The Growing Debate over FDA Reform
By Derek Link
Early in the AIDS crisis, when the epidemic's disastrous scope could not yet be imagined, AIDS activists pressed the Food and Drug Administration (FDA), the federal agency that regulates the testing, sale and promotion of drugs, for a faster and more humane response to this public health emergency. On October 11, 1988, thousands of AIDS activists from across the nation descended on the FDA's headquarters in Rockville, Maryland. They demanded faster approval of new AIDS therapies and focused public attention on the glacial pace of this federal bureaucracy. Over the last eight years, AIDS activists have continued to scrutinize the FDA's AIDS activities, serving as consultants on FDA advisory committees, issuing critical reports on its operations and winning many important victories along the way.
AIDS drugs are now approved faster, and access to them granted earlier, than anyone thought possible just a few years ago. Because of pressure and creative ideas from AIDS activists, the FDA pioneered accelerated approval and expanded access programs. One need only look at the recent past for a vivid example of the success of AIDS activists' efforts. Saquinavir, the first of the new generation of protease inhibitor drugs, was approved in a record three months, the fastest AIDS drug approval ever. All is surely not perfect at the FDA, but the agency has made substantial progress. AIDS activists still have a full regulatory agenda covering such issues as how best to use the accelerated approval process while insuring that sufficient information on drugs' actual potential is generated through post-marketing studies.
After the Republican landslide in the 1994 Congressional elections, the new Congress immediately took up the cause of FDA reform as one of its highest priorities. Accusing the FDA of murderous delays and inept bureaucracy, the new Congress adopted much of the confrontational language of AIDS activists in its debates on the FDA. The similarities between AIDS activists and Congressional Republicans end with the rhetoric, however. AIDS activists have helped to organize a national campaign in support of responsive and efficient drug regulation, but in opposition to ideological, political attacks on our nation's public health safety net. Congressional "FDA reform" could halt medical research and innovation, harm people with serious and life-threatening disease, and undermine the nation's health.
A Debate About the Role of Government
Reform of the FDA, AIDS activists recognized early, was a problem of policy, management, resources and administration. The FDA implemented faster drug approvals and expanded access programs without Congress ever passing a law. This is because the organization, policies and procedures of the FDA are not established by Federal law. With wide discretion over drug regulation, the FDA could approve drugs faster by implementing internal policy changes. This flexibility is perhaps its greatest asset; it gives the agency the ability to respond rapidly and in a non-political manner when public health emergencies, like AIDS, arise.
Instead of focusing on the management problems at the FDA, the Republican Congress has set its sites on the Food, Drug and Cosmetic (FDC) Act itself. The FDC Act gives the federal government the duty to insure that drugs, biological products and medical devices are safe and effective for the treatment of specific health conditions and evidence of that safety and efficacy is accurately represented to the American people. By seeking to amend fundamental government authority over drug regulation, the Congress has opened a debate not on the problems at the FDA but instead on the role of the federal government in medicine, pharmaceuticals and clinical research. The FDA can sometimes be frighteningly bureaucratic, but the FDC Act itself is not an obstacle for drug development. The Act fosters an environment in which medical innovation grows out of solid clinical research. People with AIDS, as well as other life-threatening diseases, need this research more than anyone
else to point the way to effective treatments.
The FDA regulates the core elements of life, totaling a quarter of all consumer spending. Any change in the government's authority over such a large segment of the economy brings out armies of industry lobbyists, each promoting its own self-interest. Encouraged by the Republican landslide, FDA-regulated industries and their advocates initiated a major lobbying and public relations campaign within a month of the 1994 election.
Industry and Politics in Congress
HIMA (the medical device manufacturers group), BIO (the biotech industry group) and PhRMA (the drug industry group) are the main industry groups pressing for substantial changes to the Food, Drug and Cosmetic Act. BIO's president, Carl Feldbaum, told the National Journal, "We're pushing [FDA reform] very hard. We have a lot of irons in the fire with the FDA."
Each of these groups has released FDA reform proposals, and has dispatched their lobbyists to the Capitol. "I think they'd like to eviscerate the FDA, but if they can't do that, they'd like to intimidate the FDA," Henry Waxman, a senior Democrat on the House Commerce committee and a leading consumer protectionist, told the National Journal.
Right-wing political organizations, with heavy funding from regulated industries, have gone on the offensive too. The Washington Legal Foundation (WLF), the Progress and Freedom Foundation and Citizens for a Sound Economy, are the three most prominent right-wing advocacy groups working on FDA reform legislation.
The WLF has run several full page ads in The New York Times and Washington Post harshly criticizing the FDA with the tag line, "The Problem with Health Care in America is the FDA." The WLF furthermore has filed several lawsuits over FDA regulations, mostly over the type of marketing strategies pharmaceutical companies can pursue. The Foundation argues that limiting the claims companies can make to the applications approved by the FDA is a violation of the First Amendment's protection of free speech.
The President of the WLF, Alan Slobodin, temporarily stepped down from his post to become a senior staff member of the House Commerce Committee, which has authority over the FDA and will draft reform legislation in the House. The Lilly Endowment, a foundation whose funds come from Indianapolis-based drug maker Eli Lilly, gave the WLF $150,000, making it one of the organization's largest financial backers.
The Progress and Freedom Foundation is perhaps the biggest player among the advocacy groups. The Foundation is closely associated with House Speaker Newt Gingrich. The Foundation is run by close Gingrich supporter Jeffrey Eisenach, and handles many of the Speaker's political activities, including organizing Progress Report, Gingrich's talk show on National Empowerment Television. Major industry contributors to the Foundation have included Burroughs Wellcome, Glaxo, Genzyme, Searle, Johnson & Johnson, Direct Access Diagnostics (now a Johnson & Johnson subsidiary), Health South Corporation, Amgen and Solvay. "This was an organization that looked like it was going to have some influence, and we wanted to have some influence with them," Lisa Raines, chief Washington lobbyist for Genzyme, has stated.
Speaker Gingrich has already interceded on behalf of some of these Foundation contributors. Last summer, Gingrich urged the FDA to move faster to approve Luvox, a Solvay drug for obsessive-compulsive disorders. Gingrich also has urged the FDA to move faster in approving an HIV home test kit manufactured by Direct Access Diagnostics. The House Ethics Committee is investigating Gingrich's relationship to Direct Access Diagnostics, as part of its overall ethics investigation of the Speaker.
The Tobacco Industry's Shadowy Role
Last year, the FDA proposed sweeping new regulations which would substantially change the way cigarettes are sold in the United States -- limiting advertising and restricting sales to minors. The new FDA regulations could have a devastating impact on tobacco industry profits -- almost all smokers start when they are teenagers.
The tobacco industry has responded with a full-scale assault on the FDA and the FDC Act. On January 2, it submitted to the FDA a 2,000 page document with 45,000 pages of supporting documents challenging its authority to regulate cigarettes.
The industry also launched an aggressive campaign contribution drive to the Republican party. In the first half of 1995, the tobacco industry pumped $1.5 million into Republican party coffers, over five times the amount from the same period in 1994, and a record level contribution of so-called "soft money" to a political party. In addition the tobacco industry has sharply increased donations to individual Republican Congressmen. Most tellingly, Thomas Bliley (R-VA), Chair of the House Commerce Committee -- the committee responsible for FDA reform legislation in the House -- received $126,476 from the tobacco industry, more than any other member of Congress.
Richard Burr (R-NC), who has received $11,350 from tobacco interests and also is a Commerce Committee member, wrote in Roll Call "I cannot understand why the FDA, which cannot efficiently perform its core mission, should be rewarded with historic jurisdiction increases [over the tobacco industry]." Although the tobacco industry has been a driving force that keeps FDA reform high on the Republican agenda, it has not been publicly identified with the reform effort. "A veteran tobacco industry hand said that Bliley has asked companies to lay low for their own benefit and his and that he doesn't want to be perceived as beating the FDA over the head because of tobacco. That message has come through loud and clear," reported the National Journal.
Preserving Patients' Rights
In response to the industry-driven assault on the FDA, patient advocacy groups have joined together in an historic coalition. The Patients' Coalition, which formed last summer, includes over 80 leading national organizations from prominent AIDS groups, such as the American Foundation for AIDS Research and GMHC, to the American Cancer Society, the National Organization for Rare Disorders and the National Health Council, which represent the largest voluntary health organizations in the country.
The coalition wrote a set of FDA reform principles informed by the common experiences of all patients with serious and life-threatening diseases. It also released a policy white paper on the real problems at the FDA. One much discussed proposal is a "sunshine law" that would permit the FDA to publicly discuss its private interactions with drug developers. Currently, companies frequently complain of FDA delays in processing their drug approval applications while the FDA refuses any comment on the grounds that such applications constitute proprietary information.
The coalition is working together on Capitol Hill and in the media, trying to ensure that FDA reform legislation serves patients' true interests. Such diverse patient groups have never worked together in such an intensive way. They have come together because all patients need federal regulations that encourage medical research and innovation while continuing to ensure that drugs are safe and effective.
FDA reform legislation has taken much longer to move through the Congress than many had predicted. Numerous hearings have been held on FDA reform issues in both the House and Senate during the first year of the 104th Congress. But legislation has been very slow to emerge. The Republicans now realize that FDA reform is more complicated than they first imagined, placing core values into question, and opening a Pandora's box of competing interests.
In both the House and Senate, there is no consensus on FDA reform. Nancy Kassebaum (R-KS), chairwoman of the Senate Labor Committee -- which has jurisdiction over the FDA in the Senate -- introduced a comprehensive ("Omnibus") FDA reform bill. Sen. Kassebaum's bill has no co-sponsors, indicating that both industry advocates and consumer protectionists in the Senate are dissatisfied with its provisions. The House Commerce Committee has had an even more difficult time with FDA reform legislation. The House committee has altogether given up drafting a single, "omnibus" FDA bill. Instead the Commerce Committee now plans many individual bills on discrete areas of the FDA's authority. The lack of consensus means the course and outcome of the FDA reform legislation is unpredictable and volatile. Individual bills or amendments to bills could be introduced that radically change the federal government's authority over drug development
The Congress now anticipates taking up FDA reform early this year. Sen. Kassebaum plans hearings on her bill over the next few weeks, and the House could start introducing bills as well. It is still unclear, though, if the Republicans can move such major legislation through while budget debates and election campaigns heat up. In any event, if a bill is eventually passed by Congress, it may bear little resemblance to the proposals being considered now.
The Kassebaum Bill
As the first introduced, Sen. Kassebaum's FDA reform bill (S.1477) is worth a close look. Written primarily by senior staffer Jane Williams, the bill is considered a moderate proposal. Sen. Kassebaum's staff have been open to the concerns and views of the Patients' Coalition. When a draft of the proposal was circulated this fall, the coalition sent a detailed analysis, some of which was incorporated into the final version.
The bill does reject many of the most radical FDA reform proposals, and, as Ms. Williams said to a meeting of the coalition, "it's the best you're going to get." Be that as it may, the bill as it now stands would harm patients with serious and life-threatening diseases by undermining incentives for medical research and innovation.
The Kassebaum bill establishes that only one efficacy study of a new drug is necessary to meet the requirement of safety and efficacy. The FDC Act presently does not define how many studies are required, but the FDA has interpreted the law to mean that two are required. On a scientific level, two studies greatly increase the likelihood of making the correct interpretation of data, especially when results are ambiguous or marginal. The FDA in any case already uses a one efficacy study requirement for new drugs if the study is a large multi-center one, or the drug in question is a high priority or the results are unambiguous. Without the FDA's discretion over the number of required studies in drug development, less clinical research will be performed, reducing the scientific foundation for new therapies.
The bill sets strict approval schedules, requiring FDA action within 120 days on New Drug Applications. Strict time-lines sound wonderful, but they in fact can slow access to drugs for patients with serious and life-threatening diseases. If the FDA must approve everything rapidly, then resources will be pulled away from high priority approvals, like break-through drugs for serious diseases, to lower priority approvals, like fourth generation sleeping pills. The FDA has inadequate resources for every drug to be a high priority. The FDA must devote more resources and staff time to reviewing drugs for the sickest patients. This proposal also fails to acknowledge the FDA's progress. Saquinavir, the first of the new generation protease inhibitor drugs, was approved in 90 days, for example.
The bill also proposes increasing the authority of the FDA's advisory committees. The FDA maintains a host of independent advisory committees that review research data and make recommendations to the agency. The decisions of FDA advisory committees are not binding on the agency. Sen. Kassebaum's bill enhances the authority of the advisory committees, making their decisions binding on the FDA. The bill would also mandate that representatives of regulated industries be included as members of the committees, a move which is presently prohibited under conflict-of-interest regulations.
The Kassebaum bill ignores ample evidence of the mediocrity and ineffectiveness of advisory committees. A 1992 study of the FDA advisory committees by the Institute of Medicine found multiple problems with them. Well-qualified people often do not serve on FDA advisory committees because of long time commitments (members serve two year terms) and low pay for professionals ($150 a day). Sen. Kassebaum's bill does nothing to fix the recruitment problems for advisory committees, and instead aggravates it by extending service to three years. Breakthrough drugs should be evaluated by skilled FDA scientists and professionals, not mediocre, part-time committee members.
The bill's most radical proposal is to create a "presumption of approvability" for some new drugs. If a drug were approved in the United Kingdom, it would have an automatic "presumption of approvability" in the United States. The FDA would have thirty days to block the automatic approval of the drug in this country. This proposal ignores some key facts. The United Kingdom has a slower drug approval process than the United States. Many AIDS drugs -- d4T, 3TC and saquinavir among them -- are not yet approved in the U.K. Every AIDS drug has been approved first in the U.S.
The presumption that the U.K. is faster is simply wrong, and it abrogates the federal government's fundamental responsibility over the safety and efficacy of drugs marketed in this country. It also ignores that the U.S. has far fewer drugs withdrawn from the market for safety reasons than other countries -- just the classic case of thalidomide.
The bill also would allow drug companies to promote and advertise so-called "off-label" uses of their products. Promotion of off-label uses refers to advertising health claims for a product that are not approved by the FDA but that are considered part of standard medical practice. The bill seeks to solve a real problem. Many drugs -- especially for cancer -- are used in ways that are not FDA-approved. Many drugs have multiple uses, but some are approved for just a single specific purpose. While many off-label uses of drugs are standard medical practice, many others are ineffective or harmful. Sen. Kassebaum's bill would allow marketing of any "medically accepted" use of a product, without saying what constitutes "medically accepted." The bill cannot distinguish between legitimate and harmful off-label uses.
Advocates for rare diseases are especially concerned about off-label promotion. They fear Sen. Kassebaum's bill will undermine the incentives for research into rare diseases created by the Orphan Drug Act. The Orphan Drug Act establishes financial, tax and patent incentives for industry to research drugs for rare diseases.
Many of the drugs used to treat rare diseases are already approved for other, more common maladies. Say two companies make the same product, but only one company conducts research into the product's use in a rare disease. The Orphan Drug Act authorizes the government to grant the company that did the research an exclusive right to market the drug for this disease. If adopted, Sen. Kassebaum's bill may well undermine this exclusivity because any manufacturer could promote all the "medically accepted" uses of its drugs, even if the company did not conduct the research on the orphan indication.
Patient advocates agree that their goal for off-label drugs should be to encourage industry and the FDA to work together to submit data on off-label uses. Applications for secondary indications should be easier and cheaper to file.
Preserving the FDC Act
More broadly, the Patients' Coalition sees the FDC Act as critical for sustaining the unprecedented era of medical research and progress, an era in which American science has been preeminent. The FDC is vital to the nation's, and indeed the world's, health because its high standards help protect the public against new therapeutic products backed only by dubious or fraudulent data.
Congressional meddling with the Act may well end up harming patients with serious diseases by reducing the amount of medical information available. Questionable, ill-advised treatment would become more likely in such circumstances.
Many AIDS activists have pressed for reform of the FDA, but not for changes to the Food, Drug and Cosmetic Act. These AIDS activists, along with their allies among patient advocacy groups, are continuing to call for an efficient and responsible FDA. At the same time, this coalition considers paramount the preservation of the federal government's crucial role in drug development and marketing.
Finding a Place
by Theo Smart
Gilead Sciences has asked the Food and Drug Administration to approve intravenous cidofovir (brand name: Vistide) as a therapy for CMV retinitis. Cidofovir's primary advantage is that it need only be infused into patients on a weekly or biweekly basis compared to once or twice daily for current medications (ganciclovir and foscarnet). This dosing schedule furthermore removes the need for the in-dwelling catheter used with ganciclovir and foscarnet. If Gilead's application is accepted without modification, cidofovir would be on a par with the two older drugs and could be administered either as initial treatment or as a salvage therapy.
The case for the new drug application rests on data from two company-sponsored studies. One compares immediate treatment with cidofovir to deferred treatment. The other is a dose comparison study.
The first study enrolled 48 patients with CMV retinitis and no systemic CMV disease. Retinitis progression was defined as advancement of the edge of an existing lesion by 750 microns or the occurrence of a new lesion 750 microns or larger in diameter. Most of those randomized to deferred therapy experienced progression of their retinitis after a median 22 days, and were then crossed over to treatment. Those who received cidofovir immediately and who remained on treatment throughout the trial did not progress for a median of 120 days.
Many patients discontinued the study prior to progression and were not counted in calculating progression rates. According to Gilead's Vice President of Clinical Research, Howard Jaffe, M.D., though, even if those who discontinued were assumed to have progressed, the median time to progression would have been approximately 70 days at worst. The median time to progression had not yet been reached in the sixteen patients crossed-over to treatment from the deferred therapy arm, but, again, many patients have discontinued therapy.
The dose comparison study includes 100 people with relapsing CMV retinitis or intolerance to standard therapies. Although an interim analysis of data from the first sixty patients last April did not at that time show a statistically significant difference between the two doses (three mg/kg of body weight vs. five mg/kg), the median time to first progression was 49 days on the three mg/kg arm vs. 115 days on the five mg/kg arm. Complete data from this study should be ready sometime in February -- if there is a statistically significant difference between the doses, the case for approval of cidofovir will be stronger.
One other study and a treatment IND (expanded access) program provide additional data for the cidofovir application. The SOCA (Studies of the Ocular Complications of AIDS) network is running a three arm trial in 90 volunteers comparing two different regimens of cidofovir and deferred treatment. It is unlikely that any efficacy data from this study will be ready by the time the FDA reviews Gilead's application, but some safety data will be available. Adverse events also are being actively monitored in the treatment IND program as physicians must submit a report with every two doses of drug. At press time, 146 patients have re istered in the protocol. (For TIND information, call 415/573-4700.)
Toxicity and Drug Interactions
All three systemic intravenous CMV therapies are toxic. Like foscarnet, cidofovir can cause irreparable, life-threatening kidney damage. A few years ago, it appeared too dangerous to be useful as a systemic therapy until researchers learned that the toxicity could be attenuated with hydration therapy and four grams of probenecid on the day of the infusion. (Probenecid helps the kidneys excrete cidofovir safely. Researchers also reduced the cidofovir regimen.) Even with probenecid and hydration, the drug at standard dose should not be administered to patients with proteinuria (high levels of protein in the urine) or elevated serum creatinine levels, both indications of kidney impairment. Dose reduction studies are underway in patients with compromised kidney function.
Probenecid produces its own side effects, including transient (lasting one to two days) fevers, nausea and rashes in about fifty percent of the patients in the Gilead studies. A few patients can have life-threatening allergic reactions. In the dose-ranging study, at least two patients required resuscitation and hospitalization within hours of treatment. One had a major drop in blood pressure and the other had a fever of 104 F, low blood pressure and severe shortness of breath. Both patients had a history of reactions to sulfa drugs (to which probenecid is structurally related). Many investigators have been giving antihistamines along with the probenecid. Discontinuing pro-benecid or lessening the dose is not an option since cidofovir's kidney toxicity is so severe.
There is little drug interaction data available for cidofovir. There seems to be no interaction with AZT. Interaction studies with ddI and Bactrim will begin soon, and other studies are being designed.
Comparison with Other CMV Drugs
Some in the community are concerned that if the FDA approves cidofovir, people may opt to use this drug before the better characterized ganciclovir or foscarnet because the dosing regimen is so much easier on patients than the daily regimens and indwelling catheters of the two older intravenous therapies. But the lack of studies directly comparing cidofovir to ganciclovir or foscarnet makes it difficult to determine which drug should be used when.
The picture is further complicated by the new availability of oral ganciclovir and the ganciclovir intraocular implants. These two approaches in combination may represent another attractive option. The implant would provide the advantages of localized therapy against CMV retinitis in the treated eye while the oral drug may provide a cover against breakthrough infections in the uninvolved eye or elsewhere in the body. Hard data on this combination will be available from an ongoing trial comparing the ganciclovir implant-oral ganciclovir combination to standard intravenous regimens. In the future, intraocular injections of cidofovir promises to provide another effective localized therapy against CMV retinitis. (For a review of the many new CMV treatments, see the July-August, 1995 Treatment Issues.)
The lack of comparative data is not an argument against FDA approval of cidofovir. Cidofovir appears to show clear clinical benefit in people who can tolerate it. But unless intravenous cidofovir is shown to be superior to other CMV therapies, or until there is more clinical experience with the drug most clinicians will relegate it to second or third CMV therapy, to be used when other approaches are failing.
FDA to Review Two NNRTIs
Boehringer Ingelheim and the newly combined entity Pharmacia & Upjohn have announced that they will soon file New Drug Applications with the FDA this spring for their respective experimental antiretroviral drugs, nevirapine and delavirdine. Both drugs are nonnucleoside reverse transcriptase inhibitors (NNRTIs) that block the action of HIV's reverse transcriptase enzyme (see the September, 1995 Treatment Issues, pages 8-9). Expanded access programs for both drugs are also in the works.
As Treatment Issues
went to press, Upjohn announced interim results from two large clinical studies of delavirdine. The data form one trial indicate that the combination of delavirdine and AZT provides more sustained responses in CD4 cell counts and viral load than either drug alone. In another trial, involving participants with more advanced disease, delavirdine plus ddI improved on the response to ddI alone only for several months. The company is now transforming its AZT plus delavirdine trial to include an AZT/3TC/delavirdine arm. (Call 800/432-4702.)
Upjohn believes its data show that even modest 70 percent (0.5 log) reductions in HIV levels achieved after eight weeks of treatment are predictive of substantially reduced disease progression for at least a year. This observation underlines the importance of mild enhancements delavirdine brings to existing nucleoside analog therapy. It provides support as well for choosing treatments on the basis of viral load response.
The company plans to initiate an expanded access program for delavirdine that will enroll up to 800 persons per month starting in March. For more information on the program, call 800/779-0070.
Boehringer Ingelheim has announced a 2,000 person clinical endpoint study of nevirapine for people with CD4 counts of 200 or below. Participants will be randomized to nevirapine or placebo. All will receive 3TC and may take whatever other nucleoside analogs they wish in combination with 3TC. For enrollment information call 617/487-9000.
The company will be meeting with community representatives over the next few weeks to work out the details for the expanded access program.
New Saquinavir Formulation
by Gabriel Torres, M.D.
Enters Clinical Trials
Hoffmann La Roche, makers of saquinavir, the first protease inhibitor to receive FDA approval for treatment of HIV infection, has just launched a large trial to test a new, more promising formulation of the drug.
The old formulation, a hard gelatin capsule with a very low bioavailability (four percent), has been used in six previous clinical trials. The drug has displayed an antiviral effect that is low in comparison to other, soon-to-be-released protease inhibitors -- at least at the standard 600 mg thrice daily dosage. A study of high doses of saquinavir (3,600 and 7,200 mg per day) done at Stanford University did show a substantial improvement in the effect on HIV levels and CD4 count.
The new trial will try the soft gelatin capsule at a dose of 1,200 mg taken three times daily, which is predicted to provide exposures to the drug similar to 7,200 mg/day with the hard gelatin capsule. The study will be double-blind and placebo-controlled (in a two to one ratio of people on saquinavir to those on placebo) for the first sixteen weeks. Other concomitant protease inhibitors are excluded, but participants may take nucleoside analogue therapies as prescribed by their physicians. They will be required to maintain a constant anti-HIV regimen for these sixteen weeks.
After the first sixteen weeks, the trial participants will be given the option of open label therapy with the soft gelatin capsule at the 1,200 mg thrice daily dose.
Six hundred volunteers are expected to be enrolled at 35 to 40 centers in the United States. They will be stratified into three groups by CD4 cell count (0 to 50, 51 to 300 and 301 to 500). One quarter of the trial group must have plasma HIV levels of greater than 20,000 copies/ml. The primary endpoints of the study will be plasma viral load by quantitative PCR and an increase in CD4 cell count. For the location of trials sites around the country, call 800/TRIALS-A.
by Theo Smart
and Expanded Trials
NTZ for Cryptosporidiosis
Unimed Pharmaceuticals has announced FDA approval of a compassionate use program providing very limited access to nitazoxanide (NTZ), an anti-crypto- sporidial agent currently in clinical trials (see Treatment Issues, September, 1995, page 14). The company is also opening a site in San Francisco at the Kaiser HIV Research Group (investigator: W.J. Fessel, M.D.) to speed the ongoing American phase II studies of the drug. Meanwhile, the Mexican licensee of the drug has initiated phase III clinical trials in that country for people with AIDS-related cryptosporidiosis. Data from this study should contribute to the eventual application for FDA approval of NTZ.
The compassionate use protocol is currently limited to 30 patients until the FDA is provided with additional safety data, but the size is expected to increase over time. Its purpose is to provide access to people with cryptosporidiosis who do not qualify for or cannot enroll in the ongoing study which excludes those who have other concurrent gastrointestinal infections such as microsporidiosis. Doctors wishing to enroll their patients in this protocol can call 800/864-6330. Twenty patients had already enrolled in this program as of early January.
AmBisome for Mycoses
An ongoing double blind study of AmBisome, the Fujisawa USA's liposome-encapsulated version of amphotericin B, is now open to people with relapsing cryptococcal meningitis (CM) that remains sensitive to fluconazole (which is used as maintenance therapy).
Previously, participation in the study had been restricted to people with primary CM. The study compares AmBisome to standard amphotericin treatment and currently has 50 patients enrolled. For information on trial sites, call the government's national clearinghouse at 800/TRIALS-A.
Liposomal versions of amphotericin are thought to be considerably safer than the unprocessed product (see Treatment Issues, April, 1994, pages 6, 9-12) A number of open-label studies have reported positive responses with AmBisome in people with CM who have failed amphotericin treatment.
Fujisawa also has opened a general compassionate use program to provide AmBisome to anyone with systemic fungal infections who is intolerant to amphotericin or for whom amphotericin would be contraindicated. The protocol is also open to patients with candidiasis resistant to the triazole antifungal medications such as fluconazole. (Maintenance therapy to prevent recurrence may require once or twice weekly infusions of AmBisome) For more information, call Fujisawa's Medical Information Line at 800/727-7003.
The First Integrase Inhibitor
by Theo Smart
The first clinical trials of an HIV "integrase inhibitor," Aronex Pharmaceuticals' AR-177, are in progress at San Francisco General Hospital. Like reverse transcriptase and protease, integrase is an essential HIV enzyme. It binds to HIV DNA, which is created by the reverse transcriptase enzyme, and integrates that DNA into the host cell's chromosomes. AR-177 does not inhibit this integrating activity (compounds that do so are years away) but rather appears to keep the enzyme from binding to the newly processed DNA in the first place.
The drug is an oligonucleotide (string of nucleotides -- the building blocks of DNA). Most oligonucleotides cannot be administered systemically, because they breakdown and rapidly pass from the body. But AR-177 is unique -- formed by seventeen nucleotides (mostly guanine), it folds upon itself to form a stable structure less prone to destruction in the blood. In animal studies, the compound was not easily metabolized and was excreted very slowly. Some drug remained in the animals' bodies a week after a single dose.
Work on this compound began because similar oligonucleotides were found to bind to the V3 loop on the HIV envelope protein gp120, potentially interfering with entry of the virus into cells. But after adding AR-177 and HIV to cell cultures with HIV, researchers were still able to detect viral DNA in the cells. Nevertheless, the drug blocked viral replication, and the HIV DNA within the cells disappeared after several hours.
This observation suggested that HIV was getting into cells, but that AR-177 was keeping the viral DNA from being integrated into the cell's DNA. Subsequent studies showed that the drug blocked binding to and early processing of viral DNA by integrase.
The phase I single dose escalation study of AR-177, directed by James Kahn, M.D, began in October. The study has reached its second dose level (1.5 mg/kg of body weight) and has already achieved blood levels that correlate with activity in laboratory cell cultures. Higher doses will be evaluated. A subsequent study evaluating the pharmacokinetics, safety and antiviral effect of multiple dosing will begin in the second quarter of this year.
At present, AR-177 is an injectable drug. The company hopes that the compound's half-life will be long enough to allow for infrequent dosing. Meanwhile, preliminary data in rodents show that the drug does have some oral bioavailability. The company is now studying an oral formulation in primates.
Testosterone for Wasting
Unimed Pharmaceuticals is starting a clinical trial of its new, rub-on testosterone gel in twenty HIV-positive men with wasting associated with low testosterone levels (hypogonadism). The ten-week dose comparison study will begin at Beth Israel Hospital in Boston, and an additional site may be added in San Francisco or Los Angeles. Call Richard Spark, M.D., at 617/667-2471 if interested.
Two testosterone patches -- Androderm, marketed by Smith-Kline Beecham, and Testoderm, from Alza -- already are approved for use in hypogonadal wasting. Testoderm must be applied to a shaved scrotum, while Androderm (just approved by the FDA in October) can be placed anywhere on the body. There is no data available to date on the use of either patch in people with AIDS, but results from at least one study should be released within the next few months.
A More Practical Therapy
by Gabriel Torres, M.D.
for Low Platelets
Immune thrombocytopenic purpura (ITP) is a relatively frequent condition in people with HIV infection. Although most common early in disease, it can occur at any stage of disease. "Thrombocytopenia" refers to an abnormally low platelet count, platelets being the blood cell fragments involved in the clotting process. Low platelet counts are associated with easy bruising and spontaneous bleeding, which can be life threatening especially if the platelet count drops below 20,000 per cubic millimeter of blood.
Treatment of ITP has been limited in the past by short duration of response, high cost and sometimes serious side effects of the available therapies. But a therapy approved last March by the Food and Drug Administration promises to improve the management of ITP. This new treatment (brand name: WinRho) utilizes the therapy that protects against the classic illness that occurs in Rh-positive babies born to Rh-negative mothers.
ITP and HIV Infection
Platelets coated with antibodies are cleared from the body, mostly by macrophages residing in the spleen and liver. This phenomenon is seen as the major factor behind ITP during HIV infection, although the source of the antibodies bound to the platelets is open to interpretation. In an individual with HIV, platelets may have particular surface antigens that become the targets of antiplatelet antibodies that make them targets for destruction. Platelets also sponge up antibody/antigen complexes as well as any free antibody floating in the blood, and both of these are present to a high degree during HIV infection.
Other factors in thrombocytopenia during HIV infection include reduced bone marrow production probably due to direct HIV infection of the megakaryocyte, the precursor stem cell of the platelet. These cells have CD4 receptors that allow HIV to adhere to the cells and alter their function. Other factors that may contribute to decreased platelet production include the low levels of interleukin-3 and interleukin-6, which serve as growth factors for megakaryocytes.
Treatment modalities for HIV-related thrombocytopenia include AZT, corticosteroids, immuno-globulin therapy and splenectomy (surgical removal of the spleen).
AZT has been considered the most effective therapy, with 30 to 90 percent of patients responding within twelve weeks of initiating the drug.1 ddI has also been tried but is much less effective. The newer antiretroviral agents have not been formally studied for this purpose, although theoretically they should provide a similar effect as AZT, by interfering with HIV infection of the megakaryocyte.
Corticosteroids can elevate platelet count in 40 to 80 percent of patients yet result in long-term remission in only ten to twenty percent of patients. They are associated with intolerable side effects in many people, including further immune suppression, reactivation of opportunistic infections such as candidiasis, herpes simplex and tuberculosis and increases in blood glucose, blood pressure and peripheral edema.
Splenectomy offers the most durable response but has some surgical risks and may increase the risk of infections with such encapsulated bacteria as pneumococcus, haemophilus influenzae, which are often effectively removed by the spleen. Patients who are to under splenectomy should be vaccinated against these two bacteria prior to surgery.
Other similar treatment modalities which have been partially successful include low dose splenic irradiation. Small studies have shown a 70 percent acute response rate and a durable response rate of 40 percent.
This procedure requires total doses of radiation of approximately 900 to 1,000 centigrays (centijoules per kilogram of body weight) administered over one month, which allows for some degree of splenic function to be preserved.
Finally, immunoglobulin (transfused antibody, also known as Ig or gammaglobulin) therapy is the quickest therapeutic approach and is used in cases of very severe thrombocytopenia and prior to surgery to rapidly lower the risk of bleeding. Immunoglobulins saturate the receptors on the platelet-trapping macrophages in the spleen, thus sparing the platelets from destruction.
The duration of response is only about one to three weeks and sustained remissions from a single course of treatment occur in less than ten percent of patients. The cost of immunoglobulin therapy is about $1,500 to $2,000 per treatment, which makes long-term therapy prohibitive.
WinRho, also called anti-D antibody therapy, consists of concentrated antibodies that bind to the Rh antigen on red blood cells. WinRho, like broader immuno-globulin therapy, is thought to act by overloading the reticuloendothelial system by increasing the number of antibody-coated cells to eliminate. WinRho will lead to some reduction in the number of red blood cells, but not enough to cause significant anemia. The treatment will not work in patients who are Rh-negative or who have had their spleen removed.
In one study by Bussell and others,
43 Rh-positive patients with ITP were treated with WinRho at a dose of 10 mg/kg of body weight followed by daily doses of 20 mg/kg until either their platelet count increased to a minimum of 20 to 30,000 per mm3 or hemoglobin levels decreased greater than 2 gm/dl of blood, indicating the onset of anemia. The mean platelet increase was 95,000 per mm3, with children having better responses than adults.
In the largest study to date, 267 patients treated at New York Hospital/Cornell University between 1987 and 1994, had mean platelet increases of 76,000 cells. Study participants with HIV had a poorer response (a mean increase of 49,000 platelets per mm3) than HIV-negative ones.
Again, younger patients (less than eighteen years of age) had a better response than older ones. Changing the dose of WinRho did not alter the response rate or the decrease in hemoglobin levels, which were on average 0.8 gm/dl. The HIV-positive patients had a lower decrease in hemoglobin than the HIV-negative patients. Concomitant use of AZT affected neither the platelet response nor the rate of red blood cell clearance. CD4 cell counts were not adversely affected by the WinRho treatment, nor was there any other evidence of acceleration of HIV disease progression.
- Stricker RB. Hematology-Oncology Clinics of North America. Apr 1991; 5(2):249-65.
- Calverley DC, Jones GW, Kelton JG. Annals of Internal Medicine. Jun 5, 1992; 116(12 pt1):977-81.
- Bussel JB et al. Blood. May 1, 1991; 77(5):1884-93.
- Scaradavou A et al. American Society of Hematology Thirty-Seventh Annual meeting, December 1-5, 1995; (abstract).
by Theo Smart
Found in Cells
Not long after HIV was identified, many researchers noticed that it was very difficult to culture the virus from the blood of many infected people, particularly those free of symptoms. Investigating this phenomenon, Jay Levy, M.D., of the University of California San Francisco, determined that activated CD8 lymphocytes in these cultures were responsible. Dr. Levy found that activated CD8 cells from HIV-negative donors, and SIV-infected primates, also halted the growth of HIV in cell cultures. This activity was not due to CD8 cells directly killing HIV-infected cells, as one might expect considering their commonly accepted antiviral role. Rather, something that these cells produced, which Dr. Levy referred to as the cell antiviral factor (CAF), was keeping the virus in check.
Since proportionally more CD8 cells are required to block the virus in cultures derived from patients with advanced HIV disease, Dr. Levy concluded that these CD8 cells were not producing as much CAF. He reported that CAF could be what is responsible both for the long period of clinical latency that most people with HIV experience and for the continued health of many long-term survivors. He also believes that production of CAF ebbs before CD4 cells become depleted and people develop symptoms.
CAF's exact chemical identity proved to be extremely elusive. Dr. Levy could isolate no one substance secreted by CD8 cells that could affect this dramatic suppression of HIV. His work languished, garnering little interest or support from the National Institutes of Health.
Last month, Dr. Levy's discovery regained the spotlight, when two groups separately claimed to have identified CAF. Researchers from the Paul Ehrlich Institute in Langen, Germany reported in a letter to Nature (December 7, 1995, page 563) that a cytokine called lymphocyte chemoattractant factor, or IL-16, has a strong suppressive effect on HIV. The other team, led by Drs. Paulo Lusso and Robert Gallo, formerly of the National Cancer Institute, argued that CAF was not one, but three different substances acting in concert to keep the virus in check (see Science, Dec. 15, 1995, pages 1811-5). Dr. Levy, though, does not believe that CAF has truly been identified by either group.
Dr. Paul Reinhard Kurth and the other German investigators have been working with a factor isolated from the CD8 cells of African green monkeys that suppresses SIV, the monkey virus similar to HIV. The Germans found that this factor is virtually identical to human IL-16. However, the observed HIV-suppressive activity of pure IL-16 was not as dramatic as that of the crude material extracted from the CD8 cell cultures.
In a review accompanying the Nature letter, Anthony Fauci, M.D., director of the National Institute of Allergy Infectious Diseases, suggested that IL-16 may be working together with other suppressive factors. How IL-16 works is unknown, but it does bind to the CD4 receptor and may inhibit CD4 cell activation. At the doses that Dr. Kurth's group used, IL-16 was not toxic to cells and so perhaps has some therapeutic potential.
Dr. Gallo's team took a CD8 cell line that was particularly effective at suppressing HIV, removed the actual cells and separated the remaining substances in the culture. They found three proteins, previously dubbed RANTES, MIP-1a and MIP-1b, that had potent anti-HIV activity at nontoxic levels in cell culture. These proteins belonged to the chemokine family, which heretofore were known to direct lymphocytes to the site of infection or inflammation.
The researchers then added antibodies that inactivate the individual chemokines to the cultures to see which chemokine was primarily responsible for the CAF activity. Only the antibody to RANTES seemed to partially reverse some of the suppressive effect. Yet when antibodies to all three chemokines were added, all of the anti-HIV activity was eliminated. The scientists observed the same result when the antibodies were added to cell cultures taken from people with HIV and concluded that all three of the chemokines are required to keep the virus under control.
Dr. Gallo's group is currently running the chemokines through various in vitro assays to determine which aspect of the viral life cycle is disturbed by the chemokines. They may act at an early phase in the viral life cycle, but Dr. Gallo says, "there may be more than one mechanism of action."
Dr. Gallo's paper concluded with the suggestion that the people with HIV should be studied to see whether those who produce higher levels of these chemokines have a slower rate of disease progression. Does production ebb as people progress? (Dr. Gallo says other factors may emerge that reduce the chemokines' effect in people with progressive disease.)
Another area to look at is whether vaccine-induced higher levels correlate with protection against SIV infection in monkeys. At present, there is little natural history data on the secretion of chemokines (or IL-16) in people with HIV disease.
High production of chemo-kines has been noted in a large number of autoimmune disorders, such as rheumatoid arthritis and lupus. This observation raises the question of whether people with a history of such conditions are less likely to become HIV infected, or, if they do become infected, whether they progress more slowly.
Researchers have noted that it is extremely unusual to find HIV and these other conditions together, but there are a few case studies in the literature. Rather than a slower progression of HIV disease, a remission of the autoimmune disorders was observed.
William Blattner, M.D., Deputy Director of the University of Maryland institute that Dr. Gallo now directs, says, "The first thing to do is get a better understanding of the way in which these [chemokines] occur in these different populations. A single marker may not tell the whole story -- ratios or combinations may be important. It is possible that there are some suitable populations for case control studies. Our first approach will be to look at levels of these markers in patients at different stages of HIV infection, and whether these markers correlate with protection in HIV-negative people with continued high-risk exposures. But again, the initial focus is standardizing the assays."
The extent to which any of these findings will lead to the development of new therapeutic agents remains to be seen. IL-16 may suffer from the same fate as other cytokines that have shown anti-HIV activity in the lab. Some of these compounds also concurrently stimulate the production of inflammatory cytokines such as TNF-a when administered in people, undermining whatever direct anti-HIV activity they might have had in the test tube. And generally, administration of the HIV-suppressor cytokines have been associated with severe side effects.
The systemic administration of chemokines poses certain problems. The most established purpose of chemokines is to direct white blood cells to the sight of the infection. If administered systemically, immune cells might wander aimlessly, confused by conflicting signals and be less likely to respond when secondary infections do occur.
Administering MIPs alternatively might make common infections life-threatening by magnifying the amount of inflammation present. In the lungs, excessive MIP-induced inflammation during pulmonary infection can lead to suffocation. Added RANTES, meanwhile, could cause side effects similar to arthritis.
Nevertheless, the chemokine levels effective in cell culture "are not showing toxic effects in the animal [rodent] toxicology studies," says Dr. Gallo. He hopes to administer the chemokines to green monkeys (the SIV model) within several weeks (although he notes that delays in the construction of his new institute make it difficult for him to say for certain).
Dr. Gallo also believes there may be some way to trigger the local secretion of chemokines. Presently, Dr. Sergio Romanagni, in Florence, is conducting experiments to determine how CD8 cells produce these chemokines, and what factors might stimulate their secretion.
Dr. Gallo's team also is manipulating the molecular structures of the chemokines to determine which subunits are responsible for the antiviral activity. Altered molecules might be developed that suppress HIV but do not have the potential side effects of the whole chemokine molecule.