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NEAT Study: new formulation of amprenavir
Reported by Jules Levin
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At today's Antiretroviral Poster Session there were several studies of interest and NATAP will be reporting on all of them by myself and the team of doctors covering this conference for NATAP . Tonite there are several drug company symposiums: Glaxo is having one on 4-drug therapy which is Trizavir plus a 4th drug such as efavirenz, nevirapine or Viread. Four drugs could be used for potency and I will be reporting on this symposium. Boerhinger Ingleheim is holding a symposium on the benefits of nevirapine on lipids and the risks of lipid elevations. Abbott's symposium will stress the potency of Kaletra and that it is hard to develop resistance to Kaletra.
Brief summary of study findings:
The proportion of patients with <50 copies at week 24 was greater for patients receiving the new amprenavir formulation than for patients receiving nelfinavir. See data below. Another key finding from the preliminary week 24 results of this study (full study is 48 weeks) comparing nelfinavir to amprenavir (new 908 formulation), was that for patients with <100,000 copies viral load before starting study drug patients receiving either drug had the same percent <400 copies and <50 copies at week 24, see data below. Both patients groups also received abacavir+3TC. But, there was a difference in response for patients with high viral load when evaluating the percent <400 and <50 copies after 24 weeks of therapy: patients receiving 908 had 71% <400 copies vs 35% for patients receiving nelfinavir; 42% of patients receiving 908 had <50 copies viral load vs 11% for patients receiving nelfinavir. In this study patients receiving amprenavir 908 (new formulation of amprenavir) did not appear to experience the problems associated with the old form of amprenavir: GI side effects leading to higher than usual drug discontinuation rates. And the pill burden is now 2 tabs for amprenavir twice daily as it used to be 8 pills twice daily.
The NEAT study is a phase III, randomized, open-label, 48-week study comparing GW433908 to nelfinavir. GW433908, 908 for short, is the new formulation of amprenavir. Amprenavir was formulated into 908 to reduce the pill burden and to hopefully improve tolerability as amprenavir (APV) causes gastrointestinal side effects. The GI side effects made APV more difficult to tolerate. 908 is administered as 1400 mg twice daily in this study but is also being studied at a lower dose along with a small dose of ritonavir to boost 908 levels in the blood. 908 is also being studied as a once per day PI also boosted by a low dose of ritonavir. 908 + low dose ritonavir is being studied in drug experienced patients vs Kaletra. 908 is taken as 2 tablets of 700 mg each twice a day in this study along with abacavir twice daily and 3TC twice daily. This is compared to 1250 mg nelfinavir twice daily plus abacavir and 3TC twice daily. A study was presented here today using 300 mg once daily 3TC and I'll report on this study as well.
In this study patients were treatment-naive; could have any CD4 count; viral load was >5000 copies/ml; and the primary endpoint of the study is to see which regimen had more patients with <400 copies/ml viral load at 24 and 48 weeks. 332 patients were screened for this study and 251 were andomized to one of the two study regimens from 29 study sites located in the USA (n=152), Panama (n=52), Puerto Rico (n=25) and South Africa (n=21). 166 patients received 908+abacavir/3TC and 83 received NFV+abacavir/3TC, patients were randomized 2:1 to 908 or NFV.
The baseline characteristics were relatively the same in both study grouos. There were 31% females, average age 37, about 32% whites, 32% African-Americans, and 45% Hispanics, 57% heterosexuals. Baseline viral load was 4.83 log on average. Interestingly, about 45% of patients had >100,000 copies/ml viral load and the study evaluates the responses to both treatment for patients with above and below 100,000 copies viral load before starting study therapy. About 47% of patients had <200 CD4s before starting therapy and 18% had <50 CD4s. The average CD4 count was 212. So, overall these study patients had fairly advanced HIV.
RESULTS:
19% in the 908 group (32/166) discontinued therapy vs 28% (23/83) in the NFV group. The main reason reported for the discontinuation appeared to be lack of viral load response: 2% (n=4) for the 908 patient group vs 11% (n=9) for the nelfinavir patient group. Discontinuations for adverse events were about the same in both groups (5% vs 6%).
VIRAL LOAD RESPONSE (ITT M=F)
--73% of the patients receiving 908 vs 54% of patients receiving NFV 54% had <400 copies/ml viral load
--For patients with <100,000 copies viral load, 74% in the 908 had <400 and 70% in the nelfinavir group had <400.
--But for patients with >100,000 copies, 71% in the 908 group had <400 (n=73) and 35% (n=37) in the nelfinavir group had <400.
-- <50 copies: all patients- 54% in 908 group, 40% NFV group; for patients with <100,000 copies of viral load at baseline - 62% 908, 63% NFV had <50; but for patients with >100,000 42% 908 vs 11% NFV.
SIDE EFFECTS: drug-related grade 2-4 adverse events
Patients receiving either drug had about the same amount of grade 2-4 adeverse events: 28% 908, 31% NFV. Diarrhea is where there was a difference: 5% of patients receiving 908 experienced diarrhea vs 17% for NFV. RasH 8% 908 vs 2% NFV. Other than these the rates of standard adverse events were relatively low in both groups. Serious adverse events: 14% 908, 16% NFV, no difference. 10% in the 908 group and 8% in NFV group withdrew from study due to abacavir hypersensitivty, which is a touch higher than usually seen in studies (5%) but the study authors said 10% was within range of that reported in open-label studies. 1 patient withdrew due to possiblr abacavir hypersensity.
With regards to GI side effects the rates of nausea, vomiting, and abdominal pain were low and about the same in both groups ranging from 1-5%. GSK reported an analysis of side effects, particularly related to GI, outside the conference abstract that compared 908 to the old formulation of amprenavir from previous studies. The percentage of patients experiencing all grades and grade 2-4 side effects were much higher for amprenavir than 908: nausea - all grades 72% vs 31, grade 2-4 31% vs 5%; vomiting- all grades 24% vs 11%, grade 2-4 11% vs 2%; diarrhea- all grades 19% vs 18%, grade 2-4 10% vs 5%; rash- 22% vs 14%, grade 2-4 19% vs 8%; headache - all grades 22% vs 7%, grade 2-4 11% vs 2%; parasthesia (oral)- all grades 26% vs 1%, grade 2-4 <5% vs 0%.
In the NEAT Study ASL & ALT elevations were about the same for both drugs, about 5% grade 3-4 lab abnormalities.
LIPIDS
They looked at triglycerides, HDL cholesterol (good cholesterol), LDL cholesterol (bad cholesterol), total cholesterol. Interestingly, within the first 24 weeks, which is as far as follow-up is so far, they rarely saw grade 3-4 elevations in lipid & glucose abnormalities in either study drug group. The average lipid values stayed at or below the recommended guidelines from the NCEP. There did not appear to be much difference between the two drugs after 24 weeks but triglycerides for nelfinavir increased a little at week 12 (<200) and then declined back to normal. HDL increased a little from about 39 to 41 for 908 at week 24. I don't think any of these changes were significant.
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