Report 2 from Chicago; Selected Highlights from Monday's Slide Session on New Antiretroviral Drugs
from Jules Levin

AG1776

Amy Patick, of Agouron Pharma, reported early data on the antiviral activity and resistance profile of this new protease inhibitor. Data from in vitro or lab studies suggest that this PI is of comparable potency to the currently available approved PIs. Patick showed data that AG1776 has demonstrated potent in vitro antiviral activity with an IC50 of about 29 nM, which is the amount of drug required to inhibit viral production by 50%.; and, an EC90 of about 61 nM. These values are comparable to the IC50 and EC90 values Patick showed for approved PIs. She showed data showing in vitro synergy when combining AG1776 with RTV (285), IDV (131+), and NFV (141+), the higher the number the better.

Patick showed in vitro cross resistance data that AG1776 suppressed viruses resistant to IDV< TRV< SQV< and NFV. This suggests that AG1776 may be effective for individuals with resistance to the approved PIs. Patick constructed a series of resistant mutants containing 1 or 2 mutations from the plasma of patients who had failed various PI containing regimens. Using the Virco phenotypic resistance assay called Antivirogram they tested the sensitivity of these viruses to AG1776. In other words, they tested whether AG1776 was effective against these resistant viruses. Please bear in mind that these are in vitro tests and although the results are encouraging the they remain to be confirmed by testing in humans. The mutant viruses carried the following single or double resistance mutations: 82/90, 84/90, 48/82, 82, 30N. The 30N mutation is associated with nelfinavir resistance. The 48 and 90 mutations are associated with SQV resistance while the 82, 84, and 90 are associated with IDV and/or RTV resistance. Patick showed data demonstrating that each mutant virus except the one with the single 30N mutation was cross-resistant with IDV, RTV, SQV andNFV. The mutant with the 30N single mutation was still sensitive to RTV, IDV, and SQV but was resistant to NFV. The virus mutant with the single 82A mutation was sensitive to SQV but cross-resistant to IDV, RTV and NFV. Importantly, all of the mutant viruses remained fully sensitive to AG1776.

Patick then showed data of the sensitivity to AG1776 of clinical isolates from patients with 4 or more PI mutations:

These data show that the clinical isolates from patients with these mutations listed in far left column were cross-resistant to RTV and IDV (except the last isolate was only 3 fold resistant to RTV). The last column shows that these isolates were all sensitive to AG1776. A reminder-these are results from in vitro studies. Similar results in humans remain to be proven. Patick said studies in treatment naïve and protease resistant individuals will begin soon. She expressed that Agouron was particularly interested in testing AG1776 in protease resistant individuals.

AG1549

KE Potts of Agouron reported early data on the anitivral activity and resistance profile for AG1549 (formerly known as S-1153) which is a new NNRTI. Potts showed in vitro antiviral activity:

This data shows that AG149 demonstrated similar potency to EFV in vitro . 1.1 nM is the amount of drug required to inhibit 50% of HIV replication. 3.4 nM is the amount of drug required to inhibit 90% of HIV replication. Again, this in vitro data remains to be established in humans.

Potts showed results of a susceptibility assay of AG1549 to viruses with single NNRTI mutants associated with NNRTI resistance. The mutant viruses contained the following single mutations: L100I, K103N, V106A, Y181C, Y188C, P236L. NVP and DLV were clearly resistant to each of these viruses containing these single mutations. AG1549 demonstrated a 3 fold increase in IC50 to the L100I mutant, no increase in IC50 to the K103N mutant (the K103N mutant is a key NNRTI mutation, 4 fold increase in IC50 to the V108A mutant, 13 fold increase to the Y181C mutant, no fold increase in the IC50 to the , and 4 fold increase in IC50 to the P236L mutant (associated with DLV resistance). This data suggests that AG1549 may be effective for individuals resistant to approved NNRTIs (NVP, DLV, EFV). These individuals may be sensitive to AG1549. This remains to be established in human studies.

Using the Virco Antivirogram phenotypic resistance assay, Potts tested AG1549 antiviral activity against viruses with multiple NRTI mutations and single or double NNRTI mutations. Potts said AG1549 demonstrated potent activity against some of the viruses, moderate activity against a few viruses, but had an apparently high IC50 (phenotypic resistance) against a few viruses. This data suggests to me that AG1549 may be have varying levels of activity against NNRTI resistant viruses which may depend on the degree of phenotypic resistance and/or the number or type of mutations. However, Potts said that DLV, EFV and NVP exhibited significant reductions in antiviral activity against most of these viruses.

Ultimately, I think a number of leading researchers believe that the more mutations or resistance that a person builds up the less likely they are to achieve a good response or any substantive response to a subsequent drug in the same class even if it shows no cross-resistance in vitro.

Potts said data from an in vitro serial passage study showed that resistance to NVP developed quickly with 1 NVP resistance developing, but that multiple resistance mutations were required for resistance to AG1549. Again, this in vitro data remains to be proven in humans.

DPC 961 and DPC 963

S Erickson-Viitannen reported early data on these two second generation NNRTIs from DuPont Pharma, which the data suggests may also be effective against NNRTI resistant viruses. In vitro data was presented suggesting that both DPC 961 and 963 were of equal potency to EFV against wild type virus but about 6 times less drug was required for both 961 and 963 to suppress 90% of replication against the K103N mutant. Several slides were shown indicating that less drug was required of 961 and 963 than of EFV to suppress single and double NNRTI mutant variants in vitro. Viitanen showed a slide indicating that 961 and 963 show a slower rate of appearance of resistant mutations in vitro. She showed a slide showing that 961 and 963 had similar oral bioavailability to EFV in the rhesus monkey. 961 and 963 showed significant oral bioavailability and long half life in the chimp suggesting once a day dosing.

Viitanen used a method called PPPP to measure the success of a drug. PPPP equals the ratio of trough levels to 90% inhibitory concentrations levels for HIV. Against wild type virus 961 and 963 were 100 fold higher than the level required to inhibit 90% of HIV replication . EFV was also well above that level but not as high as 961 and 963. The PPPP against a K103N mutant 961 and 963 provided levels 40-60 fold higher than that needed to suppress 90% of HIV replication, but EFV was just at the level needed to suppress the K103N. However, we know from clinical trials that the emergence of the K103N mutation creates 17 fold resistance to EFV. This data suggests 961 and 963 may suppress virus containing the K103N mutation. She then showed a slide indicating that 961 and 963 provided PPPP levels which may be high enough to suppress virus with multiple mutants, while the EFV PPPP ratio was below the level needed to suppress multiple mutants.

ABT-378

Rob Murphy reported 24+ weeks of data from an initial clinical study of this new protease inhibitor from Abbott Labs. Murphy said that ABT-378 trough levels are 25-100 fold above the IC50 of wild-type HIV at steady state, plasma concentrations are unaffected by food, and the drug was well tolerated in this study. A low dose of ritonavir greatly enhances the blood levels of ABT-378 and results in high plasma levels of ABT-378. So, a small amount of ritonavir will be used in combination with ABT-378. In this study individuals in Group 1 received 3 weeks of ABT-378 monotherapy (2 weeks direct observed therapy) followed by ABT-378/rtv 200/100 mg or 400/100 mg BID (twice daily) with d4T+3TC. Once Group 1 was enrolled and preliminary data was available Group 2 stated to enroll up to 69 patients. In this group everyone received 400 mg of ABT-378 but either 100 or 200 mg of ritonavir with d4T+3TC.

Median baseline HIV RNA for Group 1 (n=32) was 72,000 copies/ml (range 8,500-1.1 million), and for Group 2 (n=69) was 66,000 copies/ml (range 1,600-5.7 million). The mean baseline CD4 was 390 in Group 1 (range 2-1066) and 311 in Group 2 (range 10-824).

In Group 1 there was 1 discontinuation and there were 3 discontinuations in Group 2. Murphy said the discontinuations were due to: drug addiction, lymphoma, non-compliance, and moving to outside US.

Using an on treatment analysis, at week 24 93% and 95% were <400 copies/ml. At week 36, the percentages appeared to be holding on the graph Murphy showed. Of the 32 patients at week 24 in Group 1, Murphy reported-- 27 had <400 copies/ml; 2 had greater than 400 copies/ml (but had <1000 copies/ml); 2 had missing data because they interrupted therapy but had <400 copies/ml before and after the interruption; and 1 discontinued. In Group 2, 60 had <400 copies/ml, 3 had >400 copies/ml, 3 had missing data (Murphy had an explanation for these as well) and 3 discontinued. Using the Ultra Sensitive viral load test 24/27 (89%) in Group 1 had <50 copies/ml. Murphy said 2/27 did not have samples available for the Ultra-sensitive test. In Group 2, 60/63 (95%) had <400 copies/ml and the Ultra-sensitive test results are not yet available for this group. At week 24, the increases in CD4 cells were about 160 and the graph was still trending up at week 36.

Murphy said ABT-378 was well tolerated. The following side effects were sometimes reported as just one time events by study participants. They are not necessarily ongoing events. Most common adverse events for Groups 1 and 2-abnormal stools 6 (19%), 2 (3%); diarrhea 6 (19%), 12 (17%); asthenia (fatigue) 3 (9%), 3 (4%); headache 3 (9%), 3 (4%); nausea 1 (3%), 12 (17%); vomiting 0 , 3 (4%).

Lab abnormalities: In Group 1 there were no reports of AST/ALT >5 times above the upper limit of normal, no reports of triglycerides elevations above 1500 and 3 cases of cholesteral above 300. In Group 2, there were 5 reports (7%) of elevated AST/ALT >5 times above upper limit of normal, 2 cases (3%) reported of triglycerides above 1500 and 7 cases (10%) of cholesteral above 300. Three of the 5 AST/ALT elevations wee in patients with Hepatitis B antigen or Hepatitis C at baseline.

Murphy said none of the patient in this study withdrew due to drug related adverse events.

I have to go to evening meetings now. Tonite there are several meetings including a meeting conducted by Visible Genetics who is a manufacturer of a genotypic resistance test. There are several additional reports from today's session that I will file later.