Hello all,
I was sure we could draw conclusions from the 141 dual PI abstract ... with more complete data, I'm not so sure. It's amazing how I can spin data even to myself ... : )
Look at the following abstract, then the VRTX press release on the data that came out today. This is the dual PI data with Vertex's amprenavir. The abstract shows 1 week and 4 week data for amprenavir (141W94) + indinavir (Crix), saquinavir-sgc (Fort), nelfinavir (Viracept), and 141 alone. I drew the conclusion from that minimal data and short time frame that Viracept performed better with 141 than the other PIs.
However, see the press release with 16 week data. Crixivan was the best in combination with 141, and Viracept was the worse ... even below 141 alone (with 3TC and AZT). Now I get to point out what I should have done with the early set of results ... these are very small sample sizes, and very short time frames, and it's hard to draw too much in the way of conclusion from the data : )
btw, it appears the Viracept + 141 results were lower due to several treatment failures (3 of 6 were undetectable at 400 viral copies/ml and at 20 copies/ml) in the small sample of 6, whereas the other PI's in combination had fewer failures.
Abstract:
Abstract 06 / Session 5
Preliminary Assessment of 141W94 in Combination with other Protease
Inhibitors
J.ERON*l,R.HAUBRICH2,D.RICHMAN2,W.LANG3,M.TISDALE4,R.MYERS4,G.PAGANO5
,M.ROGERS5
lUniv. of North Carolina,Chapel Hill,NC,USA; 2Univ. of California, San
Diego, SanDiego,CA,USA,3ViRx, Inc., San Francisco,CA,USA,4GlaxoWellcome,
Stevenage,UK; 5GlaxoWellcome, RTP, NC, USA.
Objective:To assess the safety, tolerance, and acute antiviral activity
of combination HIV protease inhibitor therapy in HIV infected subjects
with >200 CD4+ cells/mm3 and HIV RNA >10,000 copies/mL.
Methods:Eligible adults with no prior HIV protease inhibitor exposure
were randomized to receive 141W94 800 mg TID plus one of the following:
saquinavir (soft gel cap (SQV)) 800 mg TID, indinavir (IDV) 800 mg TID,
nelfinavir (NLF) 750 mg TID. A fourth cohort received 141W94 alone for 3
weeks followed by the addition of zidovudine 300 mg BID + 3TC 150 mg
BID.
Results:27 patients have been enrolled. The majority of subjects are
white males with a median age of 39.1 years.ÿViral load data are
available for 16 subjects at week 4.
Log10 HIV RNA Conies/mL Week 2
Log10 HIV RNA Copies/mL
Week4
GroupNBaseline
Median Median Change
from Baseline**NBaseline
MedianMedian Change
from Baseline
SQV+141 54.66-1.8334.45-2.53
lDV+141 65.06-2.3055.14-2.57
NLF+14134.73-2.5444.88-3.18
141*34.09-1.3244.26-1.74
*AZT+3TC added at week 3
**Lower limit of detection of HIV RNA assay was 40 copies/mL
The combinations were well tolerated and had potent antiviral activity.
13/16 subjects had a decrease in viral load to less than 400 copies/mL
by week 4. The most common adverse events were diarrhea, perioral
tingling/numbness, nausea, rash, headache and flatulence. Evaluation of
pharmacokinetic data is ongoing.
Conclusions:During the initial 4 weeks of this study, the combinations
were generally well tolerated and had significant antiviral activity.
Continued investigation of these combinations is ongoing.
Press Release:
Double Protease Inhibitor Regimens Containing Vertex's HIV Protease Inhibitor, Amprenavir, Show Promise
Investigational Protease Inhibitor Amprenavir Appears Potent, Well Tolerated
CHICAGO, Feb. 2 /PRNewswire/ -- Combining the investigational anti-HIV protease inhibitor amprenavir (formerly 141W94, VX-478) with any one of three currently available protease inhibitors may result in highly potent antiviral regimens that appear to be generally well tolerated by patients.
Early results from a small phase II open-label study presented today at a major AIDS meeting being held in Chicago compared the combinations of amprenavir+nelfinavir, amprenavir+indinavir, amprenavir+saquinavir (soft gel caps), and amprenavir+ the nucleoside analogues Epivir(R) (lamivudine; 3TC)+ Retrovir(R) (zidovudine; AZT) over 16 weeks of treatment. Patients in the study had not previously been treated with protease inhibitors, had CD4 cell counts greater than 200 and viral loads greater than 10,000 copies/mL.
At 16 weeks, the combination of amprenavir+indinavir resulted in median viral load drops of 3.75 logs, with 5 of 6 patients having below detectable levels of virus (less than 400 copies/mL). The amprenavir+saquinavir arm showed a median 2.94 log drop in viral load with 5 of 5 patients having undetectable virus, and the amprenavir+nelfinavir arm showed a median 1.84 log drop in virus with 3 of 6 patients having undetectable virus. Interestingly, the amprenavir+Epivir+Retrovir arm showed a 2.79 log viral load drop with 2 of 3 patients having undetectable virus.
Furthermore, an ultra sensitive assay of HIV RNA after 16 weeks of therapy showed that 4 of 6 patients in the amprenavir+indinavir arm had undetectable virus (less than 20 copies/mL), 2 of 5 in the amprenavir+saquinavir arm were undetectable, and 3 of 6 were undetectable in the amprenavir+nelfinavir arm. Two of three patients in the amprenavir+Epivir+Retrovir arm were undetectable using the ultra sensitive measure.
"Despite the fact that this study is very small, the results suggest that double protease inhibitor combinations containing amprenavir are highly potent and may have promise in future regimens," said Joseph P. Eron, M.D., associate professor of medicine at the University of North Carolina, Chapel Hill, School of Medicine.
Nine out of 34 patients who were randomized in the trial discontinued study medication early due to consent withdrawal, lost to follow-up, or, in one case, due to adverse events. Patients reported in this study are those who had completed 16 weeks at the time of the analysis.
Adverse events observed in this study were generally mild and appeared to occur with similar frequency across the various study groups. Most commonly reported events included diarrhea, perioral tingling/numbness, nausea and vomiting, cutaneous events, abdominal pain and flatulence, and headache. The most commonly reported adverse events associated with amprenavir in trials to date include nausea, vomiting, headache and rash.
"Most combination therapies to date have included one protease inhibitor," said Eron. "However, in some patient populations, this kind of regimen is not as potent as it needs to be. The concept behind studying two protease inhibitors together is to try to further maximize the strength of anti-HIV treatment regimens. The preliminary results of this study with amprenavir offer hope that this is possible."
Amprenavir is currently being studied in phase III clinical trials in various combinations in various patient populations. Amprenavir is being studied using twice daily dosing without restrictions regarding dosing with or without food. Amprenavir is being studied in pediatric trials utilizing one or both of two pediatric formulations of the drug - a small 50 mg capsule or an oral solution.
In another study presented today, data suggested that amprenavir in combination with the investigational nucleoside analogue abacavir (formerly 1592) results in highly potent antiviral activity. Both amprenavir and abacavir are being developed in clinical trials by researchers at Glaxo Wellcome.
"We are very encouraged by the clinical data that are emerging regarding amprenavir and are looking forward to receiving the results of large, phase III clinical trials in the coming months," said Michael Rogers, Ph.D., international project leader for amprenavir at Glaxo Wellcome.
"These are the first reported results of dual protease inhibitor regimens that include amprenavir, and we are highly encouraged," added Dr. Vicki L. Sato, Vertex Senior Vice President and Chief Scientific Officer. "Treatment with two protease inhibitors is becoming more common, and this study highlights amprenavir's versatility in double-protease combinations."
Amprenavir was discovered by scientists at Vertex Pharmaceuticals which licensed the compound to Glaxo Wellcome.
Glaxo Wellcome is the pharmaceutical industry leader in HIV research and therapies. In addition to the investigational compounds amprenavir and abacavir, both in phase III clinical trials , the company manufactures and markets the two most widely prescribe anti-HIV drugs, Epivir and Retrovir. The company recently received FDA clearance to market Combivir(R) (lamivudine/zidovudine), the first and only anti-HIV therapy to combine antiretroviral drugs in one formulation in an attempt to encourage adherence to combination therapy. The company also markets Mepron(R) (atovaquone) as a treatment for mild to moderate cases of pneumocystis carinii pneumonia.
Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) is engaged in the discovery, development and commercialization of novel, small molecule pharmaceuticals for the treatment of diseases for which there are currently limited or no effective treatments. The Company is a leader in the use of structure-based drug design, an approach to drug discovery that integrates advanced biology, biophysics and chemistry. The Company is concentrating on the discovery and development of drugs for the treatment of viral diseases, multidrug resistance in cancer, autoimmune diseases, inflammatory diseases, and neurodegenerative diseases.
Epivir and 3TC (lamivudine) and Retrovir and AZT (zidovudine) are trademarks of the Glaxo Wellcome Group of Companies. Indinavir is manufactured and marketed by Merck. & Co. Saquinavir is manufactured and marketed by Hoffmann-La Roche. Nelfinavir is manufactured and marketed by Agouron Pharmaceuticals.
There can be no assurance that clinical trials will continue, that initial clinical trial results will be predictive of any future results, that drugs under development by the Company or its partners will receive marketing approval from the U.S. Food and Drug Administration or other regulatory authorities, or that drugs, if any, which receive such approval will be marketed successfully. Investors are also directed to consider other risks and uncertainties discussed in documents filed with the Securities and Exchange Commission.
SOURCE Vertex Pharmaceuticals Incorporated
CO: Vertex Pharmaceuticals Incorporated; Glaxo Wellcome
ST: Illinois
IN: MTC
SU:
02/02/98 11:40 EST prnewswire.com |
