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New
Nucleoside Analog Reverset (D-d4FC) Shows Promise in Phase II Study
of Treatment-experienced Patients
Reverset
(RVT) is a fluorocytidine nucleoside
analog from Incyte Pharmaceuticals. Incyte is developing RVT,
an oral, once-a-day
nucleoside analog reverse transcriptase inhibitor (NRTI), under
a collaborative licensing agreement with Pharmasset, Ltd.
The aim of
the current Phase II study (Study 203) was to evaluate the anti-HIV
activity and tolerability of once daily doses of 50mg, 100mg or
200mg RVT in treatment-experienced HIV patients (pts). In addition
to comparing antiviral activity in these groups, other objectives
include to select a dose for Phase III trials and to evaluate the
safety and tolerability of RVT in patients failing their current
treatment regimens.
This was a
multi-center, randomized, blinded, placebo-controlled, 3-stage study
consisting of (1) a 2-week add-on phase (RVT or placebo); (2) a
14-week optimized treatment phase; and (3) an 8-week safety phase
(placebo pts allowed to cross over) in treatment-experienced pts.
Results
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199
pts are enrolled at 25 sites; 120 have completed >16 wks
of therapy. |
| · |
Mean
baseline VL = 4.5 log10, presence of M184V: 60%,
M41L: 60%, 4-6 TAMs:
50%, K65R: 6%; |
| · |
After
2 weeks, mean VL changed by +0.007, -0.5, -0.3, and -0.7 log
10 for placebo, 50, 100, and 200 mg groups, respectively; |
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Pts
on 200 mg with 0-3 TAMs had 2-week VL drop of 0.8 log10,
with 4-6 TAMs, a 0.6log10 drop; |
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Pts
with M41L, M41L+L210W or w/o M41L showed similar VL decreases
(0.7 log10); |
| · |
Pts
with K65R or M184V + TAMs had more variable responses (mean
0.4 log10 drop); >20% pts had > 1 log10
drop; |
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33%
pts did not optimize at week 2. Of these, current data shows
stable VL decrease of about 0.6 log10 at wk 16 on
200 mg RVT; |
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Adverse
events were generally mild, and included headache, fatigue
and GI
disorders; |
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In
35 subjects taking RVT with didanosine/ddI
(Videx), 12 (34%) had grade 4 hyperlipasemia, usually occurring
after >12 wks of treatment; |
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Among
pts not on ddI, asymptomatic grade 4 lipase was noted in 5.4%
of pts on 200 mg RVT vs. 3.1% on placebo. |
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Pancreatitis
occurred in 3 pts on RVT+ ddI + tenofovir/TDF (Viread): 1 pt
on ddI 250 mg/TDF 450 mg, 1 pt on ddI 400 mg/TDF 300mg; all
resolved following drug discontinuation. |
In conclusion,
the authors note that Riverset 200 mg demonstrates anti-HIV activity
in treatment-experienced individuals and is generally well tolerated.
Concurrent use of RVT and ddI is contraindicated, due to risk of
pancreatitis and hyperlipasemia. The data presented, say the authors,
support continued development of RVT.
2-week
Add-on Phase
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Effect
of NRTIs in Baseline Regimen on 2-Week
Viral Load Decline with 200 mg RVT
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- Activity
retained with tenofovir, AZT, abacavir
- Activity decreased with 3TC/FTC
- Subjects not taking 3TC/FTC achieve > 1 log reduction in
2 weeks |
Week 16
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Presence
of M184V Does Not Impact
16-Week Response to 200 mg RVT
|
|
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| - Improved
response without 3TC/FTC is not related to possible resistance
to M184V + TAMs virus |
Week
16
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RVT
Provides Stable Reduction in Viral Load
when Added to a Failing Regimen
|
 |
| - Results
in subjects who did not optimize at week 2 |
Medical
Sites for RVT Study 203
Community Research Initiative of New England, Boston, USA; Hôpital
de la Pitié, Paris, France; Northwestern University, Chicago, USA;
Fannin Street, Houston, USA; Central Texas Clinical Research, Austin,
USA; 6315 SE 14th Street, Fort Lauderdale, USA; Hôpital St. Antione,
Paris, France; Kaiser Permanente, San Francisco, USA; George Washington
University Medical Center, Washington, DC, USA; Research Center
of Florida, Inc., Miami, USA; Clinical Research of West Florida,
Clearwater, USA; Hillsborough County Health Department, Tampa, USA;
University of Texas Medical Branch, Galveston, USA; EPIMED, Berlin,
Germany; Pharmasset, Inc. Tucker, USA; Incyte Corp., Wilmington,
USA.
7/27/05
Reference
C Cohen, C Katlama, R Murphy and others. Antiretroviral
Activity and Tolerability of Reverset (D-d4FC), a New Fluorocytidine
Nucleoside Analog, When Used in Combination Therapy in Treatment-
Experienced Patients: Results of Phase IIb Study RVT-203  (oral
and poster presentations). 3rd IAS Conference on HIV Pathogenesis
and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil.
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