BMS-232632: once a day protease inhibitor in early human development

I.M. Sanne from Johannesburg Hospital in South Africa reported on the safety and antiviral activity of this once a day PI in a phase 2 study. Sanne said that in vitro BMS-232632 is 2-19 times more potent then other protease inhibitors: IC50 is 2-5 nM and IC90 8-12nM vs a variety of HIV-1 isolates. Of course, in vitro findings do not necessarily translate into humans. In Durban and before at the Resistance Workshop Rich Colonna (Bristol-Myers Squibb) reported that against clinical isolates with resistance to 2 or 3 protease inhibitors BMS-232632 retains antiviral activity but it its activity wanes with more resistance. See Resistance Workshop Reports on NATAP web site for more details. Sanne reported the relative bioavailability is 57% to 80%, half-life is 4 to 7 hours, and steady state reached after multiple daily doses in about 3 days. Stage I multiple-dose PK study found increased unconjugated bilirubin levels that Sanne said was a dose related lab effect.

BMS reported that hyperbilirubinemia was successfully managed with dose reduction, and was not associated with other changes in liver enzyme functions. BMS told me offline that they have treated about 750 individuals with this PI and there has been about a 3% dose reduction rate due to elevated bilirubin (at 400 mg; 8% at 500 mg once daily). 80% of individuals who dose reduced were able to attain viral suppression to undetectable at a reduced dose (200 mg once daily). Individuals with hyperbilirubinemia eliminate the drug more slowly and achieve high drug blood levels, so 200 mg once daily is adequate for them. Clinical development for BMS-232632 is targeting 400 mg once daily. Persons with Gilbert's Disease have compromised ability to conjugate bilirubin and so may be vulnerable to this problem. In general Gilbert's Disease is benign. 7 patients in stage 1 developed clinical jaundice but stayed on medication.

Sanne reported on two studies (stage 1 and 2) . Stage 1 (n=98; about 20 in each arm) was a 12 week safety & antiviral activity study (prior to initiation of Stage 2) with a 2 week monotherapy lead-in before patients added d4T+ddI. Liver function tests were required to be <3X ULN, and total bilirubin was required to be <1.5 X ULN. Both stages compared 3 doses of BMS-232632 (200, 400, and 50 mg once daily) to nelfinavir 750 3x/day. Median baseline CD4 and viral load was 386 and 63,000 copies/ml. 63% of patients had viral load above 30,000. 52% were white and 48% non-white, and 72% were men.

In both 2-week lead-in monotherapy parts of the studies BMS-232632 achieved 1.5 log reduction in viral load. After 24 weeks in Stage 1 viral load reductions were: <400 copies/ml--52% in the 200 & 400 mg arms, 65% in the 500 mg arm, and 67% in the nelfinavir arm; <50 copies/ml--33% in the 200 mg arm, 20% in 400 mg arm, 35% in the 500 mg arm, and 38% in the NFV arm. Stage 2 was started after Stage 1 and was simply a larger study (n=300 or more; about 80 per arm), and patients were recommended to take BMS-232632 with food which enhances drug exposure and reduces drug level variability significantly. At week 12, preliminary data shows percentages <400 are 62%, 70%, 80%, and 58% in the BMS 200, 400, 500 mg arms, and 58% in the NFV arm, respectively; percents <50 are 39%, 31%, 50%, and 29%, in the BMS 200, 400, 500 mg arms, and 29% in the NFV arms. In both stages, viral load reduction was 2.5 log at weeks 24 and 12, respectively. Patients who had missing data were considered failures and this analysis was a cross between on treatment and intent to treat.

MOST COMMONLY REPORTED SIDE EFFECTS

BMS: Diarrhea (17-29%), headache (14-17%), infection (61%), abdominal pain (15-16%), nausea 13-24%. NFV: diarrhea (51-75%), infection (22-45%), headache (5-14%), abdominal pain (8-15%), nausea 7-15%).

Median CD4 increases ranged from 50-150.

The use of ritonavir to boost blood levels of BMS232632 will be explored by BMS.

Perhaps the most interesting development was that at week 24 in Stage 1 there was minimal or no change in cholesterol in the 3 BMS-232632 dose groups. But there were sustained rises in total cholesterol (30-50 mg/dL), LDL cholesterol (25-30 mg/dL), and triglycerides (20-50 mg/dL) in the NFV arm.

STUDY DISCONTINUATIONS

BMS reported 8/32 in Stage 1 and 8/16 in Stage 2 discontinued from study: nausea, abdominal pain, skin rash, recurrent lymphoma, mover out of state, patient request, lost to follow-up, pregnancy, death, other.