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New NNRTI GW695634: safety & antiviral activity; 7-day monotherapy study  
 
 
  Reported by Jules Levin
 
"Antiviral Activity and Safety of GW695634, A Novel Next Generation NNRTI in NNRTI-resistant HIV-1 Infected Patients"
 
Reported by Jules Levin
 
S Becker1, J Lelezari2, C Walworth3, P Kumar4, J Cade5, J Ng-Cashin6, Y Kim6, J Scott6, M St. Clair6, L Jones6, and W Symonds6 On Behalf of the NN210005 Study Team
 
1pacific Horizon MedicalGgroup, San Francisco, CA; 2 Quest Clinical Research, San Francisco, CA; 3 Orange County Center for Special Immunology, Fountain Valley, CA; 4 Georgetown University Hospital, Washington, DC; 5HIV Wellness Center, Las Vegas, NV; 6GlaxoSmithKline, RTP, NC.
 
This poster was presented at IAS-Rio July 2005.
 
GW695634 is a novel next generation NNRTI in early development for the treatment of HIV-1. In vitro, GW678248 potently inhibits both wild-type HIV-1 and NNRTI-resistant mutants, including virus with K103N and Y181C mutations.
 
This study investigated the safety and tolerabilility of GW695634 and GW678248 in NNRTI-experienced HIV-1 infected subjects over a 7-day monotherapy treatment period, and evaluating the initial antiviral & immunological activity of GW678248 in NNRTI-experienced subjects. Single & repeat dose PK in NNRTI-experienced subjects was studied and data will be presented at future meeting in 2005.
 
BRIEF SUMMARY: After 7 days of monotherapy viral load reductions were -1.1 log to -1.6 logs. 5/9 patients receiving highest dose of 400mg bid and 2/9 patients receiving 300mg bid in this study experienced rash, but only 1/10 receiving 200mg bid experienced rash. See below for additional safety and antiviral activity data.
 
This was a multi-center,double-blind, randomized, parallel group, placebo-controlled, dose-ranging study comparing 4 doses of GW695634 or placebo administered as monotherapy for 7 days:
 
100 mg bid (n=10)
200mg bid (n=10)
300 mg bid (n=10)
400 mg bid (n=10)
or placebo (n=10)
 
At screening patients were required to be: NNRTI resistant by current genotype or historical evidence CD4 <100 HIV RNA >2000 c/ml No ARTs were permitted for 4 weeks prior to study entry
 
Plasma HIV RNA, PK, and safety parameters were monitored daily.
 
AUTHOR CONCLUSIONS
--GW695634, the pro-drug of GW678248, demonstrated potent antiviral activity (-1.1 to -1.6) log copies/ml plasma decline) across all doses studied in this NNRTI-experienced population following 7 days of monotherapy.
 
--3 subjects harbored viruses which were generally resistant to first-generation NNRTIs, but responded to GW695634.
 
--GW695634 was generally well tolerated over 7 days.
 
These data provide "proof-of-concept" which supports further clinical development of GW695634 for use in subjects failing currently marketed NNRTIs.
 
RESULTS
--46 subjects were enrolled with a median of 2 NNRTI-associated primary mutations (range 1-4), including L100I, K103N (55%), V108I, Y108I, Y181C/I (30%), Y188C/L/H, G190S/A, and P225H. The baseline NNRTI resistance data are summarized:
 
--17 (39%) of subjects had historical evidence of prior NNRTI resistance mutations, but were wild-type by population sequencing at study entry.
 
--of the 44 subjects with baseline genotype information, 27 (61%) had at least 1 NNRTI mutation ate baseline: 9 (20%) had single mutations, 10 (23%) had 2 mutations, and 8 (18%) had 3 mutations.
 
5% had L100I
40% K103N
5% V106A/M/I
25% V108I
20% Y181C
10% Y188C/L/H
10% G190S/A
10% P225H
 
In vitro data in poster showed 20 fold resistance of GW678248 to mutant NNRTI virus with Y188L, and several fold resistance to mutants K103N/G190A and V106I//Y181C.
 
--44 NRTI-experienced HIV-1 infected men & women >18 yrs old completed the study: 1 patient discontinued the study early due to a non-serious AE at day 6 and 1 was lost to followup on day 1.
 
--the 5 treatment groups had median baseline plasma viral load values ranging from 4.4 to 4.6 log c/ml and median CD4 counts ranging from 230-345. Average age was 41-46. 2 females in study. 8 blacks, 3 Hispanics, 34 Whites.
 
--On day 8, median plasma HIV RNA-1 reductions were -1.2 log c/ml (100mg), -1.1 log c/ml (200mg), -1.6 (300mg), -1.3 (400mg), and +0.14 (placebo).
 
--significant changes in day 8 VL compared to placebo were seen across all GW695634 dose groups (p-value range <0.0001 to 0.005).
 
--GW695634 was generally well tolerated over 7 days. As summarized, the most common frequent drug-related adverse events were diarrhea, nausea, and rash. The majority of the AEs were mild to moderate in intensity.
 

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CLINICAL SAFETY DATA
In total 289 patients and healthy volunteers have received GW695634 in 6 Phase 1 studies. 155 patients/volunteers have received GW695634G in multiple dose studies: 39 (25%) developed drug-related rash; diffuse maculopapular rash (grade 2) in majority (n=35); additional isolated, local, oral mucosal involvement in 4 cases (grade 3); 6 withdrawals for asymptomatic serum transaminase elevations.
 
 
 
 
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