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Viracept (nelfinavir, aka AG-1343): Agouron's Protease Inhibitor
June 14, 1996
I'm now writing to you from the airplane, having just left San Diego and a community meeting with Agouron Pharmaceuticals, where a diverse group of community representatives gathered to address common concerns.
The day started with talks from Agouron's CEO and a few of their scientists involved in the protease inhibitor discovery project. Their CEO, Peter Johnson, talked about the company's development and his commitment to AIDS. Agouron is only about 11 years in existence. It is a small company compared to the large pharmaceutical companies with which it's competing in the protease inhibitor market. It was started to utilize new technology of drug design and development. The new technology utilized by Agouron is x-ray crystallography, which is used to identify the structure of a "target" for a drug, such as the HIV-1 protease enzyme, and then help design the structure of a drug, that may optimize its "fit" for that "target."
Mr. Johnson said their concept of "rational protein based structural design" was not initially well received when he visited large pharmaceutical company's looking for interest in the early days after the company's inception; but now, of their 360 total employees, Agouron has 150 employees (85 devoted just to HIV) devoted solely to this concept of structure based drug design, and Johnson said it is the largest group working together of any in the world; and, he said, they have the largest database of how drugs interact with targets; Agouron has a cancer drug designed by the same method that is also in late stages of development. But, Nelfinavir is expected to be Agouron's first product to be marketed.
Of importance to the AIDS community, Agouron announced at the meeting that they have recently completed their identification of the structure of CMV, and now they will be trying to develop a CMV drug. They are also working on identifying the structure of the Hepatitis C virus, again for the purpose of developing a sorely needed treatment; currently, interferon is the only approved treatment for Hepatitis C, but it isn't very effective.
We reviewed their data on safety, efficacy and resistance for Viracept; and discussed pediatrics, a women's study, expanded access and drug interactions; all of which are discussed below. They began recruiting for their phase III studies in January 1996. Prior to that, about 100 people had been treated with Viracept in phases I & II. Until data is available from the phase III studies, which won't be til about November, the data currently available and discussed below is preliminary; as you will see, it is based on a small number of study participants who have been followed for only 3-4 months. Viracept(VCT) is a non-peptidic protease inhibitor which has displayed between 20-80% bio-availability, in a variety of animals. In the rat, there is CNF penetration at therapeutic levels. Agouron reports synergistic interactions in vitro were detected with nelfinavir and either AZT, ddC, 3TC or the combination of AZT/3TC. Additive interactions were detected with ddI or d4T.
EFFICACY
Protocol #503 studied nelfinavir monotherapy (without any other drugs) in 30 drug-naive and experienced (protease inhibitor naive) HIV positive individuals with CD4 greater than 200 and viral RNA greater than 20,000, in three dosing regimens: 500, 750 and 1000 mg. 3X/day (TID).
Mean Baseline RNA and CD4-- 500 mg TID 750 mg TID 1000 mg TID -------------- -------------- ---------------- RNA 57,021 106,094 67,495 CD4 363 381 331 Number of Patients at Each Dose Regimen Dose 1 mo. 2 mo. 3 mo. 4 mo. ------ ------ ------ ------ ------ 500 mg TID 10 7 7 5 750 mg TID 10 10 9 10 1000 mg TID 10 9 9 7 total 30 26 25 22
At 4 months, the RNA reductions from baseline were:
At 4 months the CD4 increases were:
Although based on a small number of individuals for only 4 months, the RNA and CD4 improvements are promising. For phase III studies, the 500 & 750 mg TID dosing regimens were chosen for study, but not the 1000 mg dose regimen. Following, you will see data examining these same 3 doses in a combination study of Viracept and d4T where the improvements, in CD4 and RNA from both the 750 & 1000 mg dose regimens, were similar. Agouron has decided not to study the 1000 mg dose in their phase III trials, saying that the efficacy appears to be equal but, because of the higher incidence of side effects in the 1000 mg dose, they chose only to study the 500 & 750 mg dose regimens in phase III. However, in the #503 monotherapy study the 1000 mg dose produced a more pronounced decline in RNA at 4 mos.(2.2 log vs. 1.5).
Choosing a dose regimen can be complicated. At 1000 mg, indinavir displayed a higher incidence of nephrolithiasis (kidney stones), but efficacy may have appeared to be slightly better than the dose chosen and currently recommended, of 800 mg 3x/day; it was a difficult choice when Merck faced the decision between 800 TID or 1000 TID, but they also chose the safer dose. The side effects of ritonavir can be problematic at the recommended dose, 600 mg 3X/day, without raising it any higher. The combination trial currently ongoing, which is studying saquinavir+ritonavir is utilizing two different doses of ritonavir (600 mg 2X/day and 400 mg 2X/day) in combination with a variety of saquinavir dosing regimens (all are 2X/day regimens).
However, the currently recommended dose of saquinavir is 600 mg 3X/day, and its side effect profile is more benign than both ritonavir and indinavir. But its bio-availability is low (4%), which may limit its potency; therefore, some individuals are compensating by taking higher doses of saquinavir than the recommended dose regimen. A more potent and bio-available new formulation is currently in a trial, from which Roche hopes to obtain FDA approval for this new more potent formulation; however, it will not be until 1997, before the FDA reviews the trial results, as it just recently started. Incidentally, Abbott is expected to soon begin human trials for its new protease inhibitor, ABT-378, which may be superior to ritonavir.
Safety at 4 months
Diarrhea incidence was 10% at 4 mos. for the 500 & 750 mg group, but 20% for the 1000 mg group. Asthenia incidence was 10% at 4 mos, but only in the 1000 mg group. Headaches at 10% only in the 750 mg group. The company defines diarrhea as greater than or equal to grade 2 (moderate) in severity. They have characterized this side effect as consisting mostly of more frequent bowel movements per day, and looser bowel movements.
Protocol #510: Viracept and d4T
40 (10 per study arm) treatment-experienced (d4T & protease inhibitor naive) and -naive individuals, without prior protease inhibitor experience, were studied; baseline values: CD4 greater than 200; HIV RNA greater than 15,000.
d4T d4T+500 d4T+750 d4T+1000 mg VCT mg VCT mg VCT Baseline: RNA 66,445 81,467 80,386 56,448 CD4 390 367 334 310 Mean Improvements in HIV RNA & CD4 from baseline 1 month 2 months RNA- d4T -0.9 log -0.75 (n=8) 500 mg -2.0 -1.75 (n=9) 750 mg -1.9 -2.3 (n=7) 1000 mg -2.0 -2.4 (n=8) CD4- d4T +40 cells +70 500 mg +75 +105 750 mg +110 +135 1000 mg +110 +110
As you can see, there is no discernable difference between 750 and 1000 mg in this study, as measured by RNA & CD4; however, the community suggested that further out in study time a measurable difference might develop, that 2 months of data was too little by which to make such a decision. It is my understanding that the data at 3 months sustains these CD4 and RNA improvements, although it hasn't been publicly disclosed.
Safety
d4T 500 mg TID 750 mg TID 1000 mg TID +d4T +d4T +d4T n=8 n=11 n=10 n=10 Diarrhea - 18% 30% 30% Asthenia - - - 20% Headache - - - 10% Rash - - 10% -
However, Agouron claims the incidence and severity of diarrhea declines by 3-4 months.
PHASE II/III STUDIES
The following studies are enrolled except for protocol #525, which will be enrolling shortly. #525 is a unique trial comparing individuals who will be randomized to either nelfinavir added to their current therapy vs. nelfinavir added to newly started other therapy. All participants will be receiving nelfinavir open label; this trial will examine the notion that starting new drugs or therapy along with the initiation of a protease inhibitor is preferable to simply adding a protease to current therapy.
#505 monotherapy 90 pts. naive/experienced CD4, RNA above 50 CD4 #506 VCT-500,750 mg 250 pts. naive/experienced CD4, RNA +d4T #508 VCT+AZT/3TC 100 pts. naive CD4, RNA in Europe 150-500 CD4 #509 VCT-AZT+3TC 12 pts. naive CD4, RNA virology study #511 VCT-AZT+3TC 210 pts. AZT-naive CD4, RNA #525 open label 200 pts. experienced CD4, RNA VCT+RTI below 100 CD4
(Ed. note: currently enrolling anti-HIV trials, including trials studying nelfinavir and other protease inhibitors)
Clinical endpoint studies are in design. Under consideration is ritonavir vs. nelfinavir, and/or indinavir vs. nelfinavir; individuals would be randomized to either protease inhibitor and be permitted to take other approved therapy of their choice, probably except for other protease inhibitors.
Cross-resistance
Agouron officials said, they believe nelfinavir may have less potential to cause the magnitude of cross-resistance that other inhibitors may cause, but this will need confirmation. The in vitro mutation profile they have published (Antimicrobial Agents and Chemotherapy, Feb 1996, p 292-297) appears to be less extensive. But this mutation profile is not based on clinical isolates (from blood taken from individuals administered nelfinavir). They are, however, working on clinical isolates now, and will soon have information to reveal.
Expanded access
With the recent approval and availability of 3 protease inhibitors, the context of expanded access is changing. When we pressured Merck and Abbott to offer expanded access, there were very limited options to access protease inhibitors. How do we now approach expanded access for the 4th protease inhibitor? The creation of a new model for protease inhibitor expanded access programs was suggested, whereby unique criteria might be utilized to qualify individuals for the program. The original purpose of expanded access was to offer drug to individuals who did not qualify for trials and who had few, if any, remaining treatment options. Within this context a new model might emerge.
Pediatrics
A pediatric suspension has been developed. An initial pharmacokinetics study is being planned to start soon.
Women's study
Agouron is planning an open-label study for about 36 women to gather data on nelfinavir's effect on HIV related gynecological health concerns.
Drug interactions
Interaction studies are ongoing. They are about to expand these studies to include more drugs including those representative of classes of drugs most used for HIV that may have potential interactions with protease inhibitors because of their metabolism through the same hepatic (liver) pathway. However, Agouron officials said, they believe nelfinavir will have less potential for drug interactions than some of the other protease inhibitors. This also needs confirmation.
Merck, Abbott and Roche recommend that terfenadine not be co- administered with their protease inhibitors; plasma from at least two subjects in a study of terfenadine (Seldane) contained measureable levels of terfenadine in the presence of nelfinavir; however, Agouron is recommending alternative therapy (nonsedating antihistamines) that have not been associated with cardiovascular complications (e.g. loratadine).
Rifampin, a potent inducer of p450 metabolism, appeared to have substantially lowered nelfinavir trough levels in 12 subjects. Complete pharmacokinetic profiles for the study are not yet available; but, because of the pronounced changes in nelfinavir trough levels, Agouron is cautioning study investigators against concomitant use of rifampin with nelfinavir.
Agouron is planning to conduct a study of rifabutin which has similar, but generally less potent p450 inducing powers as rifampin. Alternative MAI prophylaxis regimens are suggested until results of the rifabutin study are known.
Preliminary trough level measurements suggest that only minor increases in nelfinavir concentrations may occur during treatment with ketoconazole. Based on these preliminary results, dose modification should not be required.
Preliminary study in animals find that saquinavir blood levels increase 2-3 fold when combined with nelfinavir.
At the nevirapine FDA hearing last week, concerns were raised about nevirapine's interactions with protease inhibitors. Boehringer Ingelheim, the developer of nevirapine listed indinavir, ritonavir, saquinavir -- but not nelfinavir -- as the drugs they will study for potential interaction.
Recently, all the protease inhibitor developers have been discussing studying further the combination of two protease inhibitors in one therapy. The by now famous ritonavir-saquinavir study is the first to explore this concept. Soon, it is expected that Merck will start initial studies of indinavir in combination with the new more potent formulation of saquinavir. The combination of nelfinavir/saquinavir needs to be studied. Agouron said this issue is under consideration. As well, Glaxo Wellcome says they are discussing the initiation of studying their protease inhibitor in combination with other protease inhibitors; but these concerns need to be monitored, because it is important that these studies start as soon as possible.
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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.
The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.
Last modified 6/23/96
by Jules Levin
Copyright © 1996 natap
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