>>Ambrisentan Improves Exercise Capacity and Clinical Measures in Pulmonary Arterial Hypertension (PAH)
L. Rubin, N. Galie', D. Badesch, R. Oudiz, G. Simonneau, M. McGoon, A. Manes, A. Keogh, A. Frost, D. Zwicke, R. Naeije UCSD, San Diego, CA; U. Bologna, Italy; U. Colo., Denver, CO; UCLA-Harbor MC, Torrance, CA; Hosp. Antoine Beclere, Clamart, France; Mayo Clinic, Rochester, MN; St. Vincents Hosp, Darlinghurst, Australia; Baylor U., Houston, TX; St. Lukes MC, Milwaukee, WI; Erasme U., Brussels, Belgium
INTRODUCTION: Ambrisentan is a selective ET-A receptor antagonist that may offer advantages over current therapies for PAH, particularly regarding drug interactions and liver toxicity.
METHODS: 64 patients were randomized into a 12-week blinded period to doses of 1, 2.5, 5 and 10 mg po qd, followed by a 12-week open-label dose adjustment period. The primary endpoint was change in six-minute walk distance (6MWD) at week 12. Characteristics: 61% had PPH and 39% scleroderma, anorexigen or HIV-related PAH; 36% WHO Class II and 64% Class III; Baseline 6MWD 343.979.7 meters (m).
RESULTS: Compared to baseline, ambrisentan improved 6MWD in all four dose groups at week 12, by 33.99.6 (p=0.003), 37.18.6 (p=0.0004), 38.113.2 (p=0.011), 35.111.1 (p=0.008) m, respectively. At week 16, the mean increase in 6MWD for all dose groups was 48.4 m. There was dose-related improvement in 6MWD at week 12 in PPH, ranging 31.2 to 54.1 m. WHO Class improved by one Class in 31%, by two in 5.2%, and worsened by one in 3.5%. Borg Dyspnea Index improved (range -0.6 to -1.0). Hemodynamics improved (n=28): mPAP -5.2 mmHg, CI 0.33 L/min/m2, PVR -2.8 units. Adverse events were not dose-related and there were no apparent drug interactions. Four patients developed transient elevations of serum aminotransferases >3X ULN during 24 weeks: One (>8X ULN) required drug discontinuation, one dose reductions, and two elevations were not confirmed by retesting. At study end, 48% were receiving 10 mg/day, none of whom developed elevations >3X ULN.
CONCLUSIONS: Ambrisentan improved exercise capacity and clinical measures in WHO Functional Class II-III PAH. Ambrisentan was well tolerated with a low incidence and severity of LFT abnormalities during the 24-week study.<<
From the 2004 ATS annual meeting.
What I do not know for sure is at what doses the LFTs occurred. Do you, by any chance? My understanding is that ARIES-1 uses the higher doses, and that these were the ones in which the LFTs were a bit of an issue. As such, I don't expect the results to be as stellar looking as the ARIES-2 top line results that were reported last month. ARIES-1 results are to be reported in the 2nd quarter, so my thesis at the moment is that Cramer is momoing it up, and it could get take a bit of a dump at that point.
>>AMB-222
In May 2005, the Company announced the initiation of an open-label trial in which ambrisentan is administered to PAH patients who have previously discontinued bosentan and/or sitaxsentan treatment due to serum aminotransferase abnormalities. The primary endpoint of the trial is the incidence of serum aminotransferase concentrations greater than three times the upper limit of the normal range during the 12 week trial.
The Company recently closed screening in this trial after surpassing the enrollment target of thirty patients. Thirty-six patients were enrolled in the trial, 92% of whom had discontinued bosentan and 11% of whom had discontinued sitaxsentan due to serum aminotransferase abnormalities. These percentages sum to greater than 100% since some patients had been treated sequentially with bosentan and sitaxsentan but had to discontinue both due to elevated serum aminotransferase levels. The last patient enrolled in this trial will reach the 12-week endpoint evaluation in January 2006.<<
From the company's last 10-Q. I gather results from this will be announced next month. This being a small, open-label trial, it's not going to have the same impact as the ARIES results. And once again, I don't know the doses involved. I can't find this trial at clinicaltrials.gov, but maybe I didn't search properly. Didn't help much with the ARIES trials, anyhow, as the doses weren't elucidated in that protocol, either. Perhaps the doses in the various trials, and the doses that were associated with LTF issues were made public at a presentation that I haven't come across. I'll take any help there.
Cheers, Tuck |
