Ziagen(tm) (Abacavir) Approved: Caution Essential

On December 18, the U.S. Food and Drug Administration announced the accelerated approval of Glaxo-Wellcome's abacavir (trade name Ziagen; previously known as 1592) for treatment of HIV infection in adults and children, in combination with other antiretrovirals. Abacavir is a nucleoside analog (in the same class as AZT), but has a stronger antiretroviral effect.

This drug must be used with caution, because it can cause a serious side effect, called a hypersensitivity reaction, in about five percent of patients, usually (but not always) within six weeks of starting the drug. There is no known way to predict who is at high or low risk. If the drug is stopped permanently, the hypersensitivity reaction generally goes away without further treatment; but if the drug is later restarted after the reaction, it causes a much more severe recurrence which begins rapidly and can be fatal within a day. It is urgent that patients as well as medical professionals be well informed about this problem, so that they can recognize the hypersensitivity reaction if it occurs, and get medical attention and permanently stop using the drug.

On December 18, 1998 the FDA published a short "talk paper" on abacavir, which we reproduce in full. If you use this drug, be sure to check the Medication Guide and wallet card that comes with each prescription, for information on how to recognize hypersensitivity.


FDA Approves Abacavir for HIV-1 Infection

FDA approved today abacavir (trade name Ziagen) for the treatment of Human Immunodeficiency Virus-1 (HIV-1) in adults and children. The following can be used to answer questions:

Ziagen, an oral medication taken twice daily, is one of a class of medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs) and is taken in combination with other anti-HIV medications. This combination of medicines helps to lower the amount of HIV found in the blood.

This new drug offers another choice for the treatment of HIV, a virus that mutates quickly and may become resistant to current treatment. Ziagen, available in tablet and liquid form is approved for adults and pediatric patients older than three months of age.

A potentially fatal hypersensitivity, or allergic reaction, has been associated with the use of Ziagen in at least 5 percent of patients. Symptoms of this reaction may include skin rash, fever, nausea, abdominal pain and severe tiredness.

A written list of the hypersensitivity symptoms is printed on a warning card and is provided along with a Medication Guide to patients by pharmacists. Anyone who experiences a hypersensitivity reaction must stop taking the medicine and call their health care provider immediately. Ziagen should not be taken again after a reaction occurs because more severe symptoms will arise within hours and may include life-threatening low blood pressure or death.

An abacavir hypersensitivity reaction registry has been established--physicians should register patients developing symptoms of hypersensitivity by calling 1-800-270-0425.

All NRTIs can cause lactic acidosis--a fatal metabolic disturbance that causes an abnormal buildup of lactic acid--symptoms may include an enlarged liver.

Additional reported side effects of abacavir include nausea, vomiting, fatigue, headache, diarrhea, and loss of appetite.

Accelerated approval of Ziagen was based on analyses of surrogate markers in three controlled studies of up to 24 weeks in duration. At present there are no results from controlled trials with Ziagen evaluating long-term suppression of HIV infection or AIDS.

Ziagen is manufactured and marketed by Glaxo Wellcome Inc., of Research Triangle Park, N.C.


Comment

On November 2 the FDA Antiviral Drugs Advisory Committee met to consider the approval of abacavir. The Committee voted 7 to 2 to recommend accelerated approval, but with much reluctance because of serious weaknesses in the package of data presented. As one Committee member put it, "I voted for accelerated approval. I agree with virtually everybody else that I would have liked to have seen a more complete set of data to justify that, but on balance I came down on yes."

Here are some of the gaps in current knowledge:

Little is known about the mechanism of the hypersensitivity reaction, and no risk factors are known. (Glaxo has agreed to do further work on the mechanism, on the clinical issues, and on the use of educational materials and their effectiveness, and bring the results back to the FDA when abacavir comes before it again for traditional approval.

Of the three trials most relied on by the Committee, none had data beyond 24 weeks at that time (the studies are ongoing). And two of the three trials compared abacavir plus AZT plus 3TC, vs. AZT plus 3TC only, looking for a statistically significant difference in markers of disease progression, especially viral load; this is an easy test for a drug already known to have a strong antiretroviral effect in humans. At least one of these trials will never produce much long-term comparison data, as volunteers already switched out of the two-drug arm. The third trial, abacavir plus AZT plus 3TC vs. indinavir (CrixivanŽ) plus AZT plus 3TC, is a good comparison test, but the results are not conclusive at this time.

There were other trials which failed to find a statistically significant result in favor of abacavir--for unexplained reasons.

No clinical-trial results are yet available for combining abacavir with nucleoside combinations besides AZT plus 3TC. This is unfortunate, as there is significant cross resistance between abacavir and AZT plus 3TC. Probably due to this cross-resistance, many patients with extensive prior use of AZT plus 3TC seemed to benefit little from adding abacavir (although prior short-term use of the two-drug combination--for example, for 12 or 16 weeks--did not seem to reduce abacavir's effectiveness, at least in the short-term data available so far). The panel's patient representative, Jeff Bloom, questioned whether approval now might do more harm than good, since a patient's first antiretroviral combination is so important, and potentially better combinations have not been studied. Mr. Bloom, who voted symbolically against approval (the community representative's vote does not count in the official total) was especially concerned that the only comparison with the current standard of care (the head-to-head comparison with the indinavir combination) had a 24% drop-out rate which was not explained. He also told AIDS Treatment News that he learned from other panelists that Glaxo is running tests with other abacavir combinations, but did not present these to the FDA as part of its accelerated-approval package.

A dementia trial surprisingly failed to show efficacy, and Glaxo did not ask for an indication for this use.

There were also technical issues. One of the trials had a trend toward worse CD4 response in the abacavir three-drug arm than in the two-drug control, and nobody knows why. Also, a major pediatric trial was designed years ago, with a goal of getting patients below a viral load of 10,000--which has become problematic since some of the children started with a low viral load already, leading to such a high percentage of "responders" to the two-drug control that it would be hard for any drug to prove superiority, diluting the trial's ability to get a positive result. (A lower viral-load endpoint, such as 400, could be substituted today; but to prevent good-news shopping, the FDA is reluctant to give much weight to an analysis which was not planned when the trial was designed and started. Also, it is very difficult to get the viral load below 400 in children with extensive prior antiretroviral treatment.)

The place of abacavir in HIV treatment today remains unclear. For treatment-naive patients, the drug works well with AZT plus 3TC to reduce viral load for at least 24 weeks. However, these patients have many options; and with the strong belief today that the first combination is one's best shot, they are likely to choose a combination about which more is known, at least until longer-term abacavir data becomes available. Meanwhile, those who are out of options and do need a new drug have probably already had extensive use of AZT plus 3TC; they might benefit from abacavir in another combination, but with little data to guide them, they will need to rely on intelligent guesswork.

Some Committee members were concerned that physicians less experienced with HIV might choose abacavir for its convenience--twice a day dosing with no food or water restrictions--without thinking through long-term strategies for the particular patient, or the risk of hypersensitivity reaction, especially with a physician inexperienced in treating HIV.

On the positive side, Glaxo received much credit for running a phase III pediatric trial, which the FDA strongly encouraged but did not require. It is widely agreed that data from the pediatric trial is relevant to all age groups. Also, a phase III pediatric study was necessary in this case, to learn if the hypersensitivity reaction is equally common in children, and has the same symptoms (it does seem to be the same as in adults). Our impression from a transcript of the hearing (we did not attend the meeting) is that due to the company's cooperation on the pediatric study, the FDA may have been less skeptical than it would otherwise have been, and more encouraging of wavering Committee members to vote for approval.

Over 11,000 people have already used abacavir. Due to this experience, there is substantial agreement in the AIDS community that this drug is important and necessary, and its approval was correct, even though the data available now is inadequate.

Abacavir is expected to be available in pharmacies in January. The price to wholesalers will be $3,540 annually, which is less than had been expected; ADAP (the AIDS Drug Assistance Program) will pay about $3,000 per year. (In early January we checked a retail price at a major pharmacy in San Francisco; the price was $369.09 for a bottle of 60 300 mg capsules, a 30-day supply--about $4429 per year. Hopefully mail-order or other pharmacies and their wholesalers and distributors will charge less than $889 ($4429 - $3540) to move 12 bottles of pills from the manufacturer to the patient.)

Abacavir has already been approved by California's ADAP (AIDS Drug Assistance Program), and approval is expected soon in most states.


For More Information

The most extensive information about abacavir is the transcript of the November 2 Advisory Committee hearing, available on the FDA Web site. Note that this transcript has not been edited and has transcription errors.

The transcript on the FDA Web site is hard to find. Go to http://www.fda.gov; then select Dockets, then select FDA Advisory Committees. Under 1998, select Center for Drug Evaluation and Research (CDER); then select Antiviral Drugs Advisory Committee. The transcripts are listed by date, so look for 11/2/98; then you can download either an rtf or a pdf file. Usually the rtf file is easier to download and use; the pdf file is over 40 times as large because it provides images of the pages. But the pdf file preserves the original pagination, and includes an automatic index listing every page and line where words of interest appear.