Notes on Schering-Plough/HIV community meeting held August 28 2002
Bob Roehr for posting on the ATAC web site
Community Participants: Ron Baker (San Francisco), Ben Cheng (Washington, DC), Rolf Christensen (Seattle), Lynda Dee (Baltimore), Martin Delaney (San Francisco), Bob Huff (New York), Jules Levin (New York), L. Joel Martinez (Houston), Bob Munk (New Mexico), James Musslewhite (Olympia, WA), Bob Roehr (Washington, DC), Gretchen Schmelz (New York).
Company Participants: Clifford Brass (Medical Director, Gastroenterology), Robert Consalvo (Director, Corporate Communications), Wayne Greaves (Clinical Project Director, Anti-infectives), Mark Laughlin (Senior Associate Director, Clinical Pharmacology), Marco Taglietti (VP Clinical Research), Aracelia Vila (VP Public Affairs/Community Liaison), Holly Wong (Director Public Affairs/Deputy Community Liaison).
Vila called the meeting “very important” and said the company representatives “have come to listen more than present.” Delaney briefly reviewed the history of the Coalition for Salvage Therapy (CST) and how the ATAC has evolved.
During discussion of whether the proceedings were “on the record” or not, Vila said the company’s principal concern was with compliance with Securities and Exchange Commission (SEC) regulations that they not selectively release information. Consensus quickly emerged that a “common sense” standard should be used in writing of the meeting contents and that no previously unreported data would be included.
Brass briefly reviewed Schering’s research programme for HCV therapy. He believes that improvements in outcomes over the next several years will come from better use of existing tools rather than from new drug options. Baker suggested a separate community meeting on hepatitis C and the company responded favourably.
Consalvo discussed the consent agreement that the company has entered into with the FDA concerning good manufacturing practices (GMP) at four of their drug manufacturing facilities. The company said that GMP is a constantly evolving standard that they will meet. However, the commitment of resources to upgrading those facilities may impact their responsiveness on other matters over the next few years.
Laughlin reviewed data on Sch-C and the process of the inhibition of HIV into cells, much of which had been presented at scientific meetings such as the XIV International AIDS Conference in Barcelona. Key points included:
- there is no significant inhibition or induction of the P450 cytochrome system, thus limiting potential interactions with other drugs
- half-life is about 24 hours
- clearance of drug is roughly equal through both the liver and kidneys
CCR5 receptor is the target of Sch-C and Sch-D. It is one of about 150 different types of receptors on the surface of a cell. The receptor is a G-coupled protein that binds chemokines (including MIP1-alpha, MIP1-beta, and Rantes) that can activate or block cascades of internal cellular actions. These include:
- chemotaxis – the process by which cells move following a chemical “trail,” such as toward infection to combat it
- calcium flux
Laughlin said that in developing entry inhibitors as a class of drugs, researchers have to make sure that they not only block HIV, but that they also do not disrupt internal cellular mechanisms that are crucial to cell function and fitness.
Most observers do not believe that there will be adverse effects from blocking the CCR5 receptor because humans with the delta-32 genetic mutation do not have CCR5 receptors on their cells and they live quite normal lives. However, that may not be the case with blocking CXCR4, the second coreceptor that HIV can use to enter cells. Animals that are genetically manipulated to have no CXCR4 receptors show severe developmental disability and quickly die.
Sch-C was tested against a panel of 21 viral isolates representing a variety of clades. Most showed great sensitivity to the compound, however the Russian isolate 570 was completely resistant to it. The isolate is an O clade virus, but other isolates of the clade are sensitive to the drug. Laughlin said it is unclear why the Ru-570 isolate is resistant but he suspects that it might be because of a mutation outside the V3 loop. He explained that resistance to Sch-C has not yet been characterised, partly because the relevant portion of HIV is gp-140, an envelope protein that is highly prone to mutations.
The CCR5 receptor is “a donut with a hole in the middle,” said Laughlin. He believes that Sch-C binds inside that hole, perhaps helping to explain the stability of that binding. Compound can be washed off cell cultures and a protective effect is observed for up to 24 hours.
Clinical data is based upon 52 healthy volunteers and 24 HIV-infected volunteers in Phase I trials. Headache was the most common side effect, “probably because we didn’t let them drink coffee,” said Laughlin. Most data was highly encouraging toward continued development of the drug.
The major impediment to rapid development is the observation of heartbeat irregularities seen in dogs and also in some of the Phase I patients who wore telemetry equipment and were continuously monitored throughout the entire ten-day course of the trial.
The QT interval is the time that it takes for potassium in heart cells to return to depolarisation, or electric neutrality, so that the cells can contract again in unison when they are polarised by an electrical charge. The unison firing of these cells provides a strong heartbeat that effectively pumps blood. Cells that are out of sync result in a heart that twitches and does not effectively pump blood. It is a serious condition that can quickly result in death.
There are no good baseline studies as to how frequently these events may occur and self-correct naturally in either a normal or an HIV-positive population. There is no consensus as to what deviation from the mean constitutes the range of normal and hence can be viewed as safe. The risk of QT prolongation is greatest when at rest or in people with a naturally low heart rate, and is reduced with an elevation of the heart rate through physical activity.
Laughlin said that 40-50 approved drugs cause QT prolongation, including the antibiotics erythromycin, many of the quinolones, and many antipsychotic drugs. Given the FDA’s recent concern with QT prolongation, those drugs likely would face increased scrutiny if they were seeking approval today. The agency now is requiring QT data on dosing of five times the label dosing indication sought.
Delaney expressed limited concern with the QT risk, reminding the audience of the community’s extensive experience with “poppers,” which have a similar effect on heart function.
Schering-D is not as far along in development. It is a different compound, not simply a “tweaked” version of Sch-C. It is 5-10 times more potent than Sch-C in vitro but it is unclear how that will translate in vivo, and the only way to find out is to put it into people. Initial in vitro work suggests that it has a different mutation resistance pattern and may work against virus that becomes resistant to Sch-C. A single dose study has just been completed but the data has not yet been analysed.
Laughlin said they “are going to listen to the drugs” and pursue both compounds until there is a clear winner, and if no clear winner emerges, then both may be developed. He said, “Schering-C is teaching us a lot about the targets and what is important in a drug.”
Phase II Trial Design
Greaves led the discussion of phase II clinical trials to determine the proper dosing of Sch-C. He made it clear that the presented design represented a basis for discussion with the community and the FDA, not a final design.
Through very active and extended discussion it became clear that neither the community nor the company were of a single mind as to trial design. All parties recognized the difficulty of designing a trial or trials in the current environment where a new drug must be evaluated against a standard of care regimen rather than placebo.
A deep salvage population is not ideal because Sch-C is active only against CCR5-tropic virus. Patients with advanced disease often have experienced a shift to CXCR4X4-tropic or dual-tropic virus and hence would not respond well to the drug. Negative trail results from this population might preclude development of the drug in a more promising population.
[NOTE: CCR5 and CXCR4-tropic viruses refer to the receptors used by HIV for fusion and entry into cells. The CXCR4-tropic viruses (also called X4-tropic viruses) generally appear later in the course of HIV disease and are considered more dangerous. A concern about the development of CCR5 blockers is that they would encourage the virus to “shift” to the CXCR-4 type. Schering’s data so far do not show any such shift.]
Cheng expressed concern that an intensification trial that only added Sch-C to a failing first or second regimen ran the risk of resistance developing in patients who most needed this new class of therapy. But on the other hand, modifying other portions of the regimen would make it difficult to attribute causality for any decline in viral load.
In a therapy-naive population, a standard of care regimen will result in undetectable viral load in 80+% of patients at 24 weeks, while a significant portion of detectable viral load will be attributed to initial infection with drug-resistant virus and/or inadequate adherence to the prescribed regimen. That makes it difficult to tease out the impact of Sch-C or any other drug that might be under development.
Taglietti seemed to conclude that the company would have to conduct phase II trials in both naive and experienced patients in order to get the data they need.
Exclusionary Criteria were explained by the company and accepted by the community. They include:
- primary infection
- Delta-32 mutation (people who are born with defective CCR5 receptors)
- X4-tropic virus (by the Virologic assay), because the compound is not effective against them
- HCV coinfection, because there may be no benefit to the drug, while blocking the receptor may exacerbate replication of HCV, as suggested with delta-32 mutants infected with HCV
- concurrent therapy with other drugs known to have a QT prolongation effect
- concurrent therapy with ARV, OI, and other drugs that are shown to interact with Sch-C
There appears to be no basis for excluding patients on methadone from a trial, and the company is not inclined to do so.
Brass expressed the company’s intent to have an expanded access program “if things go positively with this drug.” Delaney suggested that they plan for a program in the range of 2,000-10,000 patients, which was received positively.
The community strongly urged that it be implemented early in development of the drug, even while phase III trials are enrolling patients. Reasonable criteria might be implemented so as not to inhibit that enrolment. They might include access for patients who do not meet enrolment criteria; those who need access as part of a salvage regimen; and those who are geographically distant from a trial site.
The company did not anticipate any problems in scaling up to commercial volumes of production but cautioned that unanticipated problems may arise.
- Schering should initiate early monitoring of lipid and metabolic changes associated with the drugs, given community concerns in this area. Community members noted that BMS has built the marketing of one of its drugs around claims of low impact on metabolic disorders. The company agreed to do so.
- Schering should initiate earlier and more extensive study of possible interactions of both compounds with ARV and OI drugs, methadone, and oral contraceptives.
- Schering should begin early conversations with other companies developing entry inhibitors toward designing studies that can demonstrate synergy within the class.
- Schering should meet with the community 2 or 3 times a year while a drug is in development to discuss issues as they arise and before they reach a crisis. The company responded favourably.
- Both parties should keep the other informed of contacts with the FDA, particularly with regard to the issue of QT prolongation, to work to resolve regulatory issues in a timely manner.
The overall tenor of the meeting was one of a positive and frank discussion of issues. The company readily acknowledged that many scientific questions remain to be answered and the community members felt encouraged to continue with that process.
- Schering C and D: Drugs in development that would block the CCR5 cytokine and slow HIV’s ability to attach to uninfected cells.
- CCR5: A molecule found on the surface of CD4 cells, used by HIV to attach to the cell and infect it.
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