NEVIRAPINE: ACCELERATED APPROVAL RECOMMENDED for adults by the advisory committee June 9, 1996
On Friday June 7, the Antiviral Drugs Advisory Committee was convened to consider the application by Boehringer Ingelheim for accelerated approval of their non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine (brand name VIRAMUNE). Only half the day was needed for deliberation, as the Committee quickly decided (by a vote of 8-0) to recommend accelerated approval to the FDA, for the first NNRTI to apply for and receive approval. Indinavir's (Merck's protease inhibitor) committee recommendation wasn't as easy nor as quick. Accelerated approval for nevirapine was recommended for both drug-naive and experienced individuals in combination therapy. In this article, the following subjects will be addressed--- efficacy, safety, resistance, drug interactions, clinical endpoint studies, pediatric study, how to use nevirapine, the status of approval applications in foreign countries, contact information for the nevirapine expanded access program, and the company's report of gender/race results. Because nevirapine and protease inhibitors are hepatically metabolized, discussed below is the need for additional research in better learning how to manage individuals with liver impairment in the context of this new environment for HIV antiretroviral treatment. At the hearing, concerns were expressed by committee members and myself, because protease inhibitors and some other drugs used for HIV are metabolized by the same pathway in the liver; this is also addressed in the article.
NNRTIs have the same target of action (reverse transcriptase) as nucleosides, but have a different mechanism of action. 10 phase IIb/III trials were conducted and results from 3 were presented in support of their application: ACTG 241, BI 1037, BI 1046. As currently required for accelerated approval, clinical endpoint studies are ongoing and their status was discussed at the hearing. A total of 1,700 individuals have been treated with nevirapine (1,400 adults and 300 pediatrics), and more than 150 in pharmacokinetics trials. Maureen Myers, PhD, the Clinical Program Director for Virology Clinical Research at Boehringer Ingelheim, presented the clinical data to the panel. Some important characteristics of nevirapine are: absolute bioavailability--greater than 90%; good CSF penetration (Cerebrospinal fluid); protein binding--60%; plasma concentrations exceed the IC-50 after 1st dose; steady state reached in 4 weeks; hepatic metabolism (P450, 3A4-2B6); BID regimen (after 2 weeks at 200 mg once daily, then 200 mg twice daily); a limiting consideration in the selection of the recommended dosing regimen is the incidence of the development of a rash from nevirapine treatment. The recommended dosing regimen is 200 mg per day for two weeks (called the lead-in period) to be followed by 400 mg per day (200 mg twice per day).
ACTG 241
Randomized, double-blind, placebo-controlled, 48-week trial of triple therapy (nevirapine+AZT+ddI) vs. double therapy (AZT+ddI+placebo); there was no washout period as therapy was just added on to current therapy individuals were taking. The study examined the change from baseline of CD4 and viral load (HIV RNA); 398 participants; mean entry CD4--153 cells (range 1-433 cells); mean entry viral RNA--4.59 log copies/ml; RNA copies at baseline for triple therapy group--40,000; for the double therapy group--37,800; 6 months prior therapy required; median of 25 months prior therapy; 33% had greater than 36 months prior therapy; 66% had previous ddI or ddC experience with or without AZT.
CD4 changes. For the triple therapy group, CD4 peaked at 8 weeks with a 35 increase from baseline (bsln= 156 cells, n=196); at 24 weeks, the CD4 increase was still 25 above baseline; at 40 weeks it was 20 above baseline and then sharply dropped back to baseline (0 cell increase) by 48 weeks. The double therapy group (AZT+ddI) peaked at 8 weeks with a 20 cell increase from baseline (bsln=151 cells, n=196); by 24 weeks the CD4 decreased by 5 below baseline; at 48 weeks, CD4 was 18 below baseline.
CD4 changes from baseline
8 weeks | 24 weeks | 48 weeks | |
nevirapine+AZT+ddI (156) | +35 | +25 | 0 (back to bsln) |
AZT+ddI (151) | +20 | -5 | -18 |
HIV RNA. The baseline RNA was 40,000 (n=95) for triple therapy and 37,800 (n=93) for the double therapy group. The triple therapy group (NVP/AZT/ddI) peaked at 4 weeks with a 1.2 log decrease from baseline, which quickly started to trend back up; at 8 weeks, the reduction was 0.75 log; at 16 weeks, the reduction was 0.5 log; at 24 weeks, the reduction was 0.25 log; by 48 weeks, the reduction was only 0.12 from baseline. For the double therapy group (AZT/ddI), the RNA peaked with a 0.4 reduction from baseline at 4 weeks; by 24 weeks, the reduction was 0.10; and at 48 weeks, the RNA was 0.12 above baseline.
HIV RNA changes from baseline | 4 weeks | 24 weeks | 48 weeks |
NVP+AZT+ddI (40,000) | -1.2 log | -0.25 | -0.12 |
AZT+ddI (37,800) | -0.4 | -0.10 | +0.12 |
Performances were mitigated by drug experience: 25 months prior therapy, 33% with more than 3 yrs. prior therapy. Dr. Myers said, resistance developed more quickly, in the heavily pre-treated group, as opposed to the responses of those who are drug naive (BI 1046), which will be discussed below. The study population was divided by CD4 into 3 strata: less than 50 CD4, 51-200 and above 200. Apparently, the under 50 CD4 group benefitted less than individuals with greater than 50 CD4.
AZT-only experienced. 31% of study subjects in ACTG 241, had prior experience only with AZT. These individuals added ddI or NVP+ddI to their current AZT therapy, as opposed to other study subjects who had prior experience with ddI, ddC, AZT/ddI or AZT/ddC. This separate analysis defines more clearly, the utility of both NVP and ddI, used either as separate therapies or when used together, in a group that wasn't experienced with the other drugs or combinations, and therefore allows us to better understand its utility.
CD4 change from baseline (triple group bsln=188 cells, n=61; double group bsln=185 cells, n=62) for the group with only AZT experience--
16 weeks | 32 weeks | 48 weeks | |
NVP+AZT+ddI | +50 cells | +62 | +25 |
AZT+ddI | +37 | +25 | +5 |
Evidently, overall these individuals had greater CD4 increases that were better sustained, presumably because they had less prior treatment-experience, as their baseline CD4 and RNA were similar to the other more drug experienced group. The overall RNA benefits were also better for this group than for the more drug experienced individuals. Assumedly, resistance developed more quickly. This more clearly shows the benefit of NVP's contribution because of less noise from the extensive previous therapy.
4 weeks | 24 weeks | 48 weeks | |
NVP+AZT+ddI | -1.75 log | -0.90 | -0.63 |
AZT+ddI | -0.75 | -0.60 | -0.30 |
BI 1037.
This small study of AZT-experienced individuals was randomized, double-blind, and placebo-controlled for 60 study participants; 28 weeks in duration; CD4 range 200-500, mean count was 373 cells; median prior AZT-experience of 8 months, range of 3-24 months; mean viral RNA was 17,378 at baseline. Study subjects either continued AZT therapy with placebo or added nevirapine to their current AZT therapy. This trial examined double therapy, while ACTG 241 examined triple therapy.
CD4 changes. The CD4 increase in the NVP+AZT group peaked at 55 cells at 8 weeks; at 24 weeks the increase from baseline was 35 cells; but steeply declined by 28 weeks, to 10 cells below baseline. At 8 weeks, the AZT alone group was at baseline; at 16 weeks, the CD4 count declined by 35 below baseline; and by 28 weeks it was 40 cells below baseline.
CD4 changes from baseline
8 weeks | 16 weeks | 24 weeks | 28 weeks | |
NVP+AZT | +55 cells | +40 | +40 | -10 |
AZT | -at bsln- | -35 | -20 | -40 |
HIV RNA. The RNA reduction peaked at 1.6 log at 2 weeks. The reduction took a steep turn upwards, and by 8 weeks the reduction was only 0.20 log; by 28 weeks, the RNA was back to baseline; and at 28 weeks, the RNA was 0.20 above baseline.
HIV RNA changes from baseline
2 weeks | 8 weeks | 16 weeks | 28 weeks | |
NVP+AZT | -1.6 log | -0.2 | -at bsln- | +0.20 |
AZT | -0.10 | -at bsln- | -at bsln- | +0.20 |
Although this was a healthier study population than those in ACTG 241 (significantly higher baseline, CD4--373 vs. 150, and lower RNA, 17,000 vs, 37-40,000), apparently, double therapy is not adequately potent to suppress viral replication and delay resistance.
BI 1046.
A small group of 151 treatment-naive subjects were studied for 12 months in a randomized, double-blind, and placebo-controlled trial. The study compared triple therapy of NVP+AZT+ddI vs. AZT+ddI vs. NVP+AZT; CD4 200-600 cells; baseline measures--mean CD4 count 376 cells, range 145-755 cells; mean viral RNA--25,700 copies/ml, range 347 to 724,436. This study recently completed on May 15,
CD4 changes. The CD4 data is now available out to 52 weeks, as it has only been recently compiled and analyzed; the FDA only had the 28-week data for review in April. For the triple therapy, the CD4 increase from baseline at 4 weeks was 70 cells; at 16 weeks, the CD4 increase was 110 cells; at 20 weeks, the CD4 increase was 135 cells from baseline; at 28 weeks, the increase was 120 cells; at 40 weeks, the CD4 increase was 135; and at 52 weeks, the CD4 increase was 140 CD4. For the AZT/ddI group, at 4 weeks the increase 40 cells; at 16 weeks, the CD4 increase was 90 cells; at 28 weeks, the CD4 increase was 70 cells; at 40 weeks, the increase was 85 cells; and at 52 weeks, the CD4 increase from baseline declined to 30 cells above baseline. For the double therapy of NVP+AZT, CD4 increase peaked at 80 cells at 4 weeks; at 16 weeks, the increase from baseline was 25 cells; at 28 weeks, the CD4 increase was 10 cells; at 40 weeks, the CD4 was 15 above baseline; and at 52 weeks, the CD4 was back to the baseline.
CD4 changes from baseline
4 weeks | 16 weeks | 28 weeks | 52 weeks | |
NVP+AZT+ddI (n=51, bsln=387) | +70 cells | +110 | +120 | +140 |
AZT+ddI (n=52, bsln=392) | +40 | +90 | +70 | +30 |
NVP+AZT (n=47, bsln=346) | +80 | +25 | +10 | -at bsln- |
HIV RNA. Currently, the viral load data is only available now out to 28 weeks; for the triple therapy of NVP/AZT/ddI, the RNA peak reduction is 1.75 log at 4 weeks; at 16 weeks, it is sustained at 1.70 log; and at 28 weeks, the reduction remains sustained at 1.65 log below baseline. For the double therapy of AZT/ddI, the RNA at 2 weeks is 1.50 log below baseline; at 16 weeks, it remains at 1.50 below baseline; and at 28 weeks, it is 1.30 below baseline. For the double therapy of NVP+AZT, the initial RNA reduction is 1.75 log at 2 weeks; at 16 weeks, the reduction is 0.65 below baseline; and at 28 weeks, it is 0.40 below baseline.
RNA changes from baseline
4 weeks | 16 weeks | 28 weeks | |
NVP+AZT+ddI (n=51, bsln=17,500) | -1.75 log | -1.70 | -1.65 |
AZT+ddI (n=51, bsln=28,700) | -1.40 | -1.50 | -1.30 |
NVP+AZT (n=46, bsln=35,156) | -1.60 | -0.65 | -0.40 |
Percent of subjects assayed with RNA below limit of detection
16 weeks | 28 weeks | |
NVP+AZT+ddI (n=27) | 75% | 73% |
AZT+ddI (n=27) | 40% | 45% |
NVP+AZT (n=21) | 2% | -at bsln- |
In an initial pre-planned analysis of the trial, the difference in RNA at 28 weeks between the triple and double therapy group of AZT/ddI was not found to be statistically significant; however, the triple therapy group had a lower baseline RNA; after an adjustment in the analysis for the difference in baseline RNA between the AZT/ddI and triple therapy groups, the difference in RNA at 28 weeks was statistically significant. The NVP+AZT group had a 40% undetectable rate at 4 weeks, but this regimen was unable to sustain this level of viral suppression beyond 4 weeks. Apparently, if you can adequately suppress the virus, resistance to NVP is delayed.
Resistance.
Reduced susceptibility was associated with mutations at residues: 103, 106,
108, 181, 188 and 190, both in vitro and in vivo. In previously treated subjects, reduced susceptibility appears within 8 weeks of treatment initiation. Codon change at position 181 does not appear in subjects treated concurrently with NVP+AZT. The only drug with which cross-resistance would be expected is delavirdine which results in the same codon changes as NVP. Delavirdine is another NNRTI being developed by Upjohn and Pharmacia, and it is expected to be soon reviewed for approval by the FDA. Boehringer reported an analysis of 6 months resistance data (from the BI 1046 trial) for 4 individuals on triple therapy (NVP+AZT+ddI) and 4 on double therapy (NVP+AZT). The 4 individuals taking NVP+AZT, whether or not they were compliant with taking study drug, were resistant to NVP at 6 months. Of the 4 taking NVP+AZT+ddI, the 2 individuals who were resistant to NVP were non-compliant and were unable to keep their viral level below the limit of detection; the other 2 individuals who were not resistant to NVP were fully compliant and were below the limit of detection for the full 28 weeks of the study. Boehringer defined non-compliance as a subject who failed to take at least one study drug for at least 28 days. This resistance data is based on a small number of individuals, so additional resistance research is needed for nevirapine, as well as for other drugs, because we need to better understand the resistance relationships of all HIV antiretroviral treatments.
Results by gender/race
In pharmacokinetics studies, Boerhinger reported, there were no gender differences in NVP oral clearance or plasma concentrations; and, no marked difference in steady-state trough concentrations by race.
In ACTG 241, there were 20% female and 26% non-caucasian participants. Boerhinger reported, gender and race did not significantly affect CD4 or RNA changes on triple therapy; and, there was no evidence of interaction between gender/race and treatment group in CD4 or RNA changes, i.e, results weren't inconsistent due to gender or race. Lastly, there was no evidence of effect on safety profile.
Safety
There was a 22% incidence rate for the occurrence of a rash; but the incidence rate for a severe rash (grade 3 or 4) was 6%. 6.7% of study subjects permanently discontinued in the presence of a rash. For those individuals using fluconazole there was a 6% greater chance of developing a rash (25% of study particpants were using fluconazole), than for those not using fluconazole (19%). If a rash emerged, 50% of the time it was dissipated by 2 weeks; by 1 month, 80% were dissipated. If an individual has to discontinue NVP treatment due to a rash, it is not recommended to attempt a re-challenge (try the drug again). It is the company's experience, that upon re-challenge a severe rash occurs. Mild or moderate rashes do not compel discontinuation; rashes occur predominately early in treatment. The risk for rash is greatest in the first 6 weeks of NVP treatment. If a rash occurs, you should inform your doctor; Boehringer recommends, if a rash occurs during the dose lead-in period, you should not dose escalate; and, if a rash is uncomfortable you should discontinue.
At Vancouver, the company will distribute an educational booklet, to the public, discussing the matter of a rash and nevirapine.
At the Int'l. AIDS Conference in Vancouver, additional data on protease inhibitors will be reported. I will be at Vancouver reporting daily highlights to you via the NATAP internet homepage at: http://www.aidsnyc.org/natap
Of course, following the conference, NATAP will be reporting full details of important data, on the NATAP homepage; look for an update to our bound 46-page booklet--"HIV Protease Inhibitor Report--2nd edition."
As a result of NVP treatment in trials, 5.4% of study participants have experienced abnormally elevated liver function tests (LFTs--SGOT & SGPT). There has been a 2% rate of study discontinuation, as a result of abnormal LFT elevation. Some individuals have experienced similar responses to protease inhibitors. As well, in ACTG 241, BI 1037 and BI 1011, study participants experienced a 10% incidence in the elevation of GGT--a liver related laboratory test.
Liver research needed. At the hearing, in the open session, I addressed this issue by suggesting that because we have so many new antivirals which are hepatically metabolized--protease inhibitors, NNRTIs--and because so many individuals have impaired liver function (due to extensive drug experience, Hepatitis B & C), therefore the industry and the FDA (and the NIH) should start designing studies to explore how to manage these individuals in the context of administering these new antiretrovirals. As use of these antiviral drugs become more widespread, and continue to be used simultaneously with other drugs (some of which are popular and effective prophylaxis treatments), liver-related side effects may become increasingly more evident; and, treatment strategies will become increasingly more limited for this population.
This may emerge as a problem as individuals with some liver impairment start combining two protease inhibitors, or start transitioning from one protease inhibitor to another or as an individuals length of exposure to protease inhibitors builds over time and their liver starts to wear from it. Of course, more effective research initiatives into Hep. B & C would also be helpful. The effectiveness of currently available treatments for these liver diseases are very limited, particularly for Hep. C. This is an issue that deserves more attention and needs follow-up. The protease inhibitor manufacturers, and the NNRTI manufacturers are some of the world's largest and wealthiest corporations, who have the resources to address this issue; but, they have been busy getting their drugs approved. Now, it may be time for them to address these concerns.
Drug Interactions. "It was suggested, at the hearing, that doctors monitor their patients during the first few weeks of nevirapine therapy, if they are taking any drugs that may have potential interactions". Nevirapine is hepatically metabolized (P450, 3A4-2B6). Consequently, there are concerns about potential drug interactions. Protease inhibitors and other drugs are similarly metabolized. The company did not have much data on drug interactions to present at the hearing. An interaction study with saquinavir is ongoing; they had some data on 11 of 24 subjects being studies. It is preliminary, but the average response of the eleven subjects was that saquinavir blood levels were lowered by 16%. However, the graph of the 11 subjects indicated that some had 50% increases in saquinavir blood levels. The company said, it is not unusual to have such variable results, and it is too soon to assign a number to the change in saquinavir blood levels. Studies with indinavir and ritonavir are about to begin. Until these studies are completed, it is recommended that individuals do not combine nevirapine with protease inhibitors.
As well, other drugs have potential for interaction with nevirapine. Studies are being planned with drugs that are representative of the major classes of drugs which are used by people with HIV. At the hearing, the committee raised concerns about the following drugs: rifampin, dapsone, azole drugs, methadone, rifabutin and ketoconazole. The company said, in vitro, ketoconazole inhibited the metabloilism of NVP, but when a small amount of participants in BI 1046 were studied who were taking ketoconazole and NVP, NVP levels weren't changed; this merits further attention and investigation. Aside from ketoconazole, it seems that some of these aforementioned drugs or other drugs in the same class may cause a 15% reduction of nevirapine in steady state blood levels. The company predicted some of these drugs will suffer reduced blood levels from interaction with nevirapine. Again for emphasis, it was suggested that doctors monitor their patients during the first few weeks of nevirapine therapy, if they are on any drugs that may have potential interactions. Dr. Chris Mathews, a committee member, was concerned about a reduction in the therapeutic plasma levels for those drugs which are necessary for prevention of opportunistic infections (OI); and thereby, this may cause failure of that therapy and the development of an OI. In my public commentary to the committee, I expressed concern about this issue and reminded the panel that Abbott came prepared to their hearing with more extensive data on drug interactions. Dr. Myers, of Boerhinger said, nevirapine was a mild to moderate enzyme inducer; but, the FDA said they will be working with the company on drug interaction studies. This concern should be closely monitored.
How to use this drug. With the availability of nevirapine, we have more drugs in our arsenal with which to design treatment strategies. As I discussed in my talk for the open commentary as this hearing, nevirapine provides additional options for everyone. For individuals who may be intolerable to other nucleosides, may have depleted treatment options, or may have failed other drugs, nevirapine offers an option with which to strategize. For both drug-naive and experienced, protease inhibitor therapy could be postponed or saved for future use, while a person could use nevirapine therapy prior to a protease inhibitor. Again, until we have more information from interaction studies, it is recommended that nevirapine is not to be combined with concurrent use of a protease inhibitor.
In the studies discussed above, Nevirapine clearly was more potent in 3-drug combinations then in 2-drug combinations; nevirapine was more effective for drug-naive individuals than for the drug-experienced population. Apparently, the more experience and the more diverse that experience, the less effective nevirapine.
A number of committee members expressed preference that the drug be used in triple therapy rather than double therapy, but were unwilling to restrict the labeling indication to its use only in a 3-drug combination. If you are able to start 2 drugs never before used, simultaneous to initiating nevirapine therapy, the studies indicate that the efficacy of nevirapine and the overall benefits to CD4 and viral load will be greatly enhanced; because, if you can adequately suppress viral replication, resistance is delayed and the drugs efficacy is sustained; the less exposure you may have had to a drug, the better the possibilities are for suppressing virus replication and delaying resistance.
Expanded Access Program. If you, your doctor or any other interested party would like information about the availability of nevirapine through the company's expanded access program, you can call toll-free 1-800-595-5494; or, you can make contact by fax at 1-800-535-5652.
Clinical endpoint studies. ACTG 193a has been ongoing for a while and compares--NVP+AZT+ddI vs. AZT+ddI vs. AZT+ddC vs. AZT alternating ddI; it was intended to examine survival and progression to clinical AIDS; but, because of the availability of protease inhibitors, the start of ACTG study 320 (which examines Crixivan in a clinical endpoint study), and because ACTG 193a study monitors have said they believe they have enough endpoints already--subjects are being rolled out of the trial.
BI 1090 is a clinical endpoint trial with a recruitment goal of 2,000; however, only 250 subjects have been recruited and the prospects for enrollment in the USA, where protease inhibitors are generally available, may be slower, until they can allow co-administration of NVP with protease inhibitors. International recruitment is more encouraging because protease inhibitors are less available. The committee expressed concern about the prospect of not obtaining adequate data on clinical endpoints. As you may know, FDA regulations require that for full or traditional approval adequate clinical endpoint data must be provided to the FDA.
Pediatric trial. Enrollment continues in ACTG 245, which is a randomized, double-blind, placebo controlled trial for 432 HIV+ children with greater than 24 weeks of prior antiretroviral therapy and clinical progression. It is intended as a 48-week comparison of NVP+AZT+ddI vs. NVP+ddI vs. AZT+ddI. The trial is studying safety/tolerance, CD4 count, HIV RNA, pharmacokinetics/pharmacodynamics, and clinical response (growth, ND/NP status, survival). The trial initiated in August of 1994 and is slated for completion in February 1997. Nevirapine has demonstrated significant CSF (Cerebrospinal Fluid) penetration in this pediatric population. 9% (11/123) of pediatric study subjects receiving nevirapine treatment had a rash that was equal to or greater than a grade 2 rash. 100% of rashes occurred in the first 28 days after NVP treatment initiated. 0.8% (1/123) experienced a serious (grade 3/4) rash.
Foreign countries. Applications for approval were filed in May in Australia and New Zealand. an application will be filed this month in Canada; in July, an application will be filed in South Africa; company representatives will be meeting shortly with European officials to discuss the submission of surrogate marker data. In Europe, accelerated approval is not yet recognized; clinical endpoint data is still required for approval. It is expected that by early '97, surrogate marker data will be submitted to European officials.
We can be hopeful, that with the availability of more and better antiretroviral drugs and drugs for opportunistic infections, our prospects are improving for turning this disease into a chronic and manageable one. We need to pressure and encourage the federal government to provide an environment friendly to HIV research. This could include a specially designed package of incentives, including financial and tax incentives, to encourage adult and pediatric AIDS research. The federal research effort controlled by our NIH can and should be improved. As well, the FDA must be focused on reviewing and approving beneficial AIDS drugs as expediently as possible. If all Americans could fully appreciate the tragedy and consequences of the AIDS health epidemic, then congress and the administration would be more responsive to this crisis, that faces America and the World.
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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.
The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.
Last modified 8/29/96
by Jules Levin
Copyright © 1996 natap
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