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Fuzeon (T-20) Story
Reported by Jules Levin
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There isn't much new important information or data at this conference. Today there has been some interesting new data regarding the recently and first approved entry inhibitor T-20. Fuzeon (also called T-20) is a fusion inhibitor and hopefully the first of a number of entry inhibitors that will be successfully developed. For now Fuzeon is the only entry inhibitor able to be successfully developed. A number of research efforts by companies are ongoing in trying to discover and develop entry inhibitors. Roche and Trimeris, the makers of Fuzeon, are also developing T-1249, which in early data results shows itself to be effective in suppressing T-20 resistance. At a press conference just held at the conference Roche & Trimeris talked with the international press and media. Fuzeon was approved for commercial availability in the USA and the European Union in May 2003 and in Switzerland in March 2003. Roche and Trimeris are exploring improving the administration and delivery of T-20 and their second generation fusion inhibitor T-1249 by looking at pegylation and other delivery methods whereby perhaps administration would be less often than daily.
In an oral presentation today, Julio Montaner reported the results of a study finding that if patients in the phase III T-20 studies (TORO I and II) had 4 positive predictive factors 80% were able to achieve <400 copies/ml (undetectable viral load) at week 24 if they received Fuzeon plus an optimized background regimen compared to 50% of patients who received an optimized background regimen (OB) without Fuzeon. If a patient had 3 positive predictive factors 59% receiving Fuzeon plus OB had <400 copies/ml vs 34% not receiving Fuzeon with their OB. If a patient had 2 positive predictive factors and received Fuzeon plus OB 47% had <400 copies/ml compared to 19% in the patients not receiving Fuzeon with their OB. For patients with 1 predictive factor receiving Fuzeon plus OB 23% had <400 copies/ml vs 3% in the OB regimen. And if a patient had 0 predictive positive factors 15% receiving Fuzeon vs 2% not receiving Fuzeon had undetectable HIV. The statistical signifucance was p<0.05 for all these comparisons. Montaner found these to be the positive predictive factors for achieving <400 copies/ml:
--CD4 count >100
--viral load <100,000 copies/ml
--having prior use of <10 antiretroviral HIV drugs
--having 2 or more active HIV drugs in the optimized background regimen
It was an interesting panel of speakers including Robert Gallo, Dani Bolognesi (the co-discoverer of T-20), Cal Cohen, David Cooper, and David Reddy (Roche). Gallo and Bolognesi spoke for about 20 minutes and gave an interesting overview of HIV tracing history from the discovery of HIV, it's identification as a retrovirus, the possibility of a vaccine for HIV, and the development of HIV therapy. David Reddy said Roche is committted to HIV. He said Roche is offering their HIV drugs at cost in the developing world at prices 30-50% below generic company prices. He said Roche will not file patents on any HIV drugs in the world's least developing countries. And in places where they have a patent they will not enforce it. Roche officials addressed T-20 reimbursement in the USA; they said T-20 is approved by ADAP in the USA now in 19 States, which covers about 60-70% of HIV-infected individuals, and it's expected that a number of other State's will soon be covering T-20. All State Medicaid programs are covering T-20.
Reddy said that Fuzeon is the "most complicated drug ever manufactured" and in fact production and supply has been difficult. Reddy said that in December 2002 Roche said that by the end of 2003 there would be enough drug to support 12,000 to 15,000 patients. New information he said was that production is improved and so they now expect to have enough drug to support 18,000 patients by the end of 2003.
48-Week T-20 Study Results
Tomorrow, Wednesday in the Late Breaker oral session the new 48-week data from the Toro I and II studies will be presented. These are the large phase III studies that supplied the data for T-20 approval by the FDA. At the press conference Roche gave us a preview of the data.
Previously reported results of TORO I and II showed 33% of patients receiving Fuzeon plus an optimized background regimen of additional drugs had <400 copies/ml of HIV viral load compared to 15% of patients who received an optimized regimen without Fuzeon. The new 48-week data shows responses are holding up. At week 48, 30% of patients receiving Fuzeon regimen have <400 copies/ml vs 12% not receiving Fuzeon. After 24 weeks patients receiving Fuzeon regimen had increase of 71 CD4 cells and at week 48 the increase was 91 from baseline. Roche also reported that the mean duration of suppression was 3 times longer for patients receiving Fuzeon regimen than for those not receivinf Fuzeon (32 weeks vs 11 weeks).
Among patients whose virus was sensitive to one drug in the background regimen, 29% of patients in the Fuzeon arm achieved undetectable viral load, compared to 7%in the group not receiving Fuzeon. Among patients who had at least 2 active HIV drugs in their background regimen 38% achieved undetectable viral load at week 48 compared to 18% in the group not receiving Fuzeon. The speakers on the panel said that Fuzeon does not appear to cause major exacerbation of known toxicities associated with ART. This suggests they are not observing major increases in lipids but the analysis is ongoing examining lipids and body changes using objective evaluations such as DEXA.
Predictive Factors Found In Successful Therapy with T-20
In an oral talk today Julio Montaner presented an "Analysis of virological response of Fuzeon in TORO: implications for patient management". The objective of this study was to explore the effect of demographic, baseline, and treatment factors on virological response after 24 weeks of treatment on Fuzeon containing regimens; to formulate guidance for the best use of Fuzeon based on the results from the TORO studies in triple class experienced patients. Montaner stressed that this study is exploratory and the results are preliminary.
The study used a multiple logistic regression analysis to evaluate specific factors in trying to assess what predictive factors are associated with success or failure with Fuzeon therapy. The researchers evaluating the following factors in their analysis:
Demographics
-age, gender, race, Body Mass Index (BMI)
Baseline disease characteristics
-HIV viral load
-CD$ cell count
ARV treatment history
-type of prior ARV exposure, total and by class
-prior Kaletra (LPV/r) experience
Treatment factors
-number of active ARVs in optimized regimen by phenotypic testing (PSS)
-type of ARVs in background regimen (LPV/r, tenofovir)
-treatment adherence (to oral ARVs and T-20)
The virologic response at week 24 was:
--52% receiving Fuzeon plus OB (optimized background) vs 28% had >1 log reduction in viral load
--37% had <400 copies/ml if they received Fuzeon plus OB vs 16% not receiving Fuzeon
--23% had <50 copies/ml if they received Fuzeon plus OB vs 9% if they did not receive Fuzeon. The differences in all this data are highly significant (p<0.0001)
Multiple regression analysis for all patients in achieving HIV RNA <400 copies/ml at week 24: T-20 use, baseline CD4 greater than 100, active ARVs, and the use of Kaletra were predictive of better response in the study.
Clinically relevant parameters for patients initiating Fuzeon treatment. Of the multiple factors studied these were considered the most relevant because they are the most commonly used in clinical practice:
--disease stage
--treatment history
--activity of background regimen
Montaner said baseline CD$ count >100 cells (odds ratio 2.4, p<.0001), baseline viral load (odds ratio 1.8, p<.0022), treatment history/number of prior ARVs <10 (odds ratio 1.8, p<.0058), and >2 active ARVs in background were predictive for success in therapy in this study (<400 copies/ml at week 24).
Patients with at least 2 active HIV drugs in their background regimen were better able to achieve <400 copies/ml at week 24: if patient had 0 active drugs in background regimen 18% had <400 c/ml, if patient had 1 active drug 35% had <400 (compared to 13% for patients not receiving Fuzeon), with 2 active ARVs 53% had <400 (vs 21% for patients not receiving Fuzeon, with 3 active ARVs 52% vs 38%), with 4 active drugs 45% (vs 26%) had <400, and with 5 active drugs 50% (vs 20%) had <400. The cut-off appears to be two active drugs. Having at least 2 or more active HIV drugs in the background regimen appears to be an important predictive factor for success.
For patients with <100 CD4 at baseline, if they had 10 or less prior ARVs 34% receiving Fuzeon vs 24% not receiving Fuzeon had <400 copies/ml at week 24. If patients had <100 CD4s and had previously used >10 ARV 23% receiving Fuzeon vs 5% not receiving had <400 copies/ml.
For patients with >100 CD4s at baseline: if they had prior use of 10 or less ARVs 68% receiving Fuzeon compared to 39% not receiving Fuzeon had <400 copies/ml; if patients had >100 CD4s at baseline and had prior use of 10 or more ARVs 45% had <400 c/ml when receiving Fuzeon vs 17% who did not receive Fuzeon.
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