icon-folder.gif   Conference Reports for NATAP  
  42nd ICAAC Meeting
San Diego, Sept 27-31, 2002
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New Entry Inhibitors In Early Development
Reported by Jules Levin
  Below is a press release from Progenics, the company based in Tarrytown, NY, is developing 2 entry inhibitors. Following the press release are 2 poster abstracts being presented today at the conference.
Progenics Reports Positive Results of Completed Phase II Clinical Study of HIV Entry Inhibitor PRO 542; PRO 140 CCR5 Inhibitor on Target to Enter Clinic in 2003
SAN DIEGO--(BUSINESS WIRE)--Sept. 27, 2002--Progenics Pharmaceuticals, Inc. reported positive findings from a completed Phase II clinical trial of its investigational HIV entry inhibitor, PRO 542.
Single doses of PRO 542 reduced concentrations of the human immunodeficiency (HIV) in the blood by 60% to 80% in a target population of highly treatment-experienced patients with PRO 542-sensitive virus. The viral-load reductions were sustained throughout the six-week follow-up period, and no serious side effects were observed. The Company also announced that it has begun multi-dose Phase II clinical studies of PRO 542 as salvage therapy of HIV-infected individuals who are no longer responding to currently available antiretroviral medications. In addition, the Company presented an update on its PRO 140 anti-CCR5 antibody, which is preparing to enter clinical trials. The presentations were made at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Diego.
"The prolonged duration of PRO 542's antiviral effect was a particularly striking finding of this study, since we had expected that the virus levels would return to baseline during follow-up," said Jeffrey M. Jacobson, M.D., Assistant Chief and Program Director, Division of Infectious Diseases at Beth Israel Medical Center in New York City and Principal Investigator of the study. "The trial results provide strong support for expanded Phase II studies of multi-dose PRO 542 therapy in this patient population."
Sustained reduction in blood levels of virus, or "viral load," is a primary goal of HIV therapy. Following treatment with a single 25 mg/kg intravenous dose of PRO 542, patients experienced viral-load reductions of 0.4 to 0.6 log(10) copies/mL on average. The antiviral effects were statistically significant for as long as four weeks post-treatment (p = 0.038, two-sided test) and were observed in 80% of prospectively treated salvage therapy patients. Notably, the patients' blood levels of virus had not returned to baseline at the conclusion of the six-week follow-up period. The study further demonstrated that PRO 542 continued to be well tolerated, and no serious side effects were reported.
Assay results correlate with PRO 542 responders
The completed Phase II trial utilized HIV resistance-testing technology from ViroLogic, Inc. ViroLogic's PhenoSense HIV Entry assay was used to assess the susceptibility of the patients' viruses to PRO 542. The assay results correlated with the magnitude of viral-load reductions in patients treated with PRO 542. This screening technology is also being utilized within the recently initiated multi-dose trial of PRO 542.
The Company's new findings confirm previously reported results indicating that PRO 542 was particularly active in treatment-experienced patients with high viral loads (greater than 100,000 copies/mL) and/or low CD4 counts (less than 200 cells/mm(3)). The patients in the completed study harbored viruses that were resistant to two of the three approved classes of antiretroviral the rapies.
"We are pleased that PRO 542 reduced viral loads in individuals who are most in need of new treatment options," said Robert J. Israel, M.D., Sr. Vice President of Medical Affairs at Progenics. "These results confirm our earlier findings on the activity of PRO 542 in patients who are no longer responding to conventional therapy. The completed trial supports further development of PRO 542 as an infrequently administered intravenous agent."
PRO 542 belongs to a new class of drugs, viral-entry inhibitors, which are intended to prevent HIV from entering and infecting cells. Unlike currently approved therapies that block viral replication in cells already infected with HIV, PRO 542 is an antibody-like molecule that is designed to target and neutralize the virus in the bloodstream. Because of its novel mechanism of action, PRO 542 has the potential to be broadly active against both wild-type viruses and viruses that have acquired resistance to existing classes of antiretroviral therapies. To date, PRO 542 has been used to treat more than 50 HIV-infected individuals.
Company provides update on PRO 140, second HIV viral-entry inhibitor
In a second presentation at the ICAAC meeting, Progenics reported that in laboratory studies a humanized version of its PRO 140 HIV-entry inhibitor reproduced the compelling therapeutic profile of its "parent" mouse antibody. PRO 140 is a monoclonal antibody that is designed to block HIV entry by binding to a portion of the receptor that the virus uses to infect cells. Humanized PRO 140 inhibited entry of multiple strains of HIV into immune system cells, in vitro. In addition, it demonstrated the unique ability to block HIV entry via CCR5, while leaving the normal function of this receptor unaffected. Preclinical testing and manufacturing scale-up are expected to be completed in the coming months, with Phase I clinical trials scheduled to begin in 2003.
PRO 542, a Novel Inhibitor of HIV-1 Attachment and Entry, Blocks Infection in trans of T Cells by Dendritic Cell-Associated Virus
1 Progenics Pharmaceuticals, Inc., Tarrytown, NY, 2 Population Council, New York, NY, 3 Weill Medical College of Cornell University; Department of Microbiology and Immunology, New York, NY, 4 Weill Medical College of Cornell University; Department of Pediatrics, New York, NY Background: HIV-1 entry is a promising target for a new generation of antiretroviral medications. Currently in Phase 2 testing, PRO 542 (CD4-IgG2) is a third-generation, tetravalent CD4-based protein that potently neutralizes primary viruses by blocking their attachment to CD4+ target cells. This agent broadly inhibits HIV-1 replication in cultures of primary human peripheral blood mononuclear cells (PBMCs). However, other primary cell types provide targets and reservoirs for HIV-1 in vivo. Methods: We explored the activity of PRO 542 on a diverse panel of primary target cells, including PBMCs, macrophages, dendritic cells (DCs), and umbilical cord blood mononuclear cells. Additional studies examined infection of PBMCs by DC-associated virus in trans. The extent of viral replication was determined by p24 ELISA of culture supernatants. Results: PRO 542 was highly active in each of the above settings. The median IC90 values observed for the various cell types clustered about those observed for PBMCs (~3 g/mL). PRO 542 blocked infection in trans with similar efficiency and was particularly effective in inhibiting infection of macrophages, which typically express lower levels of CD4. The ability of PRO 542 to effectively block infection in trans suggests that an important fraction of DC-associated infectious virus is accessible to inhibitors during entry. Studies are ongoing to further explore this issue. Conclusions: PRO 542 broadly protects relevant primary cells from HIV-1 infection by neutralizing both free and DC-associated virus. These findings have important and positive implications for therapies based on inhibiting HIV-1 attachment and entry.
Entry Inhibitor PRO 140 Suppress HIV in Test Tube
abstract title (H-178): Inhibition of HIV-1 Entry without Receptor Antagonism by the Humanized Anti-CCR5 Antibody PRO 140.
W.C. OLSON1, J.P. GARDNER1, T.J. KETAS1, B.M. SULLIVAN1, S.I. ROSENFIELD1, K.A. NAGASHIMA1, J.P. MOORE2, P.J. MADDON1-1 Progenics Pharmaceuticals, Inc., Tarrytown, NY, 2 Weill Medical College of Cornell University, New York, NY
CCR5 is a requisite fusion coreceptor for primary HIV-1 isolates and provides a promising target for a new generation of antiretroviral agents. PRO 140 is an anti-CCR5 monoclonal antibody (mAb) that broadly and potently blocks R5 virus entry (Trkola et al., J. Virol. 75:579, 2001). The parent mouse antibody was recently humanized to support repeat dosing in man, and humanized PRO 140 is entering Phase 1 clinical testing. Humanized PRO 140 was comparatively evaluated for its breadth of antiviral activity and effects on human immune cells in vitro. The antiviral activity was examined using both whole-virus p24 assays and a novel fluorometric membrane fusion assay. The virologic studies examined a broad range of wild-type and drug-resistant HIV-1 isolates and diverse primary target cell types. Immunologic studies explored the mAb's effects on both chemokine and non-chemokine signaling pathways. RESULTS: PRO 140 was broadly active in blocking HIV-1 replication in diverse and clinically relevant primary target cells, such as T cells, macrophages, and dendritic cells (DCs). The median IC90 values for the different viruses and cell types clustered about 5 g/mL. This agent was similarly effective in blocking infection of T cells by DC-associated virus in trans. Complete suppression of viral replication was obtained at PRO 140 concentrations that had little or no effect on CC-chemokine signaling through CCR5 and other normal immunologic activities. Conclusions: Humanized PRO 140 broadly and potently blocks HIV-1 entry through CCR5 without interfering with the receptor's normal activity. This unique and compelling therapeutic profile warrants advancement of humanized PRO 140 into human clinical testing.