Pivotal Phase 3 data from GTXI's enobosarm phase 3 trials in muscle wasting in NSCLC patients will read out later in 3q-2013. I haven't had time to write up a more detailed post but I thought I would post the relevant notes and quotes below for those in search of background info on the program and the clinical trials.
Note that Ligand Pharma LGND has a similar, phase 2-ready SARM drug LGD-4033. The enobosarm data has been described by LGND management as a gating event for partnering of this compound.
Note that Ligand Pharma LGND has a similar, phase 2-ready SARM drug LGD-4033. The enobosarm data has been described by LGND management as a gating event for partnering of this compound.
SeekingAlpha earnings call transcript
enobosarm phase 3 trials completely enrolled December 2012 in NSCLC muscle wasting patients (325 pts each). 80 sites, majority exUS, did not answer Q as to % in US. Add to Pt doublet. All subjects done May 2013. Data in 3q. Our market research suggests 700-750m peak US sales in this indication [elaborated in q&a as $1500/month low end times 170,000 pts, 5 months duration, tier 3]. Planning additional studies
"in this indication, clinical benefit is defined as maintaining or improving total lean body mass or muscle assessed by DEXA and improving physical function assessed by the Stair Climb Test at day-84. The co-primary endpoints for each of these studies consist of a responder analysis of clinical benefit. Durability of the drug is being evaluated as a secondary endpoint at five months of treatment in those patients who are determined to have responded at day-84. This is not an appetite drug." [contrast to megace]
"We intend to share the top-line data for both studies, POWER 1 and POWER 2, at the same time. The top-line data at a minimum will include the co-primary endpoints of lean body mass and physical function and safety, as well as an update on the survival information at that time." [OS is key 2nd safety endpoint. pool two trials together - won't have reached 450 events, will reveal # deaths per arm per trial... FDA: all we care about is that the trend doesn’t go negative and it can be purely descriptive.]
q&a
-primary endpoint at 3 months, but not unlock data until 5 months (secondary endpt of durability)
Okay. So, do you think you kind of need to see the durability as effective at five months? Do you need the five-month data to be positive as well as the three-month in order to file the drug?
Mitchell Steiner
Well, as you know – the answer is it doesn’t have to be positive, and I’ll tell you – let me say it different way. Because of the fact it’s a five-month endpoint and because of the fact that we’re not powered to show a positive effect at five months from the standpoint of durability, it’s purely descriptive. The FDA sees it as a key secondary endpoint. And so it’s not like you have to have “statistical significance”, but the FDA is interested in seeing what happens to those patients that respond at day-84. [have not decided whether to release durability data with topline results..."But just talking out loud, if we have it, there’s no reason why we can’t share it." ]
how the activity of enobosarm could vary depending on what the non-taxane is that’s used.
Mitchell Steiner
Yes. So our belief is it should not vary. We do not think we’ll have in effect on any of the chemotherapies that enobosarm is metabolized by glucuronidation. And so consequently, it’s – and the body has a huge capacity for glucuronidation. So we’re not expecting, whether it’s a taxane or a non-taxane or platinum, that we will have any appreciable drug-drug interactions of – we’re not concerned about that.
dsmb meets in april and we will comment on outcome after that
Okay, great. Then just regarding the tests, the functional test for example, when are they performed? Are they performed periodically or only at three months or five months?
Mitchell Steiner
They’re being performed at – they’re being performed at baseline, day-42, day-84, day-147.
enobosarm phase 3 trials completely enrolled December 2012 in NSCLC muscle wasting patients (325 pts each). 80 sites, majority exUS, did not answer Q as to % in US. Add to Pt doublet. All subjects done May 2013. Data in 3q. Our market research suggests 700-750m peak US sales in this indication [elaborated in q&a as $1500/month low end times 170,000 pts, 5 months duration, tier 3]. Planning additional studies
"in this indication, clinical benefit is defined as maintaining or improving total lean body mass or muscle assessed by DEXA and improving physical function assessed by the Stair Climb Test at day-84. The co-primary endpoints for each of these studies consist of a responder analysis of clinical benefit. Durability of the drug is being evaluated as a secondary endpoint at five months of treatment in those patients who are determined to have responded at day-84. This is not an appetite drug." [contrast to megace]
"We intend to share the top-line data for both studies, POWER 1 and POWER 2, at the same time. The top-line data at a minimum will include the co-primary endpoints of lean body mass and physical function and safety, as well as an update on the survival information at that time." [OS is key 2nd safety endpoint. pool two trials together - won't have reached 450 events, will reveal # deaths per arm per trial... FDA: all we care about is that the trend doesn’t go negative and it can be purely descriptive.]
q&a
-primary endpoint at 3 months, but not unlock data until 5 months (secondary endpt of durability)
Okay. So, do you think you kind of need to see the durability as effective at five months? Do you need the five-month data to be positive as well as the three-month in order to file the drug?
Mitchell Steiner
Well, as you know – the answer is it doesn’t have to be positive, and I’ll tell you – let me say it different way. Because of the fact it’s a five-month endpoint and because of the fact that we’re not powered to show a positive effect at five months from the standpoint of durability, it’s purely descriptive. The FDA sees it as a key secondary endpoint. And so it’s not like you have to have “statistical significance”, but the FDA is interested in seeing what happens to those patients that respond at day-84. [have not decided whether to release durability data with topline results..."But just talking out loud, if we have it, there’s no reason why we can’t share it." ]
how the activity of enobosarm could vary depending on what the non-taxane is that’s used.
Mitchell Steiner
Yes. So our belief is it should not vary. We do not think we’ll have in effect on any of the chemotherapies that enobosarm is metabolized by glucuronidation. And so consequently, it’s – and the body has a huge capacity for glucuronidation. So we’re not expecting, whether it’s a taxane or a non-taxane or platinum, that we will have any appreciable drug-drug interactions of – we’re not concerned about that.
dsmb meets in april and we will comment on outcome after that
Okay, great. Then just regarding the tests, the functional test for example, when are they performed? Are they performed periodically or only at three months or five months?
Mitchell Steiner
They’re being performed at – they’re being performed at baseline, day-42, day-84, day-147.
Citi webcast via SeekingAlpha
prior DSMB meeting was in October 2012
"Think of it as a testosterone product that’s not a steroid but it mimics testosterone, binds to the androgen receptor, it builds muscle, it builds bone.
But unlike testosterone, it does not cause hair growth, for example, in women. It doesn’t cause the voice box to get large. It doesn’t cause edema in men, at least (inaudible). It’s a selective agent."
"In cancer patients, they selectively lose muscle and then after they lose muscle they begin to lose fat. And if you give them nutrient fat calories back they do not grow that muscle back. They are in total catabolic activity. So they really need help with an anabolic agent.
So with that said, why do we pick non-small cell lung cancer? The reason we picked non-small cell lung cancer is we did a Phase IIB with five different cancer types. All of the cancer patients lose muscle and then lose fat.
But lung cancer is one of those cancers where they lose it in a timeframe that you can do a clinical trial and get the answer in an expeditious manner and it’s also the number one, unfortunately, cancer, both in men and women, so it’s a large market."
"Muscle loss is independent of fat and it’s the muscle that’s a quality tissue that gets the patient into trouble. So half the patients with non-small cell lung cancer will present with muscle loss. Another 70% will go on to lose muscle and 88% already complaining at the time of diagnosis Stage 3, Stage 4 that already have lower body functional limitations, including inability to climb stairs, lift or carry 10 pounds, walk a quarter mile, stoop, crouch or kneel."
"Now, the Phase IIB, we did an analysis. It was an ad hoc analysis to look at the data the same way we’re looking at the data in our Phase IIIs. And essentially there were 61 of the 159 patients in this study that had non-small cell lung cancer and the mean weight loss at entry was 9.7%.
And we were able to show that when you look at a responder’s analysis, the definition of a responder’s analysis – we usually pick this definition – is this is the definition that the FDA and GTx agreed would represent clinical benefit. That’s important.
What you don’t want to do is be in a position where you look at your active compound versus your placebo and at the end of the study then have a discussion with FDA about what the clinical benefit means.
So what we did was we picked clinical benefit definition first, which is defined as maintaining your lean body mass and the second clinical benefit would be a 10% improvement in power measured by stair climb.
If you hit that, you’re a yes. If you die, you’re a no. If you don’t come in for the assessment, you’re a no. If you come in for the assessment and you don’t make it, you’re a no."
"So we did that in this study for physical function, stair climb. About 20% of the placebo patients were able with their chemotherapy alone to have the ability to improve their stair climb power by 10% or more. With the Enobosarm it was 42%.
And for lean body mass, being able to maintain their lean body mass or improve, it was 24% and it was 42% for Enobosarm"
start sarm right with first line chemo
one study with pt-taxane, one with non taxane
data in july/august timeframe..it's dynamic (8 countries and 80 sites to clean up). 1) primary endpt 2( safety 3)OS update
"And the reason it’s an update is because we need to hit 450 deaths to make a decision and we will not have hit 450 deaths at the time that we present the top line data but we’ll at least tell you the numbers of deaths in each of the arms. This way you can get a sense. All the FDA cares about and it’s descriptive is that we’re not a detriment to survival."
"The IP is strong. We have the first composition of matter of patent would run out in 2024. And with the patent extension of five years, it would be 2029. We have issued patents in the us, issued patents in Japan and we just recently learned that there’s been no opposition to our patents in Europe and we expect that one to be issued shortly."
q&a - shooting for nda filing end of 13/early 14- depends on data as well as phase 1 trials that we are running for the label. fast track makes priorty review more likely but not guaranteed
prior DSMB meeting was in October 2012
"Think of it as a testosterone product that’s not a steroid but it mimics testosterone, binds to the androgen receptor, it builds muscle, it builds bone.
But unlike testosterone, it does not cause hair growth, for example, in women. It doesn’t cause the voice box to get large. It doesn’t cause edema in men, at least (inaudible). It’s a selective agent."
"In cancer patients, they selectively lose muscle and then after they lose muscle they begin to lose fat. And if you give them nutrient fat calories back they do not grow that muscle back. They are in total catabolic activity. So they really need help with an anabolic agent.
So with that said, why do we pick non-small cell lung cancer? The reason we picked non-small cell lung cancer is we did a Phase IIB with five different cancer types. All of the cancer patients lose muscle and then lose fat.
But lung cancer is one of those cancers where they lose it in a timeframe that you can do a clinical trial and get the answer in an expeditious manner and it’s also the number one, unfortunately, cancer, both in men and women, so it’s a large market."
"Muscle loss is independent of fat and it’s the muscle that’s a quality tissue that gets the patient into trouble. So half the patients with non-small cell lung cancer will present with muscle loss. Another 70% will go on to lose muscle and 88% already complaining at the time of diagnosis Stage 3, Stage 4 that already have lower body functional limitations, including inability to climb stairs, lift or carry 10 pounds, walk a quarter mile, stoop, crouch or kneel."
"Now, the Phase IIB, we did an analysis. It was an ad hoc analysis to look at the data the same way we’re looking at the data in our Phase IIIs. And essentially there were 61 of the 159 patients in this study that had non-small cell lung cancer and the mean weight loss at entry was 9.7%.
And we were able to show that when you look at a responder’s analysis, the definition of a responder’s analysis – we usually pick this definition – is this is the definition that the FDA and GTx agreed would represent clinical benefit. That’s important.
What you don’t want to do is be in a position where you look at your active compound versus your placebo and at the end of the study then have a discussion with FDA about what the clinical benefit means.
So what we did was we picked clinical benefit definition first, which is defined as maintaining your lean body mass and the second clinical benefit would be a 10% improvement in power measured by stair climb.
If you hit that, you’re a yes. If you die, you’re a no. If you don’t come in for the assessment, you’re a no. If you come in for the assessment and you don’t make it, you’re a no."
"So we did that in this study for physical function, stair climb. About 20% of the placebo patients were able with their chemotherapy alone to have the ability to improve their stair climb power by 10% or more. With the Enobosarm it was 42%.
And for lean body mass, being able to maintain their lean body mass or improve, it was 24% and it was 42% for Enobosarm"
start sarm right with first line chemo
one study with pt-taxane, one with non taxane
data in july/august timeframe..it's dynamic (8 countries and 80 sites to clean up). 1) primary endpt 2( safety 3)OS update
"And the reason it’s an update is because we need to hit 450 deaths to make a decision and we will not have hit 450 deaths at the time that we present the top line data but we’ll at least tell you the numbers of deaths in each of the arms. This way you can get a sense. All the FDA cares about and it’s descriptive is that we’re not a detriment to survival."
"The IP is strong. We have the first composition of matter of patent would run out in 2024. And with the patent extension of five years, it would be 2029. We have issued patents in the us, issued patents in Japan and we just recently learned that there’s been no opposition to our patents in Europe and we expect that one to be issued shortly."
q&a - shooting for nda filing end of 13/early 14- depends on data as well as phase 1 trials that we are running for the label. fast track makes priorty review more likely but not guaranteed
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