1. Fortovase bid
2. Amprenavir 48 week update
3. MKC-442: week 24 (with d4T+ddI); PK and safety in pregnant women and newborns: preliminary resistance profile

Cal Cohen reported on preliminary 24 and 48 week data for the TIDBID study which compares a Fortovase twice daily regimen with a Fortovase 3 times per day regimen and a regimen containing Fortovase (FTV) twice daily combined with nelfinavir twice daily.

This is a randomized, open-label, phase III study which plans to enroll 825 people. The study primary endpoint is 24 weeks with a treatment extension to 48 weeks. Patients were stratified by baseline viral load: 5,000 to 30,000 copies/ml vs >30,000 copies/ml. The patients were also stratified by treatment naïve vs experienced but I’m only reporting the naïve data here. There were about 3 times as many naïve enrolled in study than experienced. The range of viral loads in the <30,000 strata was about 2100 to 30,000 and in the >30,000 strata it was 30,000 to about 3 million.

The study compared:

FTV 1200 mg TID + 2 new NRTIs (n=145)

FTV 1600 mg BID + 2 new NRTIs (n=141)

FTV 1200 mg BID + NFV 1250 BID + 1 new NRTI (n=135)

Baseline—As reported by investigators the mean baseline viral loads including all study participants (naïve & experienced) were about 60,000 copies/ml in the FTV TID regimen, 52,000 in the FTV BID regimen, and 57,000 in the FTV+NFV arm. The mean CD4s were about 312 in each arm.

Discontinuations—Investigators reported 8%, 11% and 12% failed to return in the FTV TID, FTV BID, and FTV+NFV BID arms, respectively. Discontinuations for adverse events were 5%, 7%, and 9% in the 3 arms, respectively.

• At week 24 in the naïve group, using an ITT analysis (Intent-To-Treat) for those <400 copies/ml there were no differences between the 3 arms-- 61% (n=210) had <400 copies/ml in the FTV TID group, 60% (n=213) in the FTV BID group, and 58% (n=202) in the FTV+NFV BID group.

• At week 24 using an On-Treatment analysis (<400 copies/ml) Cohen said there were no differences between 3 arms—82% had <400 in the FTV TID, 78% had <400 in the FTC BID, and 75% had <400 in the FTV+NFV BID arm.

• Using the Ultrasensitive <50 copies/ml test, using an ITT analysis at week 24, the groups had comparable results—44% <50 in the FTV TID arm, 43% <50 in the TV BID arm and 44% <50 in the FTV+NFV BID arm. There were over 200 individuals in each arm.

• Using the Ultrasensitive but with an On-Treatment analysis—60% had <50 in the FTV TID, 57% in the FTV BID, and 63% in the FTV+NFV BID arms.

• Cohen said there were no differences between the three arms when viral loads were above or below 30,000 copies/ml

• But, it appears that the baseline <30,000 copy group responds better than the >30,000 group. The baseline median viral load for the <30,000 group is about 13,000 copies/ml, and the baseline median VL for the >30,000 group is about 129,000 copies/ml. When looking at the 24 week ultrasensitive data (ITT analysis) for below or above 30,000 copies/ml Cohen said there was a 50% success rate (< 50 copies/ml) in the <30,000 group and 40% had <50 in the >30,000 group, but there were no differences were seen between the 3 arms. As well, when looking at the On-Treatment analysis Cohen said there was a difference in the responses between the <30,000 and >30,000 group (about 70% vs 50). These differences may not be so pronounced when using the Amplicor (<400 copy) test. Additional data will be reported at the AIDS Conference in Lisbon at the end of October. Investigators will separate the naïve and experienced data in this <30,000> analysis.

• Preliminary (n=129) week 48 On-Treatment analysis by Amplicor and ultrasensitive data showed about 80% <400 copies/ml (80% in FTV BID, 73% in FTV TID, 75% in NFV+FTV BID) in all 3 groups and about 60% <50 copies/ml for all 3 arms.

• CD4 increases were about the same in each arm: +140 at week 24

In a virology sub-study of 138 patients for all 3 arms they looked at a preliminary analysis of genotype (protease and RT) and phenotype of 29 relapsed patients (rebound to >400 copies/ml) treated for 4-24 weeks (about 10 in each arm). SQV resistance mutation 48Vwas not seen in any patients. One patient in the FTV BID arm had a 90M mutation but no evidence of phenotypic resistance was seen.

But following viral rebound the 3TC 184V mutation was seen in 6 of 9 patients in the FTV TID arm and 5 of 10 in the FTV BID arm. This was associated with phenotypic resistance in 4 of 6 in the FTV TID arm and 5 of 5 in the FTV BID arm. About 70% of study participants were taking either d4T/3TC or AZT/3TC.

diarrhea: 15% for FTV TID, 13% in FTV BID, and 23% in FTV+NFV BID

nausea: 15% in FTV TID, 10% in FTV BID, and 6% in FTV+NFV BID

headaches: 7% in FTV TID, 2% in FTV BID and 2% IN FTV+NFV BID

84 patients reported serious adverse events. 63 had SAEs judged unrelated to study drug. 21 patients, evenly distributed across treatment regimens, had SAEs at least possibly related to one of the study drugs. Events included: gastrointestinal, hepatic, and dermatologic. There were no reported differences at week 24 between the arms for lab abnormalities.

This randomized, double-blind, phase III study compares amprenavir (APV) plus AZT/3TC to AZT/3TC in treatment-naïve individuals. Participants with viral load >400 copies/ml at week 16 were permitted to switch to open-label APV. 221 of the 232 randomized received treatment.

Baseline – median viral load and CD4 in the APV arm were 44,000 copies/ml and 442 in the APV + AZT/3TC arm.

• At week 48, 93% (n=54) had <400 copies/ml using the As-Treated analysis which is less stringent than the ITT analysis. Using the ITT analysis (n=116) where discontinuations are considered failures 42% had <400 copies/ml.
• Cd4s increased about 199 from baseline to week 48.

Investigators reported an ITT Observed Data analysis (<50 copies/ml) which is not as stringent as an ITT analysis but also not as liberal as an as-treated analysis. At week 16, 59% had <50 copies/ml (n=88), At week 48 they reported 69% had <50 copies but this included individuals who switched to APV after week 16 because their viral load was >400 copies/ml.

Investigators reported the incidence of treatment-related adverse events of at least moderate intensity through week 48:

Nausea 30%: grade 1 - 62%; grade 2 - 34%; grade 3 – 4%

Flatulence 10%

Fatigue 11%

Headache 11%

Vomiting 11%: grade 1 – 73%; grade 2 – 25%; grade 3 – 2%

Diarrhea 10%

Rash 19%: grade 1 – 31%; grade 2 – 58%; grade 3 – 11%

They reported there were no grade 3 or 4 elevations in triglycerides or cholesterol (n=113) and 1 person had hyperglycemia. One case of abnormal fat redistribution has been reported to date. The subject received over 1 year of APV and remains in study with undetectable VL. Because the study population is treatment-naïve they might be less prone to develop lipodystrophy and one year may not be enough time for lipodystrophy to develop.

Emivirine is a new NNRTI dosed twice daily. The purpose of this study was to compare antiviral activity, tolerability and safety of two doses of MKC-442 when given in combination with d4T+ddI. A second purpose is to examine the benefit of a 3 day doseescalation strategy to optimize initial tolerability.

203 NNRTI and PI naïve patients with limited experience (<28 days prior NRTI exposure) were randomized to 1 of 4 arms to receive 442 with d4T+ddI for 24 weeks:

500 mg BID MKC-442

750 mg BID MKC-442

250 mg BID for 3 days followed by 750 mg BID

375 mg BID for 3 days followed by 750 mg

Baseline—The median baseline VLs and CD4s were 21,000 copies/ml and 378 in the 500 mg arm, 33,000 and 343 in the 750 mg arm, 38,000 and 281in the 250/750 arm, and 47,000 and 308 in the 375 in the 375/750 arm.

The most common potentially MKC-442 related adverse events were headache, nausea, dizziness, and rash (majority grade 1). In the 750 mg arm 43% experienced grade 1/2 nausea, 47% grade 1/2 diarrhea, asthenia 34% (grade 1/2), 17% grade 1/2 vomiting. Investigators reported a transient grade 1/2 dizziness was experienced by 30% in this arm, and a 13% rate of grade 1/2 depression. 28% experienced a rash. Investigators reported the majority of these events were mild/moderate and transient in nature. They reported 99% of rash cases were grade 1 or 2, and the majority (83%) were treated through without interruption of MKC-442. There were 2 cases of grade 3 rash and no grade 4. 6% of patients discontinued MKC-442 due to an adverse event.

In the 500 mg bid arm 10% experienced a rash. For a number of patients, they experienced similar rates for the same adverse events as experienced in the 750 arm although the rates were a lower for some of them: diarrhea 25% grade1/2, headache 30% (grade 1/2), dizziness 18%. The authors concluded the 500 mg dose was better tolerated than the 750 mg dose. They concluded the lead in strategy did not improve overall tolerability compared to the 750 mg dose suggesting that a longer lead-in period may be warranted. A lead-in strategy using 500 mg bid for 14 days is being evaluated.

But grade 3/4 adverse events had low incidence rates. There were few reported grade 3/4 lab toxicities reported in 500 and 750 mg arms.

Since ICAAC Triangle announced that in study # 303, in which nelfinavir was combined with MKC-442, they noticed interaction concerns between MKC-442 and nelfinavir. They had previously conducted a NFV-442 interaction study in healthy volunteers and found an interaction so the dose of nelfinavir was increased to 1000 mg tid in study 303. However, the interaction between the 2 drugs in 303 was more than anticipated.

The primary purpose of this study was to evaluate the safety and pharmacokinetics (PK) of MKC-442 in HIV-infected pregnant women and their newborns. Fourteen HIV-infected and pregnant women were enrolled in one of two groups. Women were stratified based on thrir viral load to receive AZT (<20,000 copies/ml) or AZT+3TC (>20,000 copies/ml) for 21 days.

In group 1 (n=8) 750 mg bid MKC-442 was added on day 15 and continued through day 21 (cesarean section). In group 2 (n=6) 750 mg bid MKC-442 was added on day 8 and continued through day 21. Mothers and infants were monitored for viral load and MKC-442 drug levels in blood, umbilical cord plasma, amniotic fluid and colostrum.

The investigators said there was no difference between the 2 groups in maternal or infant PK parameter. The drug was well distributed in the infants: MKC-442 blood levels were 72% of those seen in mothers at birth. MKC-442 was well-tolerated in mother-infants pairs. Of the mothers who received the full course of MKC-442, 75% had <400 copies/ml at delivery. 91% of the infants had viral load <50 copies/ml in blood, 88% in amniotic fluid, and 100% in umbilical cord plasma at delivery. Additional studies are planned.

Therapy-naïve patients were enrolled in two studies to receive MKC-442 with either d4T+3TC or d4T+ddI. Genotype rsistance testing was performed on all who experienced treatment failure. Resistance to MKC-442 was seen in 23 of 138 individuals. The NNRTI mutations observed were: K103N (13/23), G190A (2/23), Y181C (2/23), A98S/K101E (1/23), K101E/V106M/V (1/23), V108I (1/23), and E138K (1/23). E138Q (1/23) and A98S (1/23) were seen, which have not been previously associated with NNRTI resistance.

Further analysis showed viruses containing the E138K or A98S remained sensitive to other NNRTIs. Viruses containing the K103N were resistant to MKC-442 and other NNRTI (DLV, EFV and NVP), and this indicates that MKC-442 is unlikely to be effective after failing efavirenz. The K103N mutation is associated with EFV failure. Viruses containing mutations at K101E, V108I, Y181C or G190A remained sensitive to one or more of the other NNRTIs. The viruses for 10 of 23 individuals (43%) remained sensitive to at least 1 other NNRTI. These studies were in vitro (conducted in the test tube) so are preliminary and inconclusive. But Triangle will conduct human trials to explore the possibilities that MKC-442 may be a good first-line NNRTI because it may be salvageable in certain genotypic situations.