 |
|
|
| |
"908": New Formulation of Amprenavir
|
| |
| |
908 vs nelfinavir in treatment-naive, and 908/r once & twice daily vs Kaletra in PI-experienced
Reported by Jules Levin
In Friday's session on "Clinical Trials and Cohorts" new research was reported in two studies of the new formulation of amprenavir called GW433908 or fosamprenavir or more commonly called "908" for short. The older version of amprenavir had a high pill count of 8 150 mg pills taken twice daily and was associated with GI side effects due to the fillers used in the formulation. The new version 908 has a lower pill count. The pills are 700 mg so when taking the 1400 mg 908 dose the pill count is 2 and when taking the 700 mg dose the pill count is 1. The rate of GI side effects appear greatly reduced with the new 908. In one study presented today 908 was compared to nelfinavir and appeared superior in the study. The viral load reductions were better. The lipid changes were not significant for either drug and were comparable for the 2 drugs, although there were more increases in triglycerides for patients taking NFV. There was more diarrhea of at least moderate severity reported for patients taking NFV (18% vs 5%).
The second study compared 908 once daily and twice daily with both regimens
using a ritonavir low dose booster to Kaletra in PI-experienced patients. The results of this
study at week 24 are reported below. The NDA filing to the FDA was submitted
in December for 908.
908 vs Nelfinavir
In the first study 908 was given twice daily to 166 patients and nelfinavir (NFV to 83. 251 patients were randomized (2:1) to open label:
--908 1400 mg twice daily (bid) vs
--NFV 1250 mg bid, plus abacavir 300 mg bid + 3TC 150 mg bid.
Patients were treatment naive and results were reported after 48 weeks of study. The study was conducted in the USA, Panama, Puerto Rico, and South Africa, but most patients were from the USA (n=153). The patient group in this study had fairly advanced HIV as seen by the baseline average CD4 count and viral load: 214 CD4; average viral load was 4.82 log or 66,000 copies/ml.
As well, 45% had >100,000 copies/ml viral load, and 18% had <50 copies/ml.
5% had hepatitis B and 15% had hepatitis C. 20% had CDC class C. 31% of study participants were women. 25% were white, 32% black, 45% hispanic.
RESULTS
At week 48, 66% taking 908 had <400 copies/ml vs 51% taking nelfinavir (ITT RD=F, Intent to Treat, rebound or discontinuation=failure). 908 performed better as well when evaluated by the more sensitive viral load test of <50 copies/ml of viral load (55% vs 41%, ITT RD=F).
So, why did 908 perform better in this study than nelfinavir? The study results showed that failures due to adverse events & other non-virologic reasons were comparable between the NFV and 908 groups. But there were fewer virologic failures for patients taking 908: 14% in 908 group vs 28% in NFV group experienced virologic failure. 10% of the patients on 908 experienced viral load rebounds and 14% did so on NFV. 4% of patients prematurely discontinued from the study due to insufficient viral load response in the 908 group vs 13% in the NFV group.
But when evaluating response by patients in this study by non-virologic failures the results were relatively comparable.
|
|
| |
 |
|
| |
Responses By Patients With High Viral Loads
Patients with high viral loads before therapy had a greater response rate with 908. For patients with >100,000 copies/ml 55% taking 908 had <50 copies/ml vs 24% taking NFV (ITT RD=F). Patients with >500,000 copies/ml also were more likely to achieve >50 copies/ml (52% vs 19%). In termms of reaching <400 copies/ml 908 performed better in this study: 67% of patients with >100,000 copies/ml viral load at baseline had <400 copies/ml viral load at week 48 compared to 35% of patients taking NFV. For patients with >500,000 copies/ml 65% taking 908 had <400 (n=23) vs 31% for patients taking NFV (n=16). CD4 increases were about the same in each group: 215.
Drug Related Adverse Events of at least Moderate Severity
There was significantly less diarrhea in the 908 group (5% vs 18%). There was more drug hypersensitivity in the 908 group (9% vs 5%) and more rash in the 908 group (7% vs 2%). For the remaining adverse events listed the profiles were comparable between the 2 drugs (nausea 4-5%, vomiting 2-4%, fatigue 1-2%, headache 2%, insomnia 1-2%, weakness 1-2%).
ALT and AST grade 3/4 elevations were about the same in both groups (5%). Surprisingly there were few grade 3/4 lipid abnormalities reported: for cholesterol (0), triglycerides (0-1%), and glucose (<1%).
Fasting Lipids
There was little difference between the two groups in terms of changes in cholesterol and triglycerides. As well, LDL and total cholesterol remained below the NCEP cut-offs while the values for HDL increased to greater than the NCEP cut-off from baseline to week 48.
--HDL (good cholesterol) increased comparably in both groups (from 36 to 47 mg/dL)
--LDL (bad cholesterol) increased comparably in both groups (from 87 to 120 mg/dL)
--And total cholesterol increased comparably in both groups (from 150 to 200 mg/dL)
-- fasting triglycerides were 150 at baseline for both NFV and 908 patients, but at week 48 increased to 200 (equal to NCEP cutoff) for the NFV patients and remained at 150 for the 908 patients
--The total cholesterol to HDL cholesterol ratio, which is often used as a marker for evaluation, remained the same from baseline to week 48 in both groups. At baseline and at week 48 the TC:HDL C ratios were below the NCEP cut-off for both 908 and NFV.
CONTEXT Study: 24-week efficacy and safety data of 908/r vs LPR/r (Kaletra) in PI-experienced patients
320 therapy-experienced patients were randomized (1:1:1) to receive open label one of 3 regimens:
--908 1400 mg once daily (qd) plus ritonavir 200 mg qd
--908 700 mg twice daily (bid) plus ritonavir 100 mg bid
--LPV 400 mg bid plus ritonavir 100 mg (Kaletra)
Patients had prior experience with at least 1 or 2 protease inhibitors. Patients could be NNRTI naive or experienced. There was no CD4 criteria. This was a non-inferiority analysis. That is, they had to show that the 908 group results were not inferior to Kaletra. The study took place in Europe, US, Chile/Puerto Rico, Canada, and Australia. 50-70% of patients were white, 19-32% black, and 7-11% hispanic. 4-7% had hepatitis B and 15% had hepatitis C.
The patients in this study also were a farly advanced group in terms of HIV progression. 34% had CDC class C. Average viral load was about 14,000 copies/ml and average CD4 counts were 234-290.
Patients were randomized to take:
--908 1400 mg qd (once daily) + ritonavir 200 mg qd
--908 700 mg bid (twice daily) + ritonavir 100 mg bid
--Lopinavir 400 mg bid + ritonavor 100 mg bid (Kaletra)
Prior ART Experience
There appeared to be a bit more NRTI and PI experience in the 908 groups and so GSK is suggesting that may be the reason why Kaletra performed better.
|
|
| |
 |
|
| |
Tenofovir was available for patients in this study so it was part of about 11-13% of regimens equally in all 3 arms.
RESULTS
Viral load reduction over the 24 week study, as evaluated by the mean time-averaged change from baseline, was: -1.48 log in the 908 qd group, -1.50 log in the 908 bid group, and -1.66 in the Kaletra group.
Efficacy Outcomes at week 24
These differences may be trends.
Virologic Success (ITT RD=F; intent to treat, rebound or discontinuation=failure)
% <400 copies
--58% in the 908/r qd regimen
--60% in the 908/r bid regimen
--69% in Kaletra group
% <50 copies
--48% in the Kaletra group
--42% in the 908/4 bid group
--40% in the 908/r qd group
There were fewer virologic failures in the Kaletra group, and non-virologic failures were comparable across all 3 groups.
|
|
| |
 |
|
| |
CD4 increases were 62-72 at week 24.
|
|
| |
 |
|
| |
 |
|
| |
Fasting Cholesterol Profile
--Total cholesterol increased very little and about the same in each group (1.5 mg/dL).
--HDL decreased -6.6 in the 908 qd arm, -3.8 in the 908 bid arm, and -4 in the Kaletra group.
--LDL did not change much: +0.4 on the 908 qd, -1.2 in the 908 bd, and +1.5 in the Kaletra arms.
--As well, fasting triglycerides did not appear to change much over the course of 24 weeks for any of the 3 groups.
|
|
| |
|
|
|
|
|
