Delavirdine (Rescriptor«) Approved

On April 4 the FDA approved delavirdine (brand name Rescriptor) "for the treatment of HIV-1 infection in combination with appropriate antiretroviral agents when therapy is warranted." This drug, developed by Pharmacia & Upjohn of Kalamazoo, Michigan, is the second non-nucleoside reverse transcriptase inhibitor approved (the first was nevirapine -- Viramune(R) -- approved June 24, 1996).

Delavirdine must be used in antiretroviral combinations, because when it was tried alone, the virus developed 50-fold to 500-fold reduced sensitivity within eight weeks, in 14 of the 15 patients in that trial. HIV which is resistant to delavirdine is likely to be cross resistant to nevirapine and other non-nucleoside RT inhibitors; however, cross resistance is unlikely with protease inhibitors, or with nucleoside analog reverse transcriptase inhibitors (AZT, ddI, etc.).

The main side effect of delavirdine is skin rash. Rash attributed to the drug has occurred in 18% of patients in phase II and III controlled trials, and has been severe enough to cause permanent discontinuation of delavirdine treatment in 4.3%.

Certain drugs must not be combined with delavirdine; others, including some protease inhibitors, probably require dose adjustments. For more information, see the package insert.

Approval History

The FDA's Antiviral Drugs Advisory Committee, meeting in November 1996, came to a tie vote on whether delavirdine should be approved -- four in favor of accelerated approval, and four against. The reason for the ambivalence is the weakness of the data from those clinical trials which have been completed so far. On the other hand, there are suggestions that this drug might be important for some individuals, especially in combinations not yet tested in formal research. The trials which have been run were designed long ago, and did not study the combinations which would be chosen today. Three trials are reported in the FDA-approved package insert:

(1) In a one-year comparison of delavirdine plus AZT vs. AZT alone, the combination was significantly better than AZT monotherapy in reducing viral load. (But this information is less relevant today than when the trial was designed, since the comparison -- AZT monotherapy -- is inadequate.)

(2) Another one-year trial compared delavirdine plus ddI vs. ddI alone. This trial found no difference in viral load, CD4 count, or clinical disease progression, except for a trend toward improvement in these blood tests only during the first few weeks.

(3) Another study showed a trend toward lower viral load with the triple combination of delavirdine plus AZT plus ddI, vs. AZT plus ddI or other combinations tested.

What is likely now is that physicians will try delavirdine in many different combinations, developing clinical experience. Meanwhile, Pharmacia & Upjohn will conduct new trials (required as a condition for approval) which hopefully will produce some definitive information on how best to use the drug.

Delavirdine will be priced at a "wholesale acquisition cost" of $2,250 annually, considered fairly low relative to other AIDS drugs. Persons now receiving delavirdine in the expanded-access program will be given enough to have a 90-day supply to allow them time to arrange for reimbursement.

For More Information

Persons needing help getting the drug paid for can call the company's reimbursement assistance line, 800/711-0807, 9 a.m. to 6 p.m. Eastern time Monday through Friday. Physicians or patients with clinical questions about the drug can call 800/432-4702, 8 a.m. to 8 p.m. Eastern time Monday through Friday.

Comments

(1) An observational report from the expanded-access program indicated that there might have been an average of more than a one-log drop in viral load from adding delavirdine to failed combination regimens containing indinavir (Crixivan(R)) -- possibly because delavirdine seems to increase blood levels of indinavir, and might help maintain trough levels. (Note: The labeling suggests a reduction of the indinavir dose if the drugs are combined.) More study is needed on possible benefits of combining these drugs.

(2) We urgently need research on measuring blood levels in order to individualize doses of drugs such as protease inhibitors, to reduce the likelihood of drug failure due to individual variations in absorption.

(3) Clinical endpoint trials: There is debate now on whether to change the FDA approval process to accept sustained reduction in viral load as proof of benefit, without also requiring "clinical endpoint" trials (which need volunteers to die or become seriously ill in a comparison group, in order to prove that a drug helped). Delavirdine will probably have to go through such trials, under current regulations. This is unfortunate, since the information really needed is how to use the drug to help reduce viral load to undetectable levels and keep it there -- not to re-demonstrate that viral load reduction is beneficial. We need studies on how to combine antiretrovirals to reduce the likelihood of drug failure -- and body-count trials are poorly suited for this purpose.

The central tragedy of clinical-endpoint trials is that they mis-focus clinical research away from critical issues, in favor of unwieldy and ethically problematic trials addressing life-and-death issues which are philosophically compelling, but medically marginal in AIDS science and medicine today.