My colleague Chris Griffin headlined his article about new drugs "in the pipeline" in last month's Newsletter with a discussion of the new protease inhibitor being developed by pharmaceutical giant Abbott Laboratories. ("Keep 'em Coming Drugs in the Pipeline," Being Alive Newsletter, March 1999) The drug is still known by its development name ABT-378.
This drug has aroused a lot of hope in the PWA community. It is a "second generation" protease inhibitor, building upon new biochemical research and the experience with the first generation of PIs in the real world. Data presented at the Chicago retroviral conference in February on patients new to PI therapy were very hopeful. More than 90% of the participants in clinical trials had viral loads below the limits of detection after six months and had average rises in CD4 cells of 160 (starting from a baseline average of 350). Best of all, the side effects reported were fairly few and mild. Fewer than 5% of the participants had to switch therapy because of intolerance to it.
The second generation PIs are at least partly free from cross-resistance to other PIs that PWAs may have acquired. This is a big deal because frequently when one becomes resistant to one drug in a class, one is automatically then wholly or partly resistant to others in that class. Abt-378 may thus provide new hope to those who are exhausting their other options through resistance and cross-resistance.
But When? Abbott will probably not be ready to file for FDA approval of ABT-378 until well into the year 2000. The company had announced a few months ago that it would plan to make a large expanded access or compassionate use program available to the community in the meanwhile, perhaps in late 1999 or early 2000. Such programs have historically been among the company's responses to activist pressure for access by desperate folks to potentially life-saving new drugs even as these drugs are wending their way through the pipeline of regulatory approval, manufacture and marketing.
Yet expanded access programs have had a number of problems in the past. Sometimes, there has been much greater demand than supply and therefore a rationing scheme such as a lottery has been necessary. Often little data are collected in the course of expanded access and thus we lose critical opportunities to learn more about who responds better and who does not. The drugs may be used unwisely by patients or providers and thus their potential wasted and perhaps resistant virus strains created as a consequence. Sometimes the companies have used these programs to take some of the pressure off in moving swiftly complete the full approval process.
Enter the Salvage Coalition Meanwhile, a number of activists around the country have organized the Coalition for Salvage Therapy to address the problem of an increasing population of people for whom the protease inhibitors and other new drugs are failing. The Coalition is exciting not just in its purpose but also in its form. It is open to anyone who wants to participate. It functions in large part via e-mail and conference calls, rather than simply face-to-face meetings, thus permitting more people to participate who do not have access to frequent conference travel. It has in fact assembled an active membership including many of the nation's serious treatment activists of all genders and colors, and is working closely with a group of European activists as well.
What is "salvage therapy?" The term is not a good one, granted, and a new one will be chosen soon, I hope! It refers to second-or third-line or even "last-chance" combination therapies for people for whom the generally recommended or first-line therapies do not work or have stopped working. Some people use the term "rescue" therapy. In any event, it is about saving lives.
Among other things, the Coalition pushes companies to deal seriously with the most advanced cases of illness and those who have failed on most or all current options. Companies generally shy away from this focus for clear, if not wholly noble, reasons. It is more difficult to show the effectiveness of a new candidate drug if you start with the hardest cases. Conversely it is easier to show efficacy among people who have never been on any antiretroviral drugs before and have relatively robust immune systems, say CD4 counts in the 300s and 400s. If a company wants its drug approved and to be favorably situated for marketing advantage, it wants to show the strongest effects possible.
The Coalition also pushes the companies to cooperate on trials and expanded access of new drugs, since we know combination therapy works better and the best possible new drugs for someone with no options to try usually involve two or three companies. Once again, both corporate dynamics (seeking an edge against one's competitors) and the FDA's need to have clear data about each new drug militate against companies' being amenable to such cooperation. The consequence, though, can be that someone who adds just one new drug to a failing combination may be placing him/herself effectively on monotherapy (if the person's body is resistant to all the drugs in the failing regimen). Avoiding this is the reason we generally recommend changing at least two drugs when it is time to make a change.
The Coalition and Abbott Over a few months of work, the Coalition came up with a proposal to Abbott that was presented in a meeting in Chicago on March 26. It contained several points: (1) It is not acceptable to wait until 2000 to start expanded access to ABT-378.
(2) Recognizing that there is not enough drug supply available in the short run, we have proposed a two-tiered phase in approach to ensure those most in need get access first.
(3) We propose a Phase I, beginning in the summer of 1999, to make the drug available to those who have immediate, urgent need.
(4) For this purpose "immediate, urgent" need is defined as any HIV-infected person who has virologically failed (means viral loads are detectable and rising) or is unable to tolerate more than one PI-containing regimen; has a CD4 count of less than 200 or an active opportunistic infection; and, in the opinion of his/her medical care provider, needs ABT-378 in order to create a viable treatment regimen.
(5) In the fall of 1999 or as the supply of the drug permits, whichever is sooner, begin Phase II of expanded access for those with urgent need, defined as failure on any PI-containing regimen, and whose provider feels he/she needs ABT-378 to construct a viable regime, irrespective of CD4 count.
(6) In both cases, enrollment in expanded access is not to be limited to any pre-ordained number of persons set by the company, but rather be open to all that meet the criteria of need.
(7) If it is possible to include other experimental drugs in the salvage regime, a participant and his/her provider are encouraged to do so, if appropriate, but neither shall access to ABT-378 be made conditional on also receiving another new drug.
Activists at the meeting reported a very thorough and hard-hitting discussion. The Abbott scientists and managers present listened closely and asked questions. We will await their response in the next week or two. The Coalition has also set out a set of principles for clinical research to help ensure that any new drug before its approval for marketing has been studied well enough in people with advanced disease and in need of rescue. Also, these guiding principles seek to make sure that we have information at the outset on potential interactions with methadone, alcohol, psychotropic drugs, other HIV and OI drugs and among people whose liver has been weakened by hepatitis or previous drug use or any other cause.
The Coalition is not just talking these principles, but has offered to help put together research protocols, patient explanations and informed consent procedures that are culturally competent, scientifically rigorous and ethically acceptable.
Note: So far, I have been alone in representing Being Alive in the Coalition for Salvage Therapy and related work. We certainly need more brainpower, diverse perspectives and fresher energy. If you are interested in working on projects like this one, please contact me at Wsenterfit@aol.com or call Juan Ledesma or Kevin Kurth at the Being Alive office.