BY OUR PHARMA CORRESPONDENT
13 September,2005: Preliminary clinical findings with a drug that blocks the entry of HIV entry are positive, reports Progenics Pharmaceuticals, Inc.
The investigational drug, PRO 140 is a novel HIV entry inhibitor. It is a humanized monoclonal antibody against CCR5 that is designed to protect healthy immune system cells from infection by the human immunodeficiency virus (HIV), the causative agent of AIDS.
Dose-dependent binding of PRO 140 to CCR5-expressing cells was reported in the clinical trial, with the highest PRO 140 concentration tested significantly coating CCR5 cells for at least 60 days. The CCR5 co-receptor is a key portal of entry used by HIV to infect immune system cells; therefore, blocking this molecular doorway represents an important therapeutic target.
The announcement of these findings were at the BioCentury: NewsMakers in the Biotech Industry Conference in New York City.
Coating of CCR5 cells with PRO 140 has been shown in prior laboratory studies to block HIV infection, and the clinical data reported today support our commitment to develop PRO 140 as a new, potentially long-acting therapy for HIV infection.Most currently available HIV drugs slow the rate of viral replication, but they act only after HIV has infected healthy cells. Viral-entry inhibitors like PRO 140 are designed to protect cells before HIV infection occurs, the company said in a press release.
The company also announced that it was awarded a $10.1 million grant from the National Institute of Allergy and Infectious Diseases for the development of PRO 140. Over the next three-and-one-half years, Progenics will work with Weill Medical College of Cornell University, Beth Israel Medical Center and Monogram Biosciences, Inc. (formerly ViroLogic, Inc.) on the project.
The PRO 140 phase 1 clinical trial was the first to examine the effects of this humanized monoclonal antibody in humans. The double-blind, randomized, placebo-controlled, dose-escalation study enrolled four groups of five normal subjects, each treated with single doses of PRO 140 (4 subjects) or placebo (1 subject) given by intravenous infusion at doses of 0.1, 0.5, 2.0 and 5.0 mg/kg. All volunteers received a full dose of study drug and have completed the scheduled 60-day follow-up.
PRO 140 was generally well tolerated at all dose levels with no clinically meaningful drug-related side effects reported. Blood tests examined binding of PRO 140 to CCR5 expressed on the surface of lymphocytes, the targets of HIV infection. Dose-dependent binding of PRO 140 to CCR5 cells was reported, with the 5.0 mg/kg dose of PRO 140 significantly masking CCR5 throughout the scheduled 60-day follow-up period. As a result, the trial has been extended to allow for continued monitoring of these subjects. Although coated with PRO 140, CCR5 cells remained circulating in the blood at normal concentrations.
All currently available HIV drugs are given at least once per day. The duration of CCR5 coating by PRO 140 suggests the possibility of infrequent dosing, measured in months. Such schedules would be attractive to many patients, the release said.
Progenics also announced that, in laboratory studies, PRO 140 was active against HIV strains that have acquired resistance to small-molecule CCR5 inhibitors. Humanized or murine forms of PRO 140 were tested for activity against viruses selected for resistance to small-molecule CCR5 inhibitors in vitro. Viruses were cultured in the presence of small-molecule CCR5 inhibitors until drug-resistant isolates emerged. Although completely insensitive to the small-molecule CCR5 inhibitors, the viruses continued to require CCR5 for infection and were efficiently inhibited by PRO 140. The viruses acquired mutations that enabled them to use CCR5 in the presence of the small-molecule inhibitors, but these mutations did not affect viral susceptibility to PRO 140. The study findings were recently published in leading peer-reviewed scientific journals (Journal of Virology, volume 78, issue 6 and Virology, volume 338, issue 1).
Progenics Pharmaceuticals Inc is a biopharmaceutical company focusing on the development and commercialization of symptom management and supportive care, human immunodeficiency virus, or HIV, infection and cancer. The company has five product candidates in clinical development and several others in preclinical development. In the area of symptom management and supportive care is methylnaltrexone, or MNTX, a compound in pivotal phase 3 clinical testing. MNTX is designed to treat the debilitating side effects of narcotic-based pain relievers, which are referred to as opioid analgesics, without interfering with pain relief. Progenics is conducting a broad clinical development program for MNTX in a number of settings. The first three indications pursuing are:
- treatment of constipation in patients with advanced medical illness (AMI) who are receiving opioids;
- treatment of patients with post-operative ileus, a paralysis of the gastrointestinal tract that frequently occurs after abdominal and other major surgeries; and
- treatment of opioid side effects in patients with chronic pain, including those suffering from headaches, joint pain, lower-back pain, sickle-cell disease, muscle pain and other disorders.
In the phase 2b clinical trial in AMI, MNTX induced a more regular laxation, or bowel movement, schedule in opioid-treated patients with advanced medical illness.
Pending successful completion of two phase 3 trials in AMI, the company expects to file a New Drug Application (NDA) during the second half of 2005.
In the area of HIV infection, Progenics is developing viral-entry inhibitors, which are molecules designed to inhibit the virus’ ability to enter certain types of immune system cells. Apart from PRO 140, it is conducting a multi-dose phase 2 clinical trial with the lead HIV product candidate, PRO 542, a genetically engineered molecule designed to selectively target and neutralize HIV.
BY OUR PHARMA CORRESPONDENT