New NNRTI and PI from Agouron: preliminary data

 

AG-1549

 

This is the new Agouron NNRTI. Their preliminary data suggests it may not be cross-resistant or may have limited cross-resistance with other NNRTIs, but the data is very preliminary. This will have to be confirmed in future studies, and Agouron will have to prove this by taking individuals who've failed Sustiva, nevirapine or delavirdine and testing if they respond to AG-1549. Initial studies in heavily pre-treated individuals showed about a 1.2 log reduction in viral load at the highest dose used so far.

 

They said resistance was slow to develop. Agouron said the drug's resistance profile made the drug attractive to them. The K103N mutation is the key mutation for efavirenz (Sustiva) .DuPont has reported that the development of this one mutation can result in 20-fold resistance to efavirenz (EFV). The development of additional mutations and additional resistance can follow. Agouron said that when working on in vitro experiments there was no resistance to AG-1549 after the K103N was present. The company said that it wasn't until they saw two or more mutations that significant resistance started to develop to AG-1549 (see V106A/F227L in table below). But, our experience with NNRTIs is that a single mutation can begin the process of resistance developing. So, until their claim is better established with data, I am circumspect that multiple mutations are required for resistance to AG-1549.

 

From in vitro experiments with susceptibility assays, researchers came up with the following preliminary resistance data. Again, this is pre-clinical and preliminary data based upon laboratory experiments. The first column lists mutations associated with resistance to delavirdine, efavirenz, AG1549, and/or nevirapine. As stated above, the K103N mutation causes resistance to EFV. On the NATAP web site is a report on NNRTI resistance which discusses the resistance and cross-resistance patterns associated with each of the NNRTIs (click here to see it). The L100I mutation is also associated with resistance to EFV. The K103N mutation is normally the first to develop for EFV and then the L100I can follow and also create increasing resistance to EFV. Columns 2-4 in the following table indicate the fold decrease in susceptibility each of the 3 drugs had when the mutation in column occurred. Low level resistance such as a fold decrease of 2 or 3 is not important. It is however sometimes difficult to know where the cutoff is. The cutoff can vary from drug to drug. The cutoff being how much fold resistance can cause actual drug failure. A fold decrease of 13 may or may not be important depending on how much drug can be safely dosed without side effects or toxicities limiting the amount of drug. Theoretically, you may be able to give enough drug to suppress a mutation that may cause 13 fold resistance. Of course, this will have to be explored in early dose ranging studies aimed at selecting a dose.

 

 
-------------Fold Change----------

 Genotypic Changes

 NVP

  DLV

 AG1549

 L100I

 2

 >84

 3

 K103N

 43

 78

 1

 V106A

 >72

 25

 4

 Y181C

 >72

 >84

 13

 Y188C

 >72

 5

 1

 F227L

 4

 <1

 1

 L234I

 <1

  2

 22

 P236L

 3

 >84

 3

 V106A/F227L

 >72

 6

 386

 

Discussion --As you can see the Y181C and the Y188C mutations can cause high-level resistance to NVP and DLV but no resistance wa seen to AG1549 with the Y188C and 13 fold resistance with the Y181C. P236L is known to be associated with resistance to DLV, but according to this in vitro data it did not cause cross-resistance to AG1549.

 

It took 9 in vitro passages to cause high-level resistance to AG1549 to develop. As you can see in the table below resistance to NVP developed after 2-3 passages. The implication is that resistance to AG1549 develops more slowly than to NVP. And, multiple mutations emerged rather than 1 or 2 mutations. As stated above our experience with NNRTIs is that one mutation can cause resistance to begin. The implication here is that multiple mutations may be required. However, a single mutation may be adequate to begin the resistance process as with other NNRTIs. Agouron says AG1549 is sensitive to virus with only the K103N.

 

 

 Drug

 No of Passages

 Genotypic Changes

 AG1549

 >9

 K103T, V106A, L234I,

V106A, F227L

 Nevirapine

 2-3

 Y181C, V106A

 

In a preliminary single dose study, there was no PK difference between taking the drug under fed or fasting conditions. Although taking drug with food can reduce nausea that has been seen when taking AG1549. The nausea could be due to the fact that patients had to take large numbers of capsules in study because they only had 25 mg capsules. They now have 200 mg capsules for future studies.

 

In a 15 day PK study, tid and bid regimens with the same daily dosing resulted in about 1.2 log reductions in viral load . So far, these were the highest reductions in VL seen and the highest doses experimented with. The patient group used in this study was very treatment experienced. They had previously taken PIs. At least half were taking concomitant nukes with AG1549. Almost all were NNRTI naïve. Interestingly, preliminarily it appears as though certain PIs may increase the blood levels of AG1549, although it is too soon to conclude this.

 

 

AG1776-new protease inhibitor

 

They reported AG-1776 resistant HIV has protease substitutions L10F, R41K, I47V, V82I, or I84V. They showed us a number of double mutant resistant viruses (82/90, 82/84, 82/90) which were resistant to RTV and IDV, and single mutant visuses (90M, 30N). AG1776 was active against these viruses. However, these mutations listed are the primary mutations associated with resistance to NFV, IDV and RTV. Usually, secondary mutations also develop following the development of the primary mutations. When the secondary and primary mutations develop broad cross-resistance beween all PIs can develop. That is why it is recommemded by many that you should consider switching to a new PI or at least stopping your current PI immediately after viral load rebound. This can be accomplished by frequent monitoring of your viral load every 4-6 weeks. If you are undetectable and see a rebound, you can immediately stop taking that PI after confirming the rebound with a second viral load test. This may prevent the development of secondary mutations and may increase the chances of responding well to a second PI regimen. If you stay on a PI after resistance starts to develop, mutations will continue to build up over time. And, the liklihood of responding well to a second PI is reduced. The best hope to remaining sensitive to a second PI after failing the first is to stop taking it as soon as viral load initially rebounds

 

They also reported observing synergy in vitro when AG1776 was combined with other PIs. They reported In animals, 1776 plasma levels were maintained above the EC95 >12 hrs.

 

ABT-378 and PNU-140690 are two PIs for which preliminary resistance data suggested they may have efficacy against protease resistant virus. ABT-378 is in a study now for individuals who have failed a previous PI regimen. Data may be available at the next Human Retrovirus meeting in February '99. Upjohn is currently planning similar studies.