The Difference Between Drugs and New Drugs

By Rob Camp

August 2004

FDA announced approvals in early August of two fixed-dose combination (FDC) antiretroviral drug products for use with other antiretroviral agents for the treatment of HIV-1 infection. FDCs are combinations of two previously approved drugs in what is understood to be an easier form, in both cases one pill a day, like Comibivir® already on the market, a combination of retrovir (AZT) and lamivudine (3TC). The two new ones are GlaxoSmithKline’s Epzicom® and Gilead Sciences, Inc.’s Truvada®. These FDC approvals provide simplified dosing regimens for one component of HIV therapy. This paper will address what is known about Epzicom. While this new approval is a new and interesting option, it consists of previously approved, possibly previously taken and failed drugs, and is not, in and of itself, useful for everyone.

Epzicom is an FDC of the antiretroviral drugs abacavir sulfate (Ziagen®) 600 mg and lamivudine (Epivir®) 300 mg. Epzicom, one pill a day, is approved based on a large well-controlled clinical study (CNA30021 or Zodiac) that showed that abacavir dosed once daily had similar antiviral effect as abacavir dosed twice daily, both taken with lamivudine and efavirenz. The difference between Epzicom and ABC/3TC separately is two pills.

Epzicom is active against HIV in a variety of different patient groups. But use of abacavir (one of Epzicom’s components) has been associated with potentially fatal hypersensitivity reactions in a growing number of patients.

Regarding the issue of first line backbone of Epzicom vs Combivir, TAG sees no cost or safety benefits for Epzicom and we caution against GSK’s petition to place Epzicom as a first-line backbone.

TAG believes that the company’s application for approval of EpzicomQD for treatment of HIV infection in adults and adolescents was correctly approved by the FDA. However, the FDA should carefully monitor the company’s education programs for both doctors and patients. Studies of Epzicom leave some uncertainty about the relative benefits for it compared to other marketed NRTI backbones. In deciding whether to use any abacavir-containing regimen, physicians and patients should be aware that the existing double-nucleoside combinations of AZT/3TC (Combivir) or AZT/FTC, d4T/3TC (or d4T/FTC), TDF/FTC (Truvada, see accompanying paper), AZT/TDF, etc may be as useful as Epzicom, without the risk of hypersensitivity or “low genetic barrier” that could lead and has led to virologic failure.

1. Activity and Efficacy

Study	Description	n	Endpoint	Length
ESS30009	Randomized, double-blind comparison of ABC/3TC + EFV vs ABC/3TC in treatment-naive	360	HIV-1 RNA <50 c/mL	Designed: 48 Weeks
CNA30021 (ZODIAC)	Randomized, double-blind trial of ABC QD vs ABC BID with 3TC QD and EFV QD in treatment-naïve	770	Non-inferiority of ABCOAD compared with ABC BID (95% CI), TLOVR	48 Weeks
CNA3014	Open label equivalence ABC + Com (lamivudine/ zidovudine) compared to indinavir/Com in treatment-naïve adults	342	HIV-1 RNA < 400 copies/mL and HIV-1 RNA < 50 copies/mL (95% CI)	48 Weeks
CAL30001	Randomized, open-label FDC vs ABC + 3TC both with TDF + an NNRTI or a PI after treatment failure	190	AAUCMB, Safety and tolerability, <400, <50, CD4 increases	48 Weeks
ESS30008	Open label, randomized FDC vs ABC/3TC BID + PI or NNRTI in experienced people	240	<400, tolerability, Efficacy, adherence, resistance	48 Weeks
ESS40001(CLASS)	ABC/3TC + EFV, AMP/r, or d4T in treatment naïve people	291	HIV-1 RNA < 400 copies/mL and HIV-1 RNA < 50 copies/mL (95% CI)	96 Weeks
CNA3005	Randomized, blinded ABC/Com vs Ind/Com in treatment naïve	262	Pop achieving < 400 and those achieving <50 c/mL, < and > 100,000.	48 Weeks

A number of studies have shown that ABC/3TC, either twice a day or once a day, is no worse than the comparitor arms. The studies above have shown that ABC QD is no worse than ABC BID and that ABC/3TC QD is no worse than ABC/3TC BID. Of note, at least one non-inferiority study was powered on a 15% difference to mean equal, vs the normal 12%; also, in some publicly-presented studies, GSK used an analysis of “Intent to Treat Observed”, a methodology not valued by the FDA, where the significance of all non-virological failures can be underemphasized.

Epzicom has demonstrated activity in combination with Sustiva, Lexiva, Kaletra, Viracept and Reyataz. It has shown activity with AZT and d4T. BID vs QD had about 5% more CD4 gain.

When to use Epzicom?

NOT with tenofovir (TDF). The probable low genetic barrier to resistance and a possible “overactive” transport mechanism (p-Gp efflux) leads quickly (by wk 12) to the appearance of K65R and the M184I/V either alone or together in up to 3/4 of people in ESS30009. 95% of people failed on ABC/3TC + TDF at 16 weeks. Even if a fourth drug is added, the resulting viral fitness after failure is going to be strong! Why is the ABC+TDF issue not a black box warning on the label? Other GSK studies, the ESS40002, the CNAAB3005, the NZTA4006 and the NZTA 4007 all showed large virological failures (between 12 and 24%) by wk 12 with the combination of Epzicom and AZT. Time to failure was shorter (4 weeks for example, in the “Tonus” study) in smaller non-GSK protocols. When will triple nucleoside regimens be in a black box? When patients have been rechallenged with abacavir following a hypersensitivity response, deaths have resulted. GSK has developed language recommending that patients who develop a hypersensitivity response while taking the drug be discontinued from therapy, and not re-challenged. FDA has adopted this language in a black-box warning about hypersensitivity.

From “Important Interim Results from a Phase III, Randomized, Double-Blind Comparison of Three Protease-Inhibitor-Sparing Regimens for the Initial Treatment of HIV Infection (AACTG Protocol A5095), DHHS, DAIDS, NIAID, NIH, NOTICE TO PHYSICIANS (HIV/AIDS Health Care Providers), March 10, 2003:

…Trizivir® users experienced virologic failure earlier and more frequently than patients who were randomized to receive either of the two other treatment regimens being evaluated in study ACTG 5095… Trizivir (ABC/3TC/ZDV) is demonstrably inferior to the other two regimens (Combivir + Sustiva, Trizivir + Sustiva), based on rates and time to virologic failure.

Although ACTG 5095 is not an Epzicom study, all three arms had what amounts to Epzicom + other agents, and the triple nuke regimen was stopped.

In a similar study, GSK ESS30009, looking at TDF+3TC+ABC vs EFV+3TC+ABC, a similar result was seen in the triple nuke arm – within 8 weeks, higher rates of virologic non-response were seen. Triple nuke regimens are not recommended, and may be harmful after failure to being able to construct good regimens.

2. Safety / Tolerability

The important safety issue regarding abacavir-containing products, including Epzicom, is hypersensitivity reaction (HSR), a serious allergic reaction. Epzicom should be discontinued a soon as a hypersensitivity reaction is suspected. Epzicom or other abacavir-containing products must not ever be restarted following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death. Information on this serious allergic reaction has been updated in the Epzicom package insert as well as the patient Medguide/Warning Card.

In the main pivotal trial, CNA30021 (Zodiac), the incidence of HSR rose from earlier studies. HSR is currently reported at <5%. This has now risen to 9% (vs 7% in the BID arm in the same study). The clinical meaning of this is that 900 / 10,000 persons on will experience hypersensitivity.

In light of this, FDA is requiring GSK to work with the community (via conference calls, meetings, etc) to help educate people in HSR and what to do about it.

HSR may involve a low-grade fever, nausea, vomiting, malaise and rash, in a minimum grouping of three of these. All five of these present upwards of 58% of the time in a 10-trial meta-comparison. Intensity of these symptoms tends to increase with duration of therapy, and resolves upon therapeutic discontinuation. In a safety analysis of Zodiac, Hernandez et al showed that most symptoms occur within the first 6 weeks, median time to onset being 9 days.

In CNAAB3005, in the ABC group, cardiac arrythmia and myocardial infarction deaths in naïve people happened between wks 30 and 35. 7% had hypersensitivity.

Other common adverse effects were nausea (42%), headache (45%), malaise / fatigue (100%), diarrhea (27%), vomiting (25%) rash (80%) and fever (60%). In a random sample of the ZODIAC participants, 26% stopped before 48 wks, due either to adverse event(s), lost to follow up, or other.

Adverse events of grade 2 (mild) or greater are reported high—62% of patients report side effects with ABC BID, while 65% reported similar events in QD.

In Zodiac, there were even greater failures and losses in both arms (ABC QD vs itself BID): 10 vs 8 virologic failure, 13 vs 11 AE withdrawals, 11 vs 13 “other” (consent withdrawn, protocol violation, clinical progression, changed therapy, other other).

Treatment discontinuations hover at 24%. Add that to clear virological failures, and 30% of the original patients did not finish the one-year study.

Is ABC a (safe) alternative for lipodystrophic events? Cholesterol and triglycerides went up significantly more in the ABC arms than in the AZT arms in CNA30024. AST and absolute neutrophils also went up. Although all these measurements were non-fasted (and the significance is thus not clear), at week 8, ABC was 50mg/dL higher in lipids!

A substudy of ESS40001 (see chart) shows some startling trends: at 96 wks, with an NNRTI, fasting total cholesterol rose 40 points, with a PI it rose 60, and with an NRTI it rose 32. Triglycerides all rose as well, with an NNRTI, +66, with a PI +90, and with an NRTI +70, all 3 classes going above the “safety zone” for NCEP III, calling for medical intervention. ABC/3TC does not help with these events, or with fat changes in any of the regimens.

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) and discontinue 3TC. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Epzicom and are co-infected with HIV and HBV. Initiation of anti-hepatitis B therapy may be warranted.

Because 3TC requires dose adjustment in the presence of renal insufficiency, Epzicom is not recommended for use in patients with creatinine clearance <50 mL/min.

Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild hepatic impairment. Because Epzicom is a fixed-dose combination and cannot be dose adjusted, Epzicom is contraindicated for patients with hepatic impairment.

In a trial of women, the prevalence of osteopenia / osteoporosis was 18.9% for women not on HAART and 20.4% for those on HAART. This vs a 6.4% for HIV-negative women gives an odds ratio of 3.15, p=0.03. In a subset analysis of the same women, use of abacavir was independently associated with lower bone mineral density.

3. Resistance

When HIV is passaged in the presence of abacavir in vitro, the first mutation to arise is the M184V mutation (that also confers resistance to 3TC). Later, mutations arise at positions 65, 74, and/or 115.

In CNAAB3005, the RT mutation most frequently observed was M184V, in 21/27 of those in the ABC group. 71% of patients had the M184 alone.

AZT (and possibly d4T) use has been previously associated with significant reductions in the selection of 65R and 74V by ABC and ddI. Mutation patterns with low genetic barriers to resistance, such as 184V plus either 65R or 74V, may increase in prevalence as ABC, ddI, and TDF use increases, particularly if they are used in the absence of thymidine analogues. Thus, AZT with ABC may be a good idea to prevent the K65R and the M74V.

First line ART therapy combinations should be chosen, in part, to minimize the potential for rapid selection of broadly cross-resistant mutants that may reduce future treatment options. Ergo, Epzicom needs a strong third drug, preferably from another class. AZT can be added as a fourth drug if you can afford it and you are not resistant to it.

4. Drug Interactions

In the FDA Package Insert, no recommendations for the ABC / methadone interaction are offered, except in a “small number of (undefined) patients”, despite evidence from a German study that looked at 16 patients on a EFV + ABC + 3TC regimen. EFV was previously seen to be a CYP 3A4 inducer, interfering with the metabolism of methadone. ABC had been shown to increase methadone clearance by some 22%. Methadone’s AUC was decreased some 39% in this study, while the primary metabolite of methadone was decreased by 14.5%. MET doses were increased by an average of 29.5% to achieve MET steady state AUCs of 255ng/ml.

5. FDA Advisory Committee Hearings: The Agency May Not Need Advice, But People With HIV Need Information

FDA’s decision to approve HIV therapies without an open public presentation of the available evidence submitted to the agency in support of the drug’s labeling means that advocates for people with HIV, physicians and patients have limited access to important information about the product that has not come from the sponsor’s public relations department. We heartily support open hearings, whenever possible. Rapid publication of the agency’s interpretation of the data set is vital, irrespective of whether
a hearing is held, but especially so when there is no public presentation of the data set.

GSK’s much-touted clinical trials database is exactly what one would imagine it to be: non-existent, except for one drug, rosiglitazone.

6. To do…

Studies that would be helpful for GSK to invest in:

ABC: Predictive genetic testing may eventually help people know beforehand whether they will get HSR or not. In small white male cohorts, HLA-B5701 has had predictive values of 46-60%. Larger trials needed.

ABC: Similarly, a patch test may be developed to eliminate morbidity and mortality after full-dose rechallenge.

ABC: One small (6 person) German study dose adjusted ABC during hypersensitivity, going from 7.5 mg / day, doubling the dose every day until reaching the 600 mg. No-one suffered a fall back. One person stopped once the full dose was reached again.

Epzicom: Less mitochondrial toxicity has not been seen yet. Please demonstrate.

Epzicom: QD may do better for those >100K. Please demonstrate.

ABC: GSK needs to evaluate possible pharmacokinetic interactions between Ziagen and other drugs that affect the p450 metabolic pathway, including ketaconazole, rifabutin, rifampin, clarithromycin, and ethinyl estradiol.

It would be helpful to show that using AZT together with ABC prevents the emergence of the K65R and the M74V. AZT + Epzicom + Sustiva vs Epzicom + Sustiva, with frequent monitoring and backup regimens designed depending on mutations that arise.

Please also see “Brand-name FDCs” and “PEPFAR”

Thanks to Daniel Raymond for help in organizing and editing this paper.

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