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TAGline/Volume 4 Issue 7

August 1997

Contents:

  1. Roche Racks Up Millions In Early Saquinavir Sales While Unwitting Patients Prime Themselves for Protease X-Resistance
  2. Metabolic Disturbances in HIV Infection Find Friend Not Foe in Protease Inhibitor Regimens
  3. How the Triple Combos Stack Up

Scammed

Roche Racks Up Millions In Early Saquinavir Sales While Unwitting Patients Prime Themselves for Protease X-Resistance

Community cries for compensation

Cynical, greedy, manipulative, opportunistic, penny-pinching, short-sighted, slipshod. Do these words come to mind when you think of Hoffmann-La Roche’s AIDS drug development effort? They should. Examples of such behavior are legion, from the fiasco that was ddC to the joke that is the current formulation of saquinavir to the curious decision by the Basel-based pharmaceutical giant to drastically curtail development of val-ganciclovir, the oral ganciclovir prodrug which offered the hope for an effective prophylaxis against cytomegalovirus (CMV) disease. As one high-placed Federal official noted, "Roche finally has a decent drug, and they’re thinking of dropping it."


Saquinavir, like ddC before it, is the most potent of its class -- in vitro. But only 4% of saquinavir makes it into the bloodstream. Seems Roche was in such a hurry to get its drug licensed as the first protease inhibitor, it never bothered to conduct the dose ranging studies which could have defined a maximum tolerated dose for saquinavir. When Roche approached the Primary Infection (today’s HIV RAC) of the ACTG to do its phase II study (ACTG 229), the dose chosen was 600 mg three times daily. This was based, Roche claimed at the time, on three European phase I studies (or, as others thought, on a limited drug supply which made higher doses impractical). While the Primary Infection cabal was never known as a bastion of open scientific debate, ACTG 229 was shrouded in a level of secrecy unusual even for it. Roche declined to present the results of its phase I studies to the committee as a whole; rather, they allowed Tom Merigan of Stanford University and Ann Collier of University of Washington at Seattle to take a peek at the alleged phase I virological response to saquinavir.

Study participants would be randomized to receive either AZT+ddC, AZT+SQV or AZT+ddC+SQV. This was one of the first of the so-called "incestuous combination" studies recently pilloried by Joep Lange, in which a company’s own drugs are studies together as much as possible -- regardless of the scientific rationale for doing so. Needless to say, the ACTG brushed aside the concerns of statisticians and activists and conducted 229 as Roche wished it to, even though doses as high as 3,600-5,400 mg/day had been tested in HIV-negative patients and found to be safe. Harvard biostatistician David Schoenfeld, whose charge it was to review the statistical merit of the 229 study design cautioned that, "the proposed study will not be able to detect whether [saquinavir] has moderate activity. (It must be remembered that ACTG 229 was developed at a time when the Primary Infection Committee of the ACTG was facing a crisis of pharmaceutical interest. Saquinavir was the only protease inhibitor they could snag for clinical trials; the Searle protease bombed, and both Abbott and Merck saw the ACTG system as unnecessarily slow and emasculating. Among the ennervated and anorexic Primary Infection leaders, Roche was the suckling pig that’d wandered into their midst. So much as a peep might scare it away. And mum it was.)

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By June 1994, Roche had detected the surrogate marker response it had hoped for: AZT+ddC+SQV produced bigger T cell rises and a larger viral load drop than either of the dual combos. And as Schoenfeld had predicted, 229 failed to show whether saquinavir was any more potent than ddC. Undeterred by this minor annoyance, Roche promptly petitioned the FDA to consider an accelerated new drug application (NDA) for saquinavir. Worried by the precedent this would set for the protease inhibitors as a class, activists wrote then FDA Commissioner David Kessler requesting that accelerated approval for saquinavir be placed on hold until a full and open public debate could take place to assess how much data would be required for accelerated approval of protease inhibitors, and how post-marketing confirmatory studies should be designed.

In the controversy that ensued, Roche quietly agreed to double the size of its pivotal efficacy trials, thereby increasing their ability to determine whether saquinavir provided any clinical benefit. Unfortunately, the study which was to first provide such evidence, Roche NV14256B, compared saquinavir to ddC to the combination of saquinavir+ddC in AZT-experienced patients. Since the utility of ddC is dubious in any population, such a control arm must be regarded as questionable. Nonetheless (and to no one’s surprise), the combination of these two drugs -- each the weakest in its class -- proved to be more potent than either drug alone. This led to accelerated approval for saquinavir by the FDA in November 1995. The drug was licensed at the dose studied in the 229 study: 600 mg three times daily, despite the fact that there was already evidence at the time (Schapiro, ICAAC 1995; Condra, Nature 1995) that a dose twice as high was more potent and equally tolerable. Moreover, it was already known at the time that suboptimal doses of protease inhibitors might predispose HIV towards the development of resistance and possibly even cross-resistance to other protease inhibitors. (Of course, we now know that saquinavir treated patients have indeed developed cross-resistance to other protease agents.) Thus, ever since saquinavir’s licensure at the end of 1995, Roche has known that the licensed dose was suboptimal and that its use could well result in widespread cross-resistance to multiple protease inhibitors.

Had saquinavir rapidly become the drug of choice for people who were failing on nucleoside analogues, a public health disaster might well have ensued. But within three months both ritonavir and indinavir were licensed, at doses which were able, when combined with reverse transcriptase inhibitors in previously untreated patients, to drive viral load down to very low levels for up to one year and could prolong health and life when compared with the current standard of care. Roche’s survival study used ddC monotherapy as the control, which no one -- even then -- regarded as the standard of care. (Although the recently completed saquinavir study, SV14604, compared the triple combination AZT+ddC+ saquinavir to the dual combination AZT+ddC and reported a 50% reduction in risk of disease progression or death for the triple combination, with a median follow-up of 17 months.) None of this, of course, deterred Roche from charging $7,000 for a year’s supply of saquinavir, an unaccountable high price for such a weak drug.

Yet Roche faced a quandary. Despite its slipshod, post-haste development plan, two potent protease inhibitors reached the market within three months of its own accelerated NDA. Even those unversed in the intricacies of retrovirology could tell that ritonavir and indinavir were far more potent than saquinavir. How could Roche redeem its drug? Two opportunities presented themselves. The first was to use the ability of other protease inhibitors -- and particularly ritonavir -- to inhibit cytochrome p450 metabolism, thereby increasing the bioavailability, exposure, half-life and maximum concentration of saquinavir to therapeutic levels. The other, more prosaic, approach was to finally begin to address the need for a more bioavailable formulation and higher dose of saquinavir itself, unassisted by complex hepatometabolic pathways. Roche proceeded to follow both leads.

Those participants lucky enough to survive ACTG 229 were given the chance to enroll in yet another antiretroviral trial: ACTG 333. Three three three was the first ever randomized study for "protease failures;" that is, people for whom protease inhibitor therapy appeared to be no longer working. ACTG 333 randomized individuals who had been taking saquinavir to receive either 1) indinavir, 2) a new soft-gel capsule of saquinavir (Fortovase) which is 4 times more bioavailable or 3) remain on the old saquinavir. Participants were told not to switch any of the other antiretroviral drugs they were taking for the first eight weeks of the study so as not to obscure the effect (or lack thereof) of the protease switch. The primary endpoint of the study was change in plasma viral load. As mandated in the protocol, the study would be terminated prematurely if the mean viral load change in any of the three treatment groups was less than 0.7 log. When an interim analysis of the first 72 patients to reach the 8-week time point showed that, in fact, no arm achieved such an RNA reduction, ACTG 333 was terminated, and patients were given the option of switching from their assigned treatments. The mean viral load reduction at 8 weeks was -0.58 logs for those who switched to indinavir and -0.23 logs for those who switched to the new saquinavir soft-gel capsule: both well within the range of variability of the PCR assay. The study officially closed 7/14.

On the heels of the 333 fiasco, Roche called various community groups in a series of anxious conference calls to try to squelch doubts raised by the study results. Roche’s entire marketing campaign for Invirase was based on the drug’s alleged tolerability and the presumption that one could use it as a first-line protease inhibitor and then go on to use others without fear of cross-resistance. ACTG 333 called this notion into question. Moreover, on one of these calls, Roche representatives revealed that saquinavir hard-gel, when used in combination with AZT and 3TC in antiretroviral naïve patients, lowered plasma viral load beneath the limit of detection in a mere 43% of patients -- fewer than AZT+ddI+nevirapine in the INCAS study (see table below). Roche’s anxieties were deepened when it apparently received a preliminary draft of the HHS Clinical Practice Guidelines and discovered that -- quelle surprise! -- saquinavir had not made the cut as a strongly recommended first-line protease inhibitor. Spurred by the prospect of being left off formularies across the country, Roche decided to accelerate its filing for FDA approval of the soft-gel Fortovase.

Thus it was on May 14th that Roche convened a conclave of treatment advocates from the East Coast and Midwest to hear the exciting new data on its soft-gel saquinavir. The meeting took place at the chic, sleek, postmodern Soho Grand Hotel in lower Manhattan. They had a new team of eager young investigators and public relations experts who, they earnestly explained, wanted to "open doors," "start an on-going dialogue" -- even "set up a community advisory board." Gasps emanated from the activists who remembered the fate of Roche’s previous community advisory board (CAB), which resigned en masse amidst screams and spilled shrimp cocktail during a melée at the Times Square Marriott Marquis in the summer of ‘92 over ddC. Roche’s new team, previously unaware of its predecessors’ plight, quickly redubbed the proposed CAB a "task force."

Clinical team manager for Invirase, (and now also for Fortovase) Laurent Fischer, M.D., presented preliminary data on saquinavir soft-gel and asserted that it provided 8-9 times the drug exposure as saquinavir hard-gel. But just to be sure, Roche is giving twice the dose (1,200 mg tid) of the new formulation (18 horse-sized squishy gel caps a day) compared with the old -- which would likely make it superior even if the new formulation were not more bioavailable. The recently completed 16-week analysis of NV15355C, which compared the two formulations in combination with two RTIs of choice (in treatment naïve individuals), showed 80% and 43% of patients with plasma viral load <500 copies/ml on the soft- and hard-gel formulations, respectively.

Activists at the meeting were skeptical, assailing Roche’s failure to define a maximum tolerated dose before bringing saquinavir hard-gel to market, and said that since the company had made its bed it must now lie in it. Some asked the company to reduce the price of the current formulation by 7/8 (to approximately $700/year) to reflect Roche’s new assessment of its potency. As for those individuals who trusted Roche one year ago and took Invirase at the FDA-approved (that is, sub-therapeutic) dose, the company has said it has no plans to compensate them for whatever subsequent treatment options this therapeutic choice may have foreclosed. After the meeting, Roche invited the activists upstairs for cocktails and refreshments. Let us hope that the Soho Grand’s cocktails were more potent than those being hawked by the unscrupulous Swiss pharmaceutical giant. I wouldn’t know; I didn’t go.



Anabolic Block

Metabolic Disturbances in HIV Infection Find Friend Not Foe in Protease Inhibitor Regimens

Refeeding paradox

On May 20-21 the Office of AIDS Research (OAR) sponsored a conference, the first of its kind on AIDS wasting syndrome. Alongside Michael Marco and TAG’s wasting maven Tim Horn, Mark Harrington was in attendance. He prepared this report.


The specific causes of AIDS wasting remain unknown. Triglyceride levels, cholesterol synthesis and total energy expenditure rise. Body fat is preserved even while protein is depleted. And profound metabolic abnormalities develop, such as hypogonadism (reductions in testosterone levels).


Protein Lost is Replaced by Fat

For reasons we don’t yet understand, metabolic dysfunctions in HIV infection result in a refeeding paradox which drives energy from protein to fat. Weight is lost in the form of lean body mass, but when it is replenished (e.g., with total parenteral nutrition (TPN), appetite stimulants such as megesterol acetate (Megace), or dronabinol (THC)), it is regained as fat. With Megace, for example, 70-100% of the weight gained back is fat. (Megace also decreases testosterone levels, helping to explain its ability to induce production of fat.) Anecdotal reports implicate some of the protease inhibitors (particularly indinavir) in exacerbating this metabolic dysfunction, but further study is needed in order to make any definitive conclusions.

In one small study (31 patients, of whom 4 were women) presented at the meeting by Sherwood Gorbach of Tufts University, most protease inhibitor-induced weight gain was found to be predominantly in the form of fat -- as opposed to lean body mass. Four months after starting protease inhibitor-containing treatment regimens, study participants’ weight had risen to levels not seen since enrollment into the study (8 1/2 months prior). When lean body mass was assessed by bio-electric impedance analysis in a subset of twenty patients, it was found that the proportion of total body weight represented by lean body mass had fallen from 83% before protease to 81% after.

Repeating the analysis with the more discriminating "anthropometric" method, the Tufts team reported a change from 81% lean body mass before protease therapy to 78% after. Both differences were statistically significant. Since the amount of absolute lean body mass among the study participants had not changed throughout the course of the study, Dr. Gorbach explained, all weight gained must have been in the form of fat. This may mean that people on protease inhibitors will need additional interventions to correct metabolic abnormalities, such as exercise, growth hormones or anabolic steroids, in order to restore lean body mass.


Possible role for weight training

In a second paper from Tufts, Ronenn Roubenoff presented a study of progressive resistance training in seven HIV-infected individuals (median CD4 cell count= 200). The training consisted of three 45 minute weight training workouts per week, with the amount of weight being increased every two weeks. Over the eight-week study period, participants experienced a 50% increase in strength. Weight rose by 3.8% (or 6.2 lbs). Of the weight gained, 79% was lean body mass and only 21% was fat (p<0.03).


Hypogonadism -- and nandrolone

Whereas uninfected males have a median of 450-700 ng/dl of free testosterone in their blood, HIV-infected men have 200-450 ng/dl. One hypothesis is that weight loss leads to hypogonadism, which leads to "nutritional partitioning." Is this borderline hypogonadism clinically significant? And will HIV-infected hypogonadic persons respond to androgen replacement therapy? One anabolic steroid, nandrolone, given at 200 mg two times weekly, increased nitrogen balance (indicating protein production) about as much as does growth hormone, and led to increased muscle mass. In a 12-week study, individuals gained 11-13 lbs, with 7-8 lbs (67%) in the form of lean body mass. Nandrolone is also said to decrease fat production.


Energy expenditure, total vs. resting, and protein turnover

Derek Macallan and colleagues of the University of California at Berkeley discussed energy expenditure and protein metabolism in AIDS. In their cohort studies, total energy expenditure was not particularly elevated in HIV infection (which contradicts some earlier reports). And, in what at first seems another paradox in AIDS wasting, HIV-infected individuals with the lowest total energy expenditure lost the most weight. This is probably because the low total energy expenditure resulted from immobilizing opportunistic infections and reduced in-take of food. During the course of such infections, individuals have heightened resting energy expenditure but reduced total energy expenditure. And as CD4 cell count decline, resting energy expenditure increases while total energy expenditure declines. In-take drives wasting.

Another useful metabolic measurement in HIV infection is called whole body protein turnover: the rate at which lean body mass is destroyed and replaced within the body. In HIV-infected individuals, whole body protein turnover is elevated by about 16-18%; in people with AIDS the percentage rises to 25%, although the number varies according to the nature of the inflammatory condition. A common theme observed and commented on in several of the meeting’s presentations appears to be what researchers in this area refer to as an "anabolic block" wherein new nutritional in-take is converted into fat -- and not into the lean body mass which was depleted during the acute infection. Considerations for people with AIDS include: 1) maintaining energy in-take, 2) consideration of anabolic steroids (in concert with resistance training where possible) when in-take is inadequate, or to direct use of nutritional supplements, 3) consideration of anti-inflammatory agents, and 4) monitoring of outcomes.

At lunch, Tim Horn, Michael Marco and I met with Judith Fradkin of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD), Fulvia Veronese and Ellen Cooper of the Office of AIDS Research (OAR) and Beverly Alston of NIAID’s Division of AIDS to discuss implementing the recommendations of TAG’s Wasting Report by increasing the amount of funding for basic research, natural history and therapeutic intervention studies for AIDS-related wasting, cachexia, and metabolic disorders. Follow-up is on-going.



How the Triple Combos Stack Up

RegimenRNA<500 cps/mlFollow-up
AZT+3TC+IDV*81%70 wks
AZT+3TC+NFV†84%40 wks
AZT+3TC+RTV†95%52 wks
Any2nukes+SQVhg†43%16 wks
Any2nukes+SQVsg†80%16 wks
AZT+ddI+NVP†57%§52 wks

*mean 23 mos. prior AZT,
†drug naïve,
§RNASources: Merck 035, Agouron 511, NUCB2019, Roche 15355, BI1046



  
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This article was provided by Treatment Action Group.
 

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