inhibiting the fusion of virus with the cell.

Receptor Prevalence

Different strains of HIV prefer one receptor or the other, or may use either receptor to infect cells.

  • 35% of strains use both CXCR4 and CCR5
  • 5% of strains are pure CXCR4 using
  • 60% of strains are pure CCR5 using
  • An infected individual may harbor different levels of both CXCR4 and CCR5 using virus
  • CXCR4 using virus independently predicts CD4 decline and HIV clinical progression and is associated with earlier mortality

Clinical Profile

The clinical program for AMD-070 is being conducted in collaboration with leading investigators at the U.S. Adult AIDS Clinical Trials Group (ACTG), which is supported by the National Institute of Allergy and Infectious Diseases at the National Institute of Health. Based on positive Phase Ia data, AnorMED plans to initiate a Phase Ib/IIa trial for AMD-070 in HIV patients in 2005. Clinical data to date shows AMD-070 is generally safe and well absorbed.

Preclinical Data

  • AMD-070 is specific for the CXCR4 receptor and does not interact with any other chemokine receptors in vitro
  • AMD-070 strongly inhibits viral infection by all CXCR4 using virus (including virus using CXCR4 alone and/or virus using CXCR4 and CCR5) in vitro
  • AMD-070 is orally bioavailable in animals
  • Suitable PK and toxicity profile for oral dosing
  • AMD-070 shows additive or synergistic effects in vitro in combination with other known anti-HIV agents
  • AMD-070 is active against CXCR4 using HIV strains that are resistant to existing antiretroviral therapies in vitro
  • Potent anti-HIV activity against CXCR4-using laboratory strains and clinical isolates

Needs in HIV

Despite advances in the development of potent antiretroviral regimens that block HIV transcription and assembly, problems of drug resistance, latent viral reservoirs and drug induced toxic effects that compromise effective viral control point to the need for new classes of anti-HIV drugs with different modes of action. Viruses that are broadly resistant to currently available anti-retroviral medications continue to represent a growing challenge for HIV therapy.

Approximately 76% of HIV-patients with measurable viral load are infected with a strain of virus that is resistant to one or more classes of antiretroviral agents, thus reducing treatment options. Unlike many existing HIV drugs that target the virus after it has infected a healthy cell, AMD-070 blocks the virus from entering a healthy cell, thus preventing the replication process.

Market Potential

Worldwide in 2003, approximately 38 million people were living with HIV, and in the same year, 3 million people died of AIDS related causes. The total number of people living with HIV in the eight pharmaceutical markets is estimated to be 1.6 million people, which includes the 80,000 who were newly infected in 2003.

Regulatory Status

In March 2003, AnorMED filed an Investigational New Drug Application (IND) with the FDA to begin its clinical program for AMD-070. The initiation of the clinical program commenced in September 2003, and the Phase Ia study results were presented in July 2004. The second study, a Phase Ib/IIa trial, is planned to begin in 2004.

Upcoming Key Events

  • Initiate Phase Ib/IIa clinical trial in HIV patients
  • Present efficacy data at appropriate HIV conferences in 2005

01-05-05

References

Abstracts & Posters

15th International AIDS Conference, 2004
Phase Ia Clinical Results: AMD-070

Biologic Activity of an Orally Bioavailable CXCR4 Antagonist in Human Subjects N. Stone
 Poster (62 KB)

11th Conference on Retroviruses and Opportunistic Infections, 2004
AMD-070 in combination with AMD887

In vitro Anti-HIV Activity Profile of AMD887, a Novel CCR5 Antagonist, in Combination with the CXCR4 Inhibitor AMD-070. D. Schols
 Abstract (81 KB)

10th Conference on Retroviruses and Opportunistic Infections, 2003

Anti-HIV activity profile of AMD-070, an orally bioavailable CXCR4 antagonist. D. Schols
 Abstract (59 KB)
Poster (144 KB)

14th International AIDS Conference, 2002

"New Drugs, New Targets" AMD-070 - A new class of HIV Entry Inhibitors that target CXCR4, a chemokine receptor. Gary Bridger
Presentation (185 KB)

9th Conference on Retroviruses and Opportunistic Infections, 2002

AMD3100, a CXCR4 Antagonist, Reduced HIV Viral Load and X4 Virus Levels in Humans. D. Schols
Abstract (11 KB)

AMD3100 CXCR4 Receptor Blocker Fails to Reduce HIV Viral Load by >- 1 Log following 10-Day Continuous Infusion/ C. Hendrix.
Abstract (10 KB)

Papers

  1. Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist. Katrien Princen. Journal of Virology. December 2004
  2. The Entry of Entry Inhibitors: A Fusion of Science and Medicine. John P. Moore. PNAS 2003. September 16, 2003
  3. HIV Tropism and CD4+ T-cell Depletion. Mark B. Feinberg, et al, Nature Medicine, Volume 8, Number 6, page 537, June 2002
  4. Safe Use of the CXCR4 Inhibitor ALX40-4C in Humans. Benjamin J. Doranz. AIDS Research and Human Retroviruses, Volume 17, Number 6, 2001
  5. Synthesis and Structure - Activity Relationships of Phenylenebis - (methylene) - Linked Bis-azamacrocycles That Inhibit HIV-1 and HIV-2 Replication by Antgonism of the Chemokine Receptor CXCR4. Gary J. Bridger. Journal of Medicinal Chemistry, Volume 42, Number 19, 1999
  6. Shift of Clinical Human Immounodeficiency Virus Type 1 Isolate from X4 to R5 and Prevention of Emergence of the Syncytium-Inducing Phenotype by Blockade of CXCR4. Jose E. Este. Journal of Virology, July 1999
  7. AMD 3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. George A. Donzella. Nature Volume 4, January 1998.
  8. Inhibition of T-tropic HIV Strains by Selective Antagonization of the Chemokine Receptor CXCR4. Dominique Schols. Journal of Experimental Medicine Volume 186, Number 8, October 20, 1997.
  9. Antiviral Efficacy In Vivo of the Anti-Human Immunodeficiency Virus Bicyclam SDZ SID 791 (JM3100), an Inhibitor of Infectious Cell Entry. Roelf Datema. Antimicrobial Agents and Chemotherapy, March 1996.
  10. The Molecular Target of Cicyclams, Potent Inhibitors of Human Immunodeficiency Virus Replication. Karen De Vreese. Journal of Virology, February 1996.
  11. Highly Potent and Selective Inhibition of Human Immunodeficiency Virus by the Bicyclam derivative JM3100. Eric De Clercq. Antimicrobial Agents and Chemotherapy, April 1994.