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  10th Conference on Retroviruses and Opportunistic Infections
Boston, Mass, Feb 10-14, 2003
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UK-427,857: new entry inhibitor, CCR5 antagonist
"Pharmacokinetics of Single and Multiple Oral Doses of UK-427,857-A Novel CCR5 Antagonist in Healthy Volunteers"
  UK-427,857, an antagonist of the CCR5 receptor with potent anti-HIV activity in vitro, is being developed for the treatment of HIV infection. Studies in healthy volunteers were conducted to evaluate the pharmacokinetics, safety and toleration of the compound. As well, an early small clinical study is ongoing in HIV-infected individuals examining safety and antiviral activity. It appears to be safe and have antiviral activity but these results will not be available until perhaps the IAS Conference in July 2003 in Paris. In the oral session on New drugs on the first day of the Conference Pfizer researchers reported the following. Over 900 compounds were synthesized and tested in 2 1/2 years. They confirmed potent activity in viral replication assays. The drug showed favorable preclinical pharmacokinetics. They did not observe any significant effects on the major physiological systems. The drug was highly selective for human CCR5. The drug was well tolerated in phase I clinical trials using single doses up to 900mg, and multiple doses up to 300mg bid. There were no clinically significant prolongations in QTc interval, and no laboratory abnormalities that preclude further clinical development. Pfizer researchers concluded this drug is a potent CCR5 antagonist, has no intracellular signaling, inhibits gp120 binding and HIV entry, and has activity against a range of primary viral isolates from all clades tested. ItŐs important to bear in mind research in this drug is early and as with all drug development barriers and challenges to development occur. Many drugs perform well in early research and are then confronted with toxicities, dosing problems, and side effects. So in preliminary studies this entry inhibitor, CCR5 antagonist, is promising, but we must temper this with mindfulness regarding potential setbacks while keeping a watchful eye on developments.
In addition, development of entry inhibitors appears at full throttle as the early development of a number of different drug candidates were presented at the conference. This is a promising class of new drugs but again most of the research is in early development except for the fusion inhibitors T-20 and T-1249. T-20 is about to receive FDA approval and T-1249 is in clinical development in HIV-infected individuals. T-1249 showed antiviral effectiveness for patients with T-20 resistance and is administered by subcutaneous injection, as is T-20, but only once daily. T-1249 is also more potent and considering these factors is an advancement from T-20. A number of drug companies have development programs for entry inhibitors including BMS, Japanese drug companies, and others. At conferences over the course of the past year starting at the 2002 Retrovirus Conference Bristol Myers Squibb has been presenting regularly about their entry inhibitor program which has a prototype and several candidates. As well, several development programs are ongoing for integrase inhibitors, also a new target for HIV drug development. Merck's program appears to be moving along well as the program is testing their integrase inhibitor now in HIV-infected for safety and antiviral activity. GlaxoSmithKiline has an integrase program in earlier development stages. At this conference the Rega Institute in Belgium presented very early developments in their integrase program. I think all these developments are encouraging for the future of HIV treatment.
Healthy male volunteers received single and multiple oral doses of UK-427,857 or placebo in two separate studies. Single doses ranged from 1-1,200 mg, multiple doses ranged from 3-300 mg bd, and 600 mg od for 12 days. The effect of food on the pharmacokinetics of UK-427,857 was also evaluated. Serial blood samples for determination of UK-427,857 plasma concentrations were collected at selected times throughout the dosing periods and for up to 72 hours following the last dose. Clinical safety evaluations, including laboratory safety tests, were performed throughout the studies. UK-427,857 is rapidly absorbed with maximum plasma concentrations being achieved in general between 0.5 and 4 hrs post-dose. For doses of 100mg and greater, the pharmacokinetics appear to be approximately proportional. The terminal half-life on multiple dosing is approximately 17 hrs and does not alter significantly with dose. A dose of 100mg twice a day achieves plasma concentrations in excess of the in vitro antiviral IC90. Evaluation of the effect of food on the plasma concentration of UK-427,857 indicated that there is a significant reduction in the rate and extent of absorption when UK-427,857 is co-administered with food. UK-427,857 was well-tolerated in single and multiple oral doses up to 900mg and 600mg once a day, respectively. The most frequently recorded adverse events were postural hypotension (only at the highest doses in both studies), asthenia, light-headedness/dizziness, abnormal vision, and headache. No laboratory abnormalities or ECG findings were observed that would preclude further development. Together these results indicate that further evaluation of UK-427,857 for the treatment of HIV infection is merited.
Retrovirus Conference 2003, Feb 10-14. S. Abel et al. Pfizer Global Research and Dev, Sandwich Labs, Kent, UK