February 9, 2009
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There's nothing like hearing the results of studies directly from those who actually conducted the research. In this interview, you'll meet two of these impressive HIV researchers and read their explanation of studies they presented at CROI 2009. After their explanation, they will answer several questions from the audience. This discussion was moderated by John Mellors, M.D.
John Mellors: Since the discovery of potent HIV protease inhibitors [PIs], a common theme of that class has been rapid metabolism and clearance from the bloodstream, requiring twice-daily or three-times-daily dosing. The use of ritonavir [RTV, Norvir] as a metabolic inhibitor of protease inhibitors caused a major advance in protease inhibitor-based therapy by allowing greater exposure with less-frequent dosing. That strategy has been dependent on one molecule, ritonavir, that is the intellectual property of Abbott Laboratories. It is only co-formulated with Abbott's protease inhibitor, lopinavir [LPV], and has been a bottleneck in efforts to co-formulate medications.
There has been a hewing cry and various protests about the availability of only one boosting agent. Also, there's been concern at a regulatory level and among clinicians about the effects of a boosting agent, such as ritonavir, used without a protease inhibitor -- let's say, used with an integrase inhibitor like elvitegravir [EVG].
Brian Kearney, Pharm.D.
Good morning. My name is Brian Kearney. I'm senior director of clinical research at Gilead Sciences located in Foster City, California.
This morning we presented data on GS-9350,1 our pharmaco-enhancer. It shares with ritonavir a mechanism-based inhibition of cytochrome P450, which is critical in terms of being able to administer a low dose, as infrequently as once a day -- to provide not only boosting of bioavailability, but slowing of systemic clearance, to allow for optimal pharmacokinetics of the drugs that we choose to boost.
As John mentioned, the anti-protease activity that molecule has raises certain questions about its ability to select resistance even at a low boosting dose. In our development program we specifically sought to have the mechanism-based inhibition that ritonavir has and remove the anti-HIV activity -- and we were able to successfully do that.
Then there were other factors that we considered in ultimately choosing GS-9350. These included, broadly speaking, improvements in other areas of its DMPK profile -- drug metabolism and pharmacokinetics. That includes more specific inhibition of cytochrome P450 3A [CYP3A] relative to competitive inhibition of other enzymes; the 2C family and 2D6 are also inhibited by ritonavir.
Also, ritonavir has a certain amount of liability in terms of being able to reduce metabolism: Whereas it boosts effectively in the background, it can cause induction. We've removed the induction liability as well by removing [GS-9350's] activity in terms of activation of nuclear receptors. And that induces a number of drug metabolizing enzymes as well as drug transporters.
Slide from GS-9350 presentation; Brian Kearney et al. CROI 2009; abstract 40. Reprinted with permission. Click here to view the full presentation.
Other aspects that we focused on included reduced effects on adipose sites in vitro. We focused on this in particular because elevations in triglycerides and cholesterol, as well as insulin resistance, are sometimes seen in patients receiving boosted regimens. We were able to show GS-9350 has less effects in vitro.
The last, and one of the key, aspects of selection of GS-9350 was its high aqueous solubility. What that allows us to do is formulate it in a solid dosage form; it also allows for a co-formulation potential.
When all of those attributes were met, we moved into the clinic and conducted two clinical studies. The first clinical study was for safety and tolerability. It was a single- and multiple-dose study, and we looked to also establish proof of concept in terms of its ability to boost CYP3A substrates. In our study, we chose to use the validated probe midazolam. We showed that GS-9350 was able to reduce metabolism of midazolam, this 3A substrate, to the same extent that ritonavir is able to do at its boosting doses.
Slide from GS-9305 presentation; Brian Kearney et al. CROI 2009; abstract 40. Reprinted with permission. Click here to view the full presentation.
After that proof of concept was met, then we moved into a co-formulation study where we co-formulated GS-9350 with our integrase inhibitor, elvitegravir, as well as tenofovir/FTC [tenofovir/emtricitabine, Truvada]. The long and short of that story was the quad formulation -- GS-9350 had 150 milligrams, co-formulated with elvitegravir and tenofovir/FTC -- reached the desirable concentrations that we had set out to reach.
Based on those data, we'll move forward into Phase 2 with this quad tablet in a head-to-head study versus Atripla [efavirenz/tenofovir/emtricitabine, EFV/TDF/FTC] in treatment-naive patients. Our intent is to start that study in the second quarter of this year.
We're also in the process of completing a study of the standalone GS-9350 tablet to boost atazanavir [ATV, Reyataz]. It's a dose-finding study to see what dose is necessary to boost atazanavir, similar to what ritonavir does in the boosted state. When those data come through, we plan to conduct a head-to-head study with the GS-9350 standalone tablet versus ritonavir to boost atazanavir -- both of those regimens, with Truvada, also on treatment-naive patients. Our goal is, pending favorable data on that PK [pharmacokinetic] study, to also start that Phase 2 study in the second quarter of this year.
John Mellors: Thank you. Robert?
Robert Guttendorf, Ph.D.
My name is Robert Guttendorf from Sequoia Pharmaceuticals. I head up the pharmacology and experimental therapeutics group there.
I'm very happy to have this opportunity to talk with you about our PKE [pharmacokinetic enhancer] program.2 As described, we are seeking to come up with an alternative to ritonavir as a booster in HIV therapy -- particularly with PIs, but also with potential application to other classes of antiretrovirals, and perhaps beyond.
We set out to try to address the limitations that ritonavir has, including its propensity to elevate certain lipids and its protease inhibitory activity, which could be associated. There's a risk [with ritonavir] of association with generating protease-resistant mutants, and also its GI [gastrointestinal] intolerability. We succeeded in those goals, in coming up with our lead compound, SPI-452.
It's probably worth mentioning that, if you aren't familiar with us: Sequoia Pharmaceuticals is a small, young company of only about 30 people, but we have a wealth of talent and experience at our disposal within the company, starting with our founder and CSO [chief scientific officer], Dr. John Erickson, with whom many of you are probably already familiar and who is here in the audience. Beyond that, we have breadth of experience and depth of experience across all stages of drug discovery and development and many different therapeutic elements. That allowed us to take this project from the initial inception of the PKE [pharmacokinetic enhancement] program to the full proof-of-concept demonstration in the clinic within only about three years.
As I mentioned, SPI-452 did have the profile that we were looking for in a lead candidate [according to the results of] in vitro and in vivo in animal studies. Pre-clinically, it demonstrated itself to be a very potent PK enhancer; it was on par with ritonavir. Our goal was to come up with something that was at least as good a booster as ritonavir, but which didn't have as many of the adverse aspects of the profile that ritonavir has.
Slide from SPI-452 presentation; Robert Guttendorf et al. CROI 2009; abstract 41. Reprinted with permission. Click here to view the full presentation.
It showed pre-clinically, and with that, we went into our clinical studies. We've conducted two so far: a single, rising-dose tolerance and a multiple, rising-dose tolerance, in which we showed that, indeed, SPI-452 does have a very safe and tolerable profile. It does not have any substantial GI side effects, andat least in the multiple-dose studies, it showed no statistically significant differences in triglycerides and LDL [low-density lipoprotein] compared to placebo.
In addition to that, we also built into each of these two studies an arm that would evaluate the ability of SPI-452 to enhance directed potential partner PI drugs -- saquinavir [SQV, Invirase] in the first study, atazanavir and darunavir [TMC114, Prezista] in the second study. The boosting that we saw for each of these compounds was quite remarkable and showed us beyond a shadow of a doubt that we were, in fact, hitting our molecular target and enhancing these PIs as we had hoped to do. These were on par with ritonavir, based on literature data.
With that, we believe that SPI-452 has great potential. We see it as potentially being developed as a stand-alone agent or as a fixed-dose combination. And it has potential applications not only within HIV as a PI booster, but also in HIV for other types of classes of antiretrovirals, and in HCV [hepatitis C virus] for some of the development compounds that are out right now -- it would be a very good adjunct for that. In addition to that, there are also opportunities for either 452 or our general PKE platform to be applied outside of the antiviral space.
John Mellors: Thank you very much. These are two exciting developments in the treatment field. Questions?
Reporter #1: Would you be nicer than Abbott and license your compound to other companies so that they can manufacture a combo pill?
Brian Kearney: I'd say we're currently doing work with atazanavir and are engaging in conversations with other companies to conduct pharmacokinetic studies to see if our drugs can work together. I think we've shown, with our collaboration with BMS [Bristol-Myers Squibb Company], that we're more than willing to work with other companies.
John Mellors: Dr. Guttendorf?
Robert Guttendorf: Yes, I would echo that. We, as well, are looking at the possibilities of fixed-dose combinations with this compound and are in discussions with a number of potential large pharma partners to look at directed fixed-dose combinations for development.
Reporter #2: The grade 3 adverse event of "discoordination" -- could you define discoordination for us?
Brian Kearney: This [refers to] a subject in our study who came to the investigator in the study and said that she felt like she was having a hard time engaging in juggling, which was one of the [things] she did to pass the time when she was in the clinic, and felt that [the drug she was taking in the study] impaired her ability to do that. Per the toxicity grading criteria, this was considered discoordination. It was a grade 3 event per her report, and she was discontinued from the study because we had predefined stopping rules: Anybody who had a grade 3 adverse event would be discontinued.
Reporter #2: Do you have plans to do a parallel track for releasing this as a booster on its own, or is it only in co-formulation?
Brian Kearney: No, we intend to bring forward a stand-alone tablet of GS-9350 as well as the co-formulation.
Reporter #2: Would that be around the same time?
Brian Kearney: Yes.
Reporter #3: After 20 years in this field, I am very suspicious of the phrase "safe and well-tolerated." Could you run down the side effect profile of your enhancer? What were the most common side effects?
Robert Guttendorf: Sure. I probably should qualify that, if I didn't, as generally safe and well-tolerated. I agree there is no drug out there that is absolutely safe; it is all in relative terms. In the single-dose study, the predominate adverse events were four episodes of headache and four episodes of pharyngitis -- not strep pharyngitis, just general sore throat. These are fairly typical in this type of a study, particularly as people are being withdrawn from caffeine for the study and that sort of thing; headaches tend to be pretty prevalent.
In the second study, the multiple-dose study, there were an additional number of headaches -- remember, again, this was over 15 days of dosing with four or five, plus a couple of extra days for the PI dosing before, during and after the SPI-452.
All told, with the number of subjects, we had over 1,000 dosing events, during which time there were about 35 reports of headache in 17 people. Eleven individuals reported nausea or emesis [vomiting] a total of 13 times among those 11. It was interesting that a majority of those tended to occur right before a subsequent dose was given, and it tended to be related to the fact that that's when they were getting their breakfast. As it turns out, I guess not everybody's as big a fan of French toast as I am, because that tended to be one of the prevalent findings and the timing of that finding. There were a few scattered episodes of loose stools as well.
Reporter #3: What was the maximum duration of SPI-452 dosing in your studies?
Robert Guttendorf: It was 15 days.
Reporter #4: What is known, if anything, about the interactions of your compounds with other drug classes that are metabolized by the CYP3A4 isoenzymes, like statins, macrolytes and rifamycins?
Robert Guttendorf: We have conducted several drug-drug interaction studies in vitro and, insofar as we are intending to modulate CYP3A activity, we anticipate that there will be a fair number of drug-drug interaction studies that we'll have to elucidate in the clinic. Obviously, in the HIV area, that's a risk-benefit decision that's pretty well accepted at this point in time. We will evaluate those in further studies. Our study to be done will be a CYP cocktail study, which will evaluate the direct effects of 452 on specific CYP isoforms. That will help guide us, along with additional in vitro studies, on the specific types of drug-drug interaction studies that we'll have to do to support our label.
Brian Kearney: We would expect [GS-9350] to have the same type of 3A-mediated interactions with drugs that metabolize by that pathway. We also intend to do these cocktail studies, which are now recommended by guidance to look at the different specific isoforms.
Reporter #4: In your talk, you said that [with SPI-452] there was a propensity to enhance the concentration of at the end of the dosing interval. That seems kind of unique. What kind of implications would that have?
Robert Guttendorf: The main advantage of that would be that you can enhance the levels and maintain the duration of the drug above its targeted levels. As you know, in order to maintain efficacy, you have to keep levels above this certain target level through the duration of the dosing period. As I think I've said, it has a predilection for doing that as opposed to enhancing the entire profile. In a sense, it's almost like a hinge: If you increase the back end without doing much to the front end, then we're increasing the extent of the efficacy window and not at the same time commensurately increasing the [Cmax?], which would lead to potential additional side effects.
Reporter #5: Dr. Kearney, you had indicated there's a trial [of GS-9350] starting in second quarter this year. My assumption is that you've talked with the FDA [U.S. Food and Drug Administration] and this is headed toward approval. Given that this drug is not a drug per se -- it's a little different than most others -- what are they going to be looking for in terms of duration and size of trial? What are you going to need to prove to them in order to get approval for this compound?
Brian Kearney: To answer the first part of your question, our intent is to start two Phase 2 studies in treatment-naive patients in the second quarter. One will be the quad-tablet compared to Atripla. The second, pending the pharmacokinetic data boosting atazanavir, is a study of 9350 versus ritonavir to boost atazanavir -- each of those combinations taken with Truvada, also in treatment-naive patients. We have had discussions with the FDA and plan to move forward with that in the United States in the second quarter.
Your second question: It is a new chemical entity and it is a drug by definition. Therefore it would be expected to have the same type of data as if you were developing a new antiviral. We worked with the agency and the expectation is that we will provide a safety database, as was mentioned by Dr. Kim [inaudible], who was one of the moderators of the session from FDA. We would seek to comply with that expectation that we would have a sufficient number of subjects studied for over a year -- this tends to be in excess of 500 subjects -- and a larger number of subjects studied for a shorter period of time. Our development program is based on that.
John Mellors: Just to hone in on this a little bit: Will it be sufficient to show that there is safety and equivalent exposure to elvitegravir as that which would be achieved with ritonavir boosting, or do you have to show efficacy as a quad-containing tablet that you would for any new first-line therapy?
Brian Kearney: A lot of the numbers, when you're talking about specific numbers required for approval, go into discussions about the size of the database characterizing the safety of the molecule. As you probably all know, that can be generated from multiple, different clinical studies in different combinations of drugs. That would be the case here as well.
One of aspect of the safety database will be from Phase 3 studies of the quad compared to different regimens that we would consider standard of care, one being Atripla. It's not that you have to show efficacy against all specific other combinations.
What is the definition of efficacy? It'll be defined by the individual Phase 3 studies, which will be designed in concert with the regulators.
Reporter #5: GI symptoms are a big concern for people taking ritonavir, especially diarrhea. In your proof-of-concept study, Brian, when comparing different doses of the compound with ritonavir and placebo, did you collect any data on GI symptoms? Is there any difference?
Brian Kearney: The overall rates of adverse events in those studies were low from single doses to multiple doses. There's no evidence of any dose dependence, between 50, 100, and 200 milligrams, in those studies. Not a lot of GI adverse events.
Reporter #6: Primarily for Robert, I'm wondering if you can maybe say a little bit about what your plans are to combine your drug or use it with boceprevir for hepatitis C. And Brian, if Gilead's also planning anything. Are there other disease models in which pharmaco-enhancement using this kind of compound might be useful?
Robert Guttendorf: At this point, we've shown proof of concept that we are able to enhance the levels of boceprevir [with SPI-452] in vitro, and we are conducting some animal studies now to help confirm that. Our ability to co-administer that with boceprevir is complicated a bit by the fact that it is also an NCE [new chemical entity] and in order to do that we would have to have some sort of collaboration and probably a new IND [investigational new drug application] in collaboration with the developers of boceprevir. However, we do look at that as a very good opportunity, as well as for other PIs in the HCV realm and some other HCV compounds as well.
Beyond the antiviral space, as I mentioned, our PKE platform is actually fairly broad-reaching. We have additional compounds in the pipeline that could come in as either stand-alone or fixed-dose combinations -- that have improved on some of the attributes of SPI-452 -- which could be used for HIV, HCV or elsewhere. In addition to that, we're also developing, additionally, selective PKEs for other CYP isoforms that may be able to be applied outside of the HIV space and antiviral space in general.
Brian Kearney: Our plans [for GS-9350] are most developed for the HIV program right now, but we are looking at opportunities in other therapeutic areas, including HCV.
John Mellors: Thank you very much.
This transcript has been lightly edited for clarity.
No comments have been made.
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