Adefovir Dipivoxil aka PMEA (Preveon)

This report on adefovir contains presentations made at ICAAC of two studies (408 & 411) reporting antiviral activity data and safety for adefovir. In the second study (408) you will see data and discussion of the potential kidney related dysfunctions that can occur as a result of taking adefovir. The syndrome starts emerging after being on adefovir 120 mg for 24 weeks. The overall study incidence of the kidney dysfunction increases to 32% by week 48. 80% of study 408 participants had resolution of symptoms 16 weeks after either stopping or reducing the dose. In a separate study of an advanced population with CD4 <100 cells (CPCRA 039) the incidence was 22%. This is an important concern because of the need for additional drugs for people who have extensive experience with and resistance to NRTIs.

As you know, individuals who've developed resistance to currently available drugs need new drugs that can be effective as part of a salvage regimen. Because of its unusual resistance profile it's been hoped that adefovir could be useful as part of a new salvage regimen for such individuals. Adefovir is taken once-a-day, adding to its appeal. The development of kidney side effects has created some concern about how to use adefovir. Researchers at Gilead Sciences are experimenting with reduced dosing from 120 mg once daily to 60 mg once daily. In new ACTG studies using adefovir patients are starting with 60 mg. In studies started earlier patients starting with 120 mg are dose reducing to 60 mg after 16 weeks. A similar approach is occurring in the adefovir expanded access program sponsored by Gilead. In the expanded access program those who start on 60 mg and experience the syndrome can reduce dose to 30 mg.

The antiviral activity and safety of 60 mg has not been well characterized but because of this safety concern it needs to be characterized. Study 417 is comparing 120 mg to 60 mg for safety and antiviral activity. Both arms are blinded but at week 24 one of the two arms had 50% less incidence of the kidney side effects. Gilead is assuming the arm with the lower incidence is the group receiving 60 mg but since the study is blinded it is uncertain. In addition, Gilead has said that the viral load reductions in both arms are similar. Some patients in 417 have dose reduced to 30 mg and eventually their data will be available. A 4 week monotherapy study of 60 mg adefovir has started and it's expected that antiviral activity data for this dose will be helpful. An additional study is planned to correlate intracellular adefovir levels with viral load reductions in the hopes that this may be helpful in selecting a minimum dose.

In vitro data was reported at Geneva by Sarah Palmer of Stanford University showing a synergy between hydroxyurea and adefovir similar to that between ddI and hydroxyurea. A clinical study is starting at Stanford using hydroxyurea with 60 mg adefovir.

Considering the potential importance of this drug to people who need salvage regimens, the findings of reduced adefovir dosing related to safety and antiviral activity are very important. New data on the reduced doses should be available in early '99.

Adefovir Dipivoxil (Preveon) in Combination with Indinavir and Reverse Transcriptase Inhibitors in Treatment-Naive Individuals

 

This is an interim 20-week report of a phase 2 open-label study (protocol #411) in which participants were randomized 1:1:1:1:1 (n=221) to 1 of 5 different arms. There were 3 3-drug arms containing adefovir (ADV)+ indinavir (IDV) with either AZT, 3TC or d4T. A 4th control arm consisting of IDV+AZT+3TC. The 4-drug arm consists of ADV+IDV+3TC+AZT.

 

5 Study Arms:

1. ADV+IDV+AZT+3TC (n=24)

2. ADV+IDV+AZT (n=22)

3. ADV+IDV+3TC (n=25)

4. ADV+IDV+D4T (n=21)

5. IDV+AZT+3TC (n=22)

 

Participants were antiretroviral therapy naive but were permitted £4 weeks RTI use; they had to have adequate hematologic, renal, and kidney function; individuals with AIDS defining event within one month prior to study were excluded.

The primary study endpoints are to measure the proportion below 400 copies/ml at weeks 20 and 48. They will be studying the development of resistance mutations.

Demographic baseline characteristics: 56% caucasian, 22% black, 17% hispanic, 89% male. The median baseline viral loads were 4.5-4.6 log (about 31,600 copies/ml) in the 5 arms. The median baseline CD4 counts ranged from 325 in the ADV+IDV+d4T arm to 415 in the ADV+IDV+AZT+3TC arm. So, the baseline CD4 counts were relatively similar.

Patient Discontinuations at Week 20

 

 ADV+IDV+AZT+3TC

 ADV+IDV+AZT

 ADV+IDV+3TC

 ADV+IDV+d4T

 IDV+AZT+3TC

 # pts completing >20 wks

 15

 17

 19

 15

 17

 # pts discontinuing <20 wks

 9

 5

 6

 6

  5

 -adverse event

  5

 5

 2

 2

 

 -noncompliance

 1

 0

 2

 1

 0

The higher incidence of dropout occurred in the 4-drug arm and was due mostly to GI intolerance. 83/114 patients completed 20 weeks on study drugs and 31/114 discontinued prior to 20 weeks.

 

Viral Load Data at Week 20: Log Reduction in Viral Load from Baseline; Proportion <400 copies/ml

 

 ADV+IDV+AZT+3TC

 ADV+IDV+AZT

 ADV+IDV+3TC

 ADV+IDV+d4T

 IDV+AZT+3TC

 

 (n=24)

 (n=22)

 (n=25)

 (n=21)

 (n=22)

Median HIV-RNA

 -2.14 log

  -2.12 log

 -2.51 log

  -2.24 log

 -2.15 log

On-Treatment analysis

 11/14 (79%)

 13/16 (81%)

 15/18 (83%)

 12/15 (80%)

 13/17 (76%)

Intent-To-Treat Analysis (NC=F)

 11/24 (46%)

 13/22 (59%)

  15/25 (60%)

 12/21 (57%)

 13/22 (59%)

 MedianCD4

 76

69

100

110

68

The differences between the 5 arms in change in HIV-RNA reductions were not significant. The Intent-To-Treat analysis used the noncompleter=failure method which includes all individuals who discontinued study for any reason and whose data may not be available: dropped off study due to moving, toxicities, treatment failures, side effects, etc. The 46% <400 copies/ml using the 4 drug regimen was due to the higher discontinuation rate in that arm.

In a table called "Grade 3 or 4 Lab Abnormalities and Serious Adverse Events", investigators reported a total of 13/114 ALT/AST elevations-- 2 in the 4-drug regimen; 1 in the ADV+IDV+AZT arm; 6 in the ADV+IDV+3TC arm; 3 in the ADV+IDV+d4T arm; and 1 in the IDV+AZT+3TC arm. This side effect occurred at the highest rate of incidence compared to the incidence of other side effects. There were no other striking lab abnormalities except for 3/24 CK elevations in the ADV+IDV+3TC group. There were 2 cases reported of hyperglycemia. There were no cases of PRTD (Proximal Renal Tunular Dysfunction)which is the kidney related toxicity reported associated with ADV. This is because the toxicity emerges after being on ADV therapy for 6 months. The next ADV study reported (protocol #408) will show individuals experiencing this side effect.

 

Efficacy and Safety of Adefovir Dipivoxil (Preveon) when Added to Standard Antiretroviral Therapy for Individuals with CD4s >200

 

Dr James Kahn, of San Francisco General Hospital, reported 48 week data from this double-blind, randomized placebo controlled study in which individuals received Adefovir 120 mg once per day or a placebo along with their antiretroviral therapy. After 24 weeks participants taking adefovir placebo could receive Adefovir, and study was open-label from 24 to 48 weeks. All participants received L-carnitine 250 mg/day which was increased to 500 mg/day during study.

The primary goal of the study was to look at changes in CD4 counts, HIV-RNA during the blinded treatment period (first 24 weeks), and safety. The Chiron bDNA assay was used to measure viral load. Participants had to be stable on an antiretroviral regimen for 8 weeks prior to study beginning. Participants were stratified by above or below 350 CD4s and above or below 50,000 copies/ml.

There were 223 individuals randomized to the placebo arm and 219 randomized to the Adefovir arm. 38/223 (14%) discontinued prior to reaching week 24 in the placebo arm and 47/219 (17%) discontinued from the Adefovir arm prior to week 24. All the analysis reported below used the intent-to-treat method. Demographically, the participants consisted of 68% whites, 17% blacks, 14% others, 92% male.

The study began in 1996. Saquinavir had been approved when the study began and during the course of the study other PIs were approved. There were 0.9% of participants receiving AZT monotherapy, 5% receiving other nucleoside monotherapy, 55% receiving nucleoside/NNRTI combinations, 8.4% receiving saquinavir combinations, and 30% receiving other PI therapies.

The baseline CD4 counts and viral loads were well balanced between the placebo and adefovir arms. In the placebo group the mean or median CD4 counts were about 330 cells, the mean viral load was about 22,800 copies/ml, and the median viral load was 9,300 copies/ml. In the Adefovir arm, the mean or median CD4 counts were about 335 cells, the mean viral load was about 27,000 copies/ml and the median was about 10,000 copies/ml.

 

Viral Load and CD4 Changes

 

Kahn showed a curve of the viral load responses of the placebo and adefovir groups from baseline through week 24 and week 48. At week 24, there was no reduction in viral load in the placebo group compared to the baseline, but there was about a 0.4 mean log reduction from baseline for the group receiving adefovir. The difference was statistically significant, and the differences between the two groups at each time point was statistically significant. At week 24, the placebo group added adefovir. The group receiving adefovir maintained the approximate 0.4 log reduction from baseline viral load at week 48. Kahn remarked that he was impressed with this durability. In the placebo group who added adefovir at week 24, they also had about a 0.4 log reduction at week 48 from week 24. This analysis was done using the bDNA viral load assay. He said they ran the samples using the PCR assay and found the results to be about the same.

 

Proportion Below <500 copies/ml. At week 24 about 15% of the group taking adefovir had <500 copies/ml. About 5% of the group taking placebo had <500 copies/ml. At week 24, those receiving placebo added adefovir. At week 48, about 25% of both groups had <500 copies/ml.

Kahn showed two charts saying that treatment changes by either of the two groups (adding PI or changing a regimen) did not effect the viral load differences between the placebo and adefovir groups.

The differences in increases in CD4 counts between the groups was modest (increase of 20 CD4 in the adefovir group) and was not statistically significant.

 

Adefovir Dipivoxil Activity Against 3TC Resistant or AZT/3TC Resistant HIV (mean log change from baseline at week 24 in viral load)

 

The key message from the following resistance information is that it appears as if the presence of 3TC resistance (as evidenced by the presence of the 3TC resistant mutation of M184V) at baseline (before starting adefovir) increases the effectiveness or viral load reduction of adefovir. You will note that when the M184V mutation is present (first 3 bullets) those receiving adefovir (active drug) had a greater reduction in viral load of than individuals who did not have the M184V mutation at baseline (second 3 bullets). The presence of the M184V seemed to make the most difference when high level AZT resistance was present. The numbers of patients in each group is at times small and their may not be statistical significance in all the groups described below. But, in vitro experiments suggested that the presence of 3TC resistance would increase adefovir activity. This may be a useful tool in using adefovir for individuals with treatment experience. You may want to use a genotypic resistance test to detect the presence of the M184V mutation.

 

- Active (n=8) -0.94 log

- Placebo (n=13) +0.09 log (p=0.001)

- Active (n=6) -0.75 log

- Placebo (n=6) +0.07 log (p=0.012)

- Active (n=39) -0.51 log

- Placebo (n=38) -0.04 log (p=0.002)

- Active (n=5) -0.65 log

- Placebo (n=4) -0.11 (p=0.491)

- Active (n=3) -0.65

- Placebo (n=2) =0.23 log (p=0.088)

- Active (n=10) -0.05 log

- Placebo (n=10) +0.05 log (p=0.397)

 

Adefovir Resistance

Julie Cherrington, of Gilead Sciences, has reported that development of mutations associated with adefovir in vitro is rare, suggesting the possibility that resistance to adefovir may be difficult to develop or may develop slowly. The resistance characteristics of adefovir appear to be unusal. Gilead will be investigating if adefovir can prevent the M184V 3TC resistance mutation from occurring. A new study will explore adding adefovir to individual's regimens whose viral load is between 50 and 400. Two doses of adefovir will be explore-60 and 120 mg. As you may know when some people fail a regimen the first mutation observed can be the M184V without any other mutations being observed. Theoretically, adefovir might prevent the M184V from emerging; or, if a person's viral load has just rebounded and the M184V has just emerged adefovir may suppress that mutation. These are just theories that will be explored.

 

Grade 3 or 4 Adverse Events

Kahn reported there were more events in those taking adefovir than those taking placebo (18 vs12). There were 5 cases of diarrhea in the adefovir group and 0 in the placebo group.

 

Grade 3 or 4 Laboratory Abnormalities

Regardless of Relationship to Study Drug

You will note a higher incidence of AST & ALT elevations in the adefovir group than the placebo group.

 

 Adefovir (n=219)

 Placebo (n=223)

 CK elevation

 11% (25)

 13% (33)

 ALT elevation

 9% (19)

 4% (8)

 AST elevation

 6% (17)

 4% (9)

 hyperbilirubinemia

 6% (13)

 2% (4)

 Neutropenia

 3% (6)

 4% (9)

 Amylase elevation

 1% (2)

 3% (6)

 No of patients w/an event*

 3% (73)

 329% (65)

* some patients reported more than one event

 

Proximal Renal Tubular Dysfunction (PRTD)

Kidney dysfunctions

PRTD was broadly defined to be broadly inclusive as having > 3 lab abnormalities within two study visits-

Rationale for laboratory thresholds that define PRTD-

PRTD started to occur after week 24, and there was a slow increase in the incidence of the onset of PRTD to about 40% of the patients at week 48. An official from Gilead Sciences, the developer of adefovir, said the 40% was a projected estimate based on a Kaplan-Meier curve. But 32% was the actual percentage of patients experiencing PRTD at week 48. This is for the patients who were randomized to receive adefovir at the start of the study. Patients either stopped adefovir or lowered the dose, and at week 16 80% of patients resolved their PRTD. From visual observation of the curve on the graph it appears that almost 90% had resolution by week 24. Kahn commented that there was a gradual onset of PRTD that could be monitored. It was generally mild and is reversible with dose reduction or discontinuation.

Ongoing studies are exploring if dose reduction is as effective as discontinuation in reversing PRTD. As well, ongoing studies are exploring PRTD and viral load reduction using a lower dose than 120 mg from the start.