AIDS TREATMENT NEWS Issue #236, December 1, 1995
John S. James

More information about a major trial of DOXIL for KS will be presented at the American Society of Hematology meeting on December 5. Of 118 patients in this trial with extensive, progressive KS (and median CD4 count of 13.5) who were randomized to DOXIL, 43.2% had a partial response, and 55.9% were stable; only one of the 118 had progressive disease. Of the 110 patients randomized to ABV, 24.5% had a partial response, 67.3% were stable, 6 patients progressed, and 3 were not evaluable. This trial tested DOXIL as first-line treatment, not after other chemotherapy had failed.

Information on another study of DOXIL for treating breast cancer will be given December 12 at a meeting of the San Antonio Breast Cancer Symposium.

The most serious danger of ordinary doxorubicin chemotherapy is toxicity to the heart, which occurs when a large cumulative dose is used. While DOXIL might be less toxic, there is too little experience with high cumulative doses to establish how much can be tolerated. Therefore, the same guidelines used for ordinary doxorubicin are being used for DOXIL -- that irreversible cardiac toxicity may occur when the total cumulative dose approaches 550 mg/m(2) (or less if patients have had certain other systemic chemotherapies, or have certain risk factors); physicians must use special monitoring if they treat beyond this level. DOXIL can also cause other toxicities, including neutropenia, which must be carefully managed by the physician.

Toxicity information is based on experience in 753 patients treated with DOXIL, in four trials. Because these patients had advanced HIV disease (median CD4 count 21, with half having a CD4 count under 50), and because they were also using many other drugs, it was often difficult to know whether particular adverse effects were due to DOXIL. The median cumulative dose was 120 mg/m(2), with only 3% of the patients receiving over 450 mg/m(2).

DOXIL must be given only by intravenous infusion.

The developer of DOXIL is Sequus Pharmaceuticals, Inc. (formerly Liposome Technology, Inc.), of Menlo Park, California.

Background: Liposomes

Liposomes are microscopic globules of fat which can be used to carry certain drugs, achieving a different targeting of the therapy than if the free drug is used. DOXIL, for example, has a half-life in the blood of about 50 hours, compared to about 10 minutes for ordinary doxorubicin. DOXIL tends to concentrate in KS lesions and in cancer tumors more than ordinary doxorubicin; why it does this is unknown, but it may be because lesions and tumors tend to have poor blood vessels. According to this theory, DOXIL remains in the bloodstream for a long time, allowing the liposomes to leak into the lesions.

Sequus Pharmaceuticals uses a special proprietary technology, called Stealth(R) liposomes, in which the liposomes are coated with a chemical to help prevent them from being recognized as a foreign particle in the body and eliminated.

Comments

* AIDSLINE currently has 12 abstracts which mention DOXIL. The evaluations in these abstracts are consistently positive.

* We have heard good anecdotal reports on DOXIL for several years; this drug seems to be well accepted by physicians and patients, although it is still chemotherapy with serious side effects. But anecdotal information is unreliable, because good news often travels farther than mediocre or bad news, leading to the repeated cycles of "miracle drug" reports followed by disappointment.

* There has been confusion about the name of the product. Originally the name was DOXIL, while the drug was in early development in the United States. But this name is also used for other purposes in other countries, and to avoid lawsuits, the name was changed to DOX-SL. But then the FDA became concerned that the "SL" in the name could lead to mistakes in which medical personnel thought the drug was for sublingual use (under the tongue) -- mistakes which would result in injury. Therefore the name is now DOXIL within the United States, and will be DOX-SL in other countries.

* Another drug which is a potential competitor to DOXIL is DaunoXome(R) (liposomal daunorubicin citrate), being developed by NeXstar Pharmaceuticals, Inc. in Boulder, Colorado. DaunoXome has received an "approvable" letter from the FDA as first-line therapy for advanced, HIV-associated KS, but has not yet been finally approved for marketing.

* Why is DOXIL only approved for patients who have failed or are intolerant to other chemotherapy -- when all the published information is on first-line use, and DaunoXome will be approved for such use? Sequus applied for the failure-or-intolerant indication, apparently because it could get an approval faster. It believes that third-party payers will reimburse first-line use, in view of the strength of the supporting data. And now that there are more data, the company will go back to the FDA to update the indication to include first-line use.

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