ICAAC Highlights, Day 3- Saturday- Clinical Studies:
From Jules Levin
BMS-232632 is the new protease inhibitor from Bristol Myers.This new protease has so far only been tested in vitro, animals, and a phaseI single dose study in uninfected individuals. It appears to be potent,has high bioavailability of 57-80% in humans tested, well tolerated in animals,and so far displays different resistance profile (resistance tables below).BMS says the pre-clinical data shows their PI to be more potent (3-13 fold)then any of the approved PIs. This drug has not yet been studied in HIV-infectedand the pre-clinical resistance data is preliminary. Clinical studies, thatis studies in HIV-infected individuals, is the only way to explore cross-resistance.However, BMS reported cross-resistance data and there was only partial cross-resistance.In the case of saquinavir, cross-resistance was low. So far, the signaturemutation appears to be N88S.
Using this PI as a first-line regimen may turn out to bea good option if limited or no cross-resistance in that direction is establishedin clinical studies. However, if you have become resistant to PI(s) already,the situation will likely be more complicated. The best way to preservePI treatment options is to catch PI failure immediately and switch to anew PI regimen before resistance mutations have an opportunity to mountup. Although BMS-232632 appears so far to have a different resistance profile, if you stay on failing protease regimens and build up resistance mutationsit will be more difficult to respond well to a new PI. This applies to anyPI.
For example, if you are failing nelfinavir, the best thingto do is to catch failure immediately by testing your viral load every 4-6weeks. If your viral load rebounds from undetectable and that is confirmedwith an immediate second test, you should talk to your doctor about consideringa switch to a new PI regimen. Several regimens would be reasonable optionsif nelfinavir was your only PI failure and you catch it immediately.
Having said that, this new BMS PI appears to be potent,and may be a once-a-day drug. If it is as potent as it appears, a low dosewould be possible. A potential outcome of that could mean less of a chanceof lipid side effects, if the side effects are related to p450 inhibition.So far, in animal studies they did not see liver toxicity. A low dose couldalso mean a low pill burden. A dose of 300 mg once a day could be one pilla day. If they need to dose 600 mg once a day that may be two pills. However,it is uncertain at this point whether the dosing will be once or twice aday. Those dosing studies are soon to be conducted.
Additional studies are planned. BMS says they are puttingthe drug on fast track development. A multiple dose study is ongoing forsafety, tolerabiliy, and PK.
Pre-Clinical Resistance Data
Three HIV strains were passaged with increasing amountsof BMS-232632 (starting with sub-optimally doses to allow resistance todevelop) to generate resistant mutatants (Table 1) to identify mutations.
Table 1. Resistance MutantsGenerated and Order of Appearance. The N88S appears to be the key mutation,but the I84V appears important mutation for strain NL4-3.
Virus Strain | Major Mutations | Fold Resistance |
RF | N88S | 4 |
N88S, M46I | 6 | |
N88S, A71V,M 46I,V 32I | 20 | |
88, I84V, 71, 46, L33F, 32 | 188 | |
| ||
BRU | 88, 71, I50L,L10Y | 42 |
88, 71, L63P, 50, 10 | 79 | |
NL4-3 | 84, 46, 32 | 6.2 |
M89L, 84, 46, 32 | 92 |
Table 2. Cross-Resistance Profiles.BMS-232632 Resistant Virus and Its Sensitivity to 5 Other Approved PIs
Strain | Major Mutations | BMS | IDV | NFV | RTV | SQV | APV |
RF | 32,46,71,88 | 20 | 5 | 15 | 3 | 2 | 1 |
RF | 32,33,46,71,84 | 180 | 20 | 20 | 41 | 2 | 7 |
NL4-3 | 32,46,84 | 6 | 2 | 2 | 41 | 1 | 3 |
NL4-3 | 32,46,84,89 | 92 | 10 | 7 | 27 | 2 | 16 |
BRU | 10,50,71,88 | 42 | 1 | 1 | 0.1 | 1 | 0.1 |
BRU | 10,50,63,71,88 | 79 | 2 | 5 | 0.1 | 1 | 0.1 |
Reading Tips-The RF strain on line with with the listed4 mutations was 20-fold resistant to the BMS PI, 5-fold cross-resistantto IDV, 15-fold cross-resistant to NFV, 3-fold cross-resistant to RTV, 2-foldcross-resistant to SQV, and no cross-resistance to APV (amprenavir). Generally,BMS resistant virus was not cross-resistant to SQV in this study. This isone in vitro study. The results can be different when clinical studies areconducted.
Table 3. Cross-Resistance Profiles.Mutant viruses selected from exposure to other PIs and then tested for cross-resistancewith subsequent exposure to BMS.
Strain | Major Mutations | BMS | IDV | NFV | RTV | SQV | APV |
IDV-RF | 32,46,82,84 | 9 | 24 | 8 | 72 | 1 | 27 |
IDV-Clinical | 10,46,63,82,84 | 6 | 15 | 6 | 21 | 6 | 4 |
NFV-RF | 30,46 | 3 | 3 | 35 | 1 | 1 | 2 |
RTV-RF | 46,82,84,90 | 7 | 29 | 22 | 71 | 8 | 28 |
RTV-Clinical | 10,63,82 | 1 | 3 | 5 | 11 | 1 | 2 |
SQV-NL | 10,48,90 | 1 | 3 | 2 | 2 | 8 | 2 |
APV-RF | 32,46,47,82 | 1 | 11 | 11 | 16 | 1 | 82 |
Reading Tips-The indinavir clinical resistant virus insecond row (IDV-Clinical) is 15-fold resistant to IDV, and 6 fold resistantto BMS, 6-fold resistant to NFV, 21-fold resistant to RTV, 6-fold resistantto SQV, and 4-fold resistant to APV.
Finally, remember that these data are all generated inthe lab or in vitro. Real resistance and cross-resitance is determined inHIV-infected humans. But, these data can be predictive.
Reports On Clinical Studies To Follow In Next Paper