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New HIV Antiretroviral Drugs: atazanavir, T-1249, plus more
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There are some interesting stories from today's opening sessions. In the morning oral session on "New Antiretrovirals" for HIV there were presentations on ten new drugs at various stages of development: 2 protease inhibitors for individuals with protease inhibitor resistant virus (one from Roche in very early development and TMC-114 for use in PI resistant patients); and some new NNRTIs in early development from GlaxoSmithKline; 5 entry inhibitors at various stages of development including the presentation I will highlight on T-1249 for T-20 resistant virus; an anti-CD4 monoclonal antibody; the first "maturation" inhibitor; a new class of integrase inhibitors. These talks offered a lot of promise as we see a bunch of new drugs being developed. All of the drugs appear promising, although most are in early development.
An interesting presentation was on UK-427,857, which is a new CCR5 (entry inhibitor) from Pfizer-Agouron. Early study results show it to be safe, tolerable, and does not have the QT prolongation problem that the Schering C CCR5 inhibitor has. Although it was not presented I hear that it UK-427,857 shows good antiviral activity which should be presented at the IAS Conference this July. More details to come. This drug appears to be a promising new CCR5 inhibitor , but this is based on preliminary data and we must wait for more data.
Another interesting story is regarding the new protease inhibitor Atazanavir. BMS reported that patients who developed viral failure on Atazanavir were sensitive or hyper-sensitive to the currently available protease inhibitors. Details below.
T-1249, A fusion Inhibitor Against T-20 Resistance
"T-1249 Demonstrates Potent Antiviral Activity over 10 Day Dosing in Most Patients who Have Failed a Regimen Containing Enfuvirtide or T-20 (ENF): Planned Interim Analysis of T1249-102, a Phase I/II Study"
T-1249 is a peptide fusion inhibitor that has shown potent antiviral activity over 14 days of administration in fusion inhibitor naive HIV-infected adults. In vitro (test tube) studies suggest that T-1249 is active against most HIV isolates resistant to enfuvirtide (ENF). This study evaluated the short-term safety and antiretroviral activity of T- (T-20) 1249 in 54 patients failing a regimen containing ENF. 53 patients were dosed, no discontinuations after dosing began.
Patients were HIV-1 infected adults participating in a phase II or III ENF study who were receiving ENF and a stable background antiretroviral regimen and
demonstrated two consecutive plasma HIV RNA values between 5,000 and 500,000 copies/ml, viral failures. Patients discontinued ENF after the evening dose and the next morning added 192 mg/day of T-1249 subcutaneously to the unchanged background regimen for 10 days. The data presented here reflect the results of the planned interim analysis of the first 25 patients. Enrollment into the study has now been completed. Patients rolled over to chronic T-1249 in a separate study.
The 25 patients were mostly men (88%) and averaged 42 yrs old. The average T-20 exposure was 70 weeks. The average time from having virally failed T-20 was 60 weeks. The average viral load was 100,000 copies/ml. Six patients enrolled from T-20 phase II studies and 19 patients from the TORO 1 study. All 25 patients completed the 10-day dosing. One patient died for reasons unrelated to the study drugs (pneumonia).
24 patients had baseline genotype or phenotype resistance tests results available. All 24 patients had genotypic resistance mutations associated with T-20. Fifteen patients had paired phenotypic results available prior to starting T-20 and at baseline before starting T-1249 in this study. The average increase in phenotypic resistance to T-20 was 77 fold compared to 2 fold for T-1249.
Three patients reported serious adverse events: grade 4 elevated ALT, bronchitis, and respiratory failure. In addition, 1 patient with a history of neutropenia developed transient grade 3 neutropenia. There was a possible allergic reaction: adverse event of rash (grade 2) associated with fever observed after completion of dosing which resolved without treatment in 48 hours. And I think the speaker said this person is now back on T-1249 therapy.
The median HIV RNA viral load reduction was from baseline at Day 11 was -1.12 log. 63% of the patients had 1 log or greater reduction in viral load on day 11.
Here's an interesting point. All patients (7/7) had >1 log viral load reduction if they were on T-20 with viral failure for 24-48 weeks and the median drop in viral load was -1.6. For patients on T-20 with viral failure for >48 weeks the average drop was 0.94 log.
The study authors concluded that T-1249 demonstrates potent short-term antiviral activity in most patients failing a T-20 regimen. (editorial note: to maintain this activity it's important to make sure additional active drugs are in the regimen). The safety and efficacy of T-1249 remain to be tested in clinical trials during chronic administration.
Atazanavir Resistance Study Suggests Sensitivity to Other Protease Inhibitors
"Emergence of Atazanavir Resistance and Maintenance of Susceptibility
to Other PIs is Associated with an I50L Substitution in HIV Protease
Emergence of Atazanavir Resistance and Maintenance of Susceptibility
to Other PIs is Associated with an I50L Substitution in HIV Protease"
Researchers from Bristol Myers Squibb, the maker of atazanavir (ATZ), reported that I50L is the signature mutation for this new once daily protease inhibitor and poster 597 today reported findings from by BMS on the significance of this mutation in their studies. Recently, the FDA granted priority review for ATZ which means that it may receive FDA approval in June. Studies of ATZ for 48 weeks show no or little increase in tryglycerides, cholesterol, as well as glucose. These studies were reported at ICAAC in September 2002 and can be found on the NATAP website in the ICAAC Conference reports and the Lipodystrophy workshop reports.
The emergence of ATV resistance was monitored in clinical studies
AI424-007, -008/044, -009, -034, -043, -045 and ACTG P1020. The
phenotype and/or genotype of >70 clinical isolates, designated as
virologic failures on ATV containing regimens and who displayed
reduced susceptibility to ATV, were determined for ATV, APV,
indinavir (IDV), lopinavir (LPV), ritonavir (RTV) and saquinavir (SQV)
and evaluated.
When viral failure to atazanavir occurs and this mutation emerges patients are still sensitive or hypersensitive to currently approved protease inhibitors. BMS reported on clinical or patient isolates (blood samples) from 26 patients, from a large number of study participants, who were treatment-naive, received atazanavir in a study, and were viral failures. Atazanavir was the only protease inhibitor they received in their regimen, as opposed to a different group of patients who received atazanavir plus saquinavir in a regimen. These patients were sensitive (<2 fold change) to ATZ before the study and developed ATZ resistance. After developing the I50L these patients were remained fully sensitive or hypersensitive to approved protease inhibitors even if they had additional mutations. These patient's viral load stayed constant, it did not continue to increase. They tested amprenavir, nelfinavir, ritonavir, saquinavir, lopinavir (Kaletra), and indinavir. Hypersensitivity suggests patients were more sensitive to other protease inhibitors when the I50L mutation was present than without it. In vitro, this sensitivity and hypersensitivty was lost when the I50L mutation was removed. So perhaps the I50L mutation needs to be maintained by keeping a patient on ATZ while adding another PI. This remains to be further researched. This study was performed with clinical patient isolates in the lab, but needs to be studied in patients.
There were 42 clinical or patient isolates with ATZ failure that did not develop the I50L mutation and this included 18 patients who received the double Pi combination of ATZ/saquinavir. These patients had decreased susceptibility at baseline to ATZ at baseline (fold change >2) with >3 key
Substitutions. They experienced multiple changes, including primary and secondary PI resistance substitutions observed for other protease inhibitors, and developed high level cross-resistance to other protease inhibitors.
Summary from poster: Atazanavir (ATV, BMS-232632) is a once daily protease inhibitor (PI) currently in late stage clinical development. Characterization of ATV- resistant viruses selected in vitro indicated that N88S, I84V and I50L
substitutions may play an important role in ATV resistance and that
multiple pathways to resistance are possible.1 Analysis of a panel of 950
clinical isolates showed that ATV had a distinct resistance profile
relative to other PIs.2 In general, reductions in ATV susceptibility
required several amino acid changes, were modest in degree and
susceptibility was retained among isolates resistant to one or two of the
currently approved PIs. There was a clear trend toward loss of
susceptibility to ATV as isolates exhibited increasing levels of cross-
resistance to multiple PIs. A genotypic characterization of this panel of
isolates demonstrated a correlation between the accumulation of 5 or
more changes at 14 key amino acids (L10I/V/F, K K20R/M/I, L24I,
L33I/F/V, M36I/L/V, M46I/L, M48V, I54V/L, L63P, A71V/T/I,
G73C/S/T/A, V82A/F/S/T, I84V and L90M) and reduced susceptibility to
ATV. Here, we confirm the identity of a unique I50L substitution as the
signature change for ATV and show that isolates harboring the I50L
substitution exhibit ATV-specific resistance and increased susceptibility
to other PIs. This unique phenotypic pattern appears to be distinct from
that observed in the presence of the I50V and 30N substitutions induced
by amprenavir (APV) and nelfinavir (NFV), respectively.
It's late now & I'm tired so this is it for tonite, I'm going to eat dinner and watch TV. But reports on these other new drug candidates will be forthcoming.
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