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
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
"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
T.J. KETAS1, I. FRANK2, B.M. SULLIVAN1, C. SPENLEHAUER3, M. NESIN4, W.C.
OLSON1, J.P. MOORE3, M. POPE2
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 µg/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 µg/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.