The RheumNow Week In Review 4 August 2017 Save
The RheumNow Week In Review 4 August 2017 by Dr. Cush
Transcription
Hi. I'm Jack Cush, executive editor of roomnow.com. This is the 08/04/2017, and that means it's the RheumNow we can review. This week, a lot of action at the FDA. Tune in, find out what gets you approved and what gets you disapproved with the big shots in Bethesda.
So at the top of the news, regulatory information, Amgen has actually submitted its BLA, the biologic license application, to the FDA for the consideration of denosumab as treatment for glucocorticoid induced osteoporosis. They have the trials. They have the data. The time is right. It would be helpful to have more options for patients so we could prevent this particularly bothersome problem.
An interesting study, about, what gives you cutaneous problems in patients with scleroderma. A study of a hundred and sixty five patients with scleroderma that looked at the influence of certain autoantibodies found that if you're double positive for anticentromere antibodies and anti IFI 16, that's inducible interferon protein 16 antibodies, you're at a substantially larger risk for vascular events, including bad ones, including digital gangrene, digital ulcers, digital pits. But, in fact, if you have this double positivity, you're threefold more likely to have very severe Raynaud's. So it's a nice biomarker, for those who may have more vascular digital disease in scleroderma. A review of patients with inflammatory bowel disease, specifically a three hundred sixteen patients who had CAT scans, looked at whether or not these patients had sacroiliitis.
What they found was that amongst the two hundred and thirty three patients with Crohn's disease, fifteen percent had CT evidence of sacroiliitis and that sixteen point nine percent or seventeen percent of of the eighty three ulcerative colitis patients also had sacroiliitis. This is however only found in five to six percent of controls suggesting that of course there is an association with those disorders, but now looking even at patients who may not have symptoms, you can find somewhere between fifteen and sixteen percent of patients who have, proven secretlyitis. Looking at, patients who have scleroderma and the risk of renal, crisis, a Japanese population of six hundred scleroderma patients with systemic sclerosis showed that only three percent developed renal crisis, a low number, and then and it may be a different population than what we're used to, but nonetheless, they did have the other risk factors for renal crisis, including digital gangrene, high dose steroid use, low albumin, and the presence of cardiac involvement. When a nice interesting study looked at the risk of infections, in patients treated between 1993 and 2013, specifically looking at hospitalizable infections. During the same period, they noted that they increased, and this is in RA patients, that the rate increased from ninety to over two hundred and six, more than doubling per 100,000 patient years, suggesting, again, hundred thousand patients followed for a year, that two hundred six of them would end up in the hospital with a serious infection.
What happened during this time period? Sepsis tripled, but what didn't go up was that pneumonia, UTI, and opportunistic infections. So there are trends towards increasing infections in the biologic era, if you will. Is that because we're treating patients who are sicker or is it the drugs? Again, it's interesting data.
A nice study looked at, the risk of, major, congenital malformations amongst patients taking etanercept. And this was data, a study that was actually sponsored by Amgen done with some outcomes researchers, and they showed that there was no increased risk of malformations when you looked at, patients who received etanercept during their pregnancy. The data was pretty impressive that they actually had etanercept exposed women and etanercept non exposed women and then normal population. They showed that the rate of major malformations was at six percent or less and not different between these groups, suggesting that, this would not be a teratogen and a risk factor for congenital anomalies. An interesting study looked at lupus hospitalization and showed that it's actually quite common and maybe more substantial than we previously realized.
This was from Mary Urowitz's group in Canada and Toronto specifically, where they looked at two forty seven lupus patients and noted four ninety one hospitalizations with a risk of hospitalization of being about one point six per patient. That these hospitalizations lasted on average eight and a half days. They found actually, my contention has always been that when a lupus patient goes into the hospital, he or she is more likely to be in the hospital for medical reasons and medication reasons rather than lupus. And in fact, their data supported this. They showed that the most common cause of hospitalization, what they call incidental causes, drug reactions, management of pain, things that are not related to lupus or lupus activity.
What they also found, and that was at thirty one, thirty six percent, thirty six percent. Active lupus was next most common, so these were lupus defined features, was the cause of hospitalization in twenty one percent of patients. And that infection, not necessarily a lupus related phenomenon, only in twenty two percent. So overall, my impressions have been true and borne out by their data. Thank you, Doctor.
Urowitz. But interestingly, death was not an uncommon event. Three percent of patients died, thirteen percent required ICU admission, and more importantly, that if you were admitted, you had a forty percent chance of rehospitalization. So there's a lot to deal with as far as sick patients and lupus and hospitalization. I think this is a nice study that documents the magnitude of this problem.
I think the highlight of the week comes from the two hearings that occurred on August 2 and August 3, wherein the FDA convened the Arthritis Advisory Committee to consider on the second, the safety of cirucoumab in rheumatoid arthritis, and on the third, the efficacy and safety of tofacitinib in patients with psoriatic arthritis. First, cirucumab. The panel met for a full day meeting and decided, although everyone agreed, the FDA and the presenters for the company Janssen, that the drug was very efficacious, had good evidence of radiographic protection. Everyone was unanimous in that opinion. But the big problem was that there was a safety signal.
And in fact, there was an imbalance specifically of all cause mortality where they identified thirty five deaths in their studies that were submitted for evaluation. One was in the placebo population and thirty four were in those treated with cerucamib. So safety was the big problem. There was an imbalance with other signals as well, but that was the major one. And the real problem here is that this study was a both studies were placebo controlled trials that did allow for early escape at week eighteen and also week forty for patients who were not responding and or needing other therapy.
When they looked at the placebo patients who crossed over and took early escape, those patients were actually quite sick, had much more disease activity, had a very different profile than the rest of the patient. It turns out that they made up a substantial number of the safety features including deaths, MACE events, infections, etcetera. So the question was, was this an unfortunate feature of a design that's supposed to be favorable to patients, allow them an exit so they don't have to withdraw placebo for six months. But by allowing such patients to withdraw, now you're stacking the deck or skewing the results. It didn't really matter whether it was related or unrelated or true.
The panelists, although they, admitted that this could be chance and, results subject to bias, that they could not approve a third IL-six inhibitor, cirucumab, when two are currently on the market, that being tocilizumab and cirilumab just approved earlier this year. So this drug will go in front of the FDA for final decision. It's unlikely it'll be approved. It's unknown whether or not the sponsor will take this further. I would guess not.
The second meeting occurred on the third and the arthritis advisory panel was asked to consider the potential approval of tofacitinib in patients with psoriatic arthritis. This was based on two trials, two large trials, over almost 800 patients, and the data was very clear. I mean, it worked as far as ACR20, fifty, seventy. It showed efficacy in dactylitis and enthesitis, and patient reported outcomes, including facet and HACS scores. It was a slew of clinical parameters that favored, strongly favored the drug, even when there was an active comparator, with adalimumab, which it was in these studies equal to.
The only problem with this particular trial, and again, the panel voted 10 to one to approve the drug for the indication of patients with moderate to severely active psoriatic arthritis. The real problem was in whether or not to include the X-ray data. One of the studies was a twenty four week study, one was a fifty two week study that actually had, an x-ray outcome. The sponsor said that the study was not done to get an x-ray indication but instead to prove that patients were not getting worse radiographically while their joints were improving clinically. And in fact, that's what was seen.
Patients did not worsen, but what they saw in placebo and actively treated patients with tofacitinib at five or ten milligrams BID that there was no advantage to the drug, and that basically the problem was that patients in this trial didn't progress very much at all, and that could be a function of getting patients in trials these days or doing x-ray outcomes. The question is, should this be a caveat and a feature for doctors to look at or should it be in the label? I think that the panelists expressed the opinion the x-ray data should not be in the label because they did not do a trial that proved whether it does work or doesn't work, and the findings that they have shouldn't be construed as an endorsement for no change because really nobody changed in the trial including the placebo populations. So that's it for this week at roomnow.com. Be sure to go to the website.
You can download slides from our daily downloads section. Right now we have featured slides on the biosimilar survey that we conducted or three months ago. And obviously there are other downloads as well. Tune in, go to the website to get these links and other news from roomnow.com. See you next week.
So at the top of the news, regulatory information, Amgen has actually submitted its BLA, the biologic license application, to the FDA for the consideration of denosumab as treatment for glucocorticoid induced osteoporosis. They have the trials. They have the data. The time is right. It would be helpful to have more options for patients so we could prevent this particularly bothersome problem.
An interesting study, about, what gives you cutaneous problems in patients with scleroderma. A study of a hundred and sixty five patients with scleroderma that looked at the influence of certain autoantibodies found that if you're double positive for anticentromere antibodies and anti IFI 16, that's inducible interferon protein 16 antibodies, you're at a substantially larger risk for vascular events, including bad ones, including digital gangrene, digital ulcers, digital pits. But, in fact, if you have this double positivity, you're threefold more likely to have very severe Raynaud's. So it's a nice biomarker, for those who may have more vascular digital disease in scleroderma. A review of patients with inflammatory bowel disease, specifically a three hundred sixteen patients who had CAT scans, looked at whether or not these patients had sacroiliitis.
What they found was that amongst the two hundred and thirty three patients with Crohn's disease, fifteen percent had CT evidence of sacroiliitis and that sixteen point nine percent or seventeen percent of of the eighty three ulcerative colitis patients also had sacroiliitis. This is however only found in five to six percent of controls suggesting that of course there is an association with those disorders, but now looking even at patients who may not have symptoms, you can find somewhere between fifteen and sixteen percent of patients who have, proven secretlyitis. Looking at, patients who have scleroderma and the risk of renal, crisis, a Japanese population of six hundred scleroderma patients with systemic sclerosis showed that only three percent developed renal crisis, a low number, and then and it may be a different population than what we're used to, but nonetheless, they did have the other risk factors for renal crisis, including digital gangrene, high dose steroid use, low albumin, and the presence of cardiac involvement. When a nice interesting study looked at the risk of infections, in patients treated between 1993 and 2013, specifically looking at hospitalizable infections. During the same period, they noted that they increased, and this is in RA patients, that the rate increased from ninety to over two hundred and six, more than doubling per 100,000 patient years, suggesting, again, hundred thousand patients followed for a year, that two hundred six of them would end up in the hospital with a serious infection.
What happened during this time period? Sepsis tripled, but what didn't go up was that pneumonia, UTI, and opportunistic infections. So there are trends towards increasing infections in the biologic era, if you will. Is that because we're treating patients who are sicker or is it the drugs? Again, it's interesting data.
A nice study looked at, the risk of, major, congenital malformations amongst patients taking etanercept. And this was data, a study that was actually sponsored by Amgen done with some outcomes researchers, and they showed that there was no increased risk of malformations when you looked at, patients who received etanercept during their pregnancy. The data was pretty impressive that they actually had etanercept exposed women and etanercept non exposed women and then normal population. They showed that the rate of major malformations was at six percent or less and not different between these groups, suggesting that, this would not be a teratogen and a risk factor for congenital anomalies. An interesting study looked at lupus hospitalization and showed that it's actually quite common and maybe more substantial than we previously realized.
This was from Mary Urowitz's group in Canada and Toronto specifically, where they looked at two forty seven lupus patients and noted four ninety one hospitalizations with a risk of hospitalization of being about one point six per patient. That these hospitalizations lasted on average eight and a half days. They found actually, my contention has always been that when a lupus patient goes into the hospital, he or she is more likely to be in the hospital for medical reasons and medication reasons rather than lupus. And in fact, their data supported this. They showed that the most common cause of hospitalization, what they call incidental causes, drug reactions, management of pain, things that are not related to lupus or lupus activity.
What they also found, and that was at thirty one, thirty six percent, thirty six percent. Active lupus was next most common, so these were lupus defined features, was the cause of hospitalization in twenty one percent of patients. And that infection, not necessarily a lupus related phenomenon, only in twenty two percent. So overall, my impressions have been true and borne out by their data. Thank you, Doctor.
Urowitz. But interestingly, death was not an uncommon event. Three percent of patients died, thirteen percent required ICU admission, and more importantly, that if you were admitted, you had a forty percent chance of rehospitalization. So there's a lot to deal with as far as sick patients and lupus and hospitalization. I think this is a nice study that documents the magnitude of this problem.
I think the highlight of the week comes from the two hearings that occurred on August 2 and August 3, wherein the FDA convened the Arthritis Advisory Committee to consider on the second, the safety of cirucoumab in rheumatoid arthritis, and on the third, the efficacy and safety of tofacitinib in patients with psoriatic arthritis. First, cirucumab. The panel met for a full day meeting and decided, although everyone agreed, the FDA and the presenters for the company Janssen, that the drug was very efficacious, had good evidence of radiographic protection. Everyone was unanimous in that opinion. But the big problem was that there was a safety signal.
And in fact, there was an imbalance specifically of all cause mortality where they identified thirty five deaths in their studies that were submitted for evaluation. One was in the placebo population and thirty four were in those treated with cerucamib. So safety was the big problem. There was an imbalance with other signals as well, but that was the major one. And the real problem here is that this study was a both studies were placebo controlled trials that did allow for early escape at week eighteen and also week forty for patients who were not responding and or needing other therapy.
When they looked at the placebo patients who crossed over and took early escape, those patients were actually quite sick, had much more disease activity, had a very different profile than the rest of the patient. It turns out that they made up a substantial number of the safety features including deaths, MACE events, infections, etcetera. So the question was, was this an unfortunate feature of a design that's supposed to be favorable to patients, allow them an exit so they don't have to withdraw placebo for six months. But by allowing such patients to withdraw, now you're stacking the deck or skewing the results. It didn't really matter whether it was related or unrelated or true.
The panelists, although they, admitted that this could be chance and, results subject to bias, that they could not approve a third IL-six inhibitor, cirucumab, when two are currently on the market, that being tocilizumab and cirilumab just approved earlier this year. So this drug will go in front of the FDA for final decision. It's unlikely it'll be approved. It's unknown whether or not the sponsor will take this further. I would guess not.
The second meeting occurred on the third and the arthritis advisory panel was asked to consider the potential approval of tofacitinib in patients with psoriatic arthritis. This was based on two trials, two large trials, over almost 800 patients, and the data was very clear. I mean, it worked as far as ACR20, fifty, seventy. It showed efficacy in dactylitis and enthesitis, and patient reported outcomes, including facet and HACS scores. It was a slew of clinical parameters that favored, strongly favored the drug, even when there was an active comparator, with adalimumab, which it was in these studies equal to.
The only problem with this particular trial, and again, the panel voted 10 to one to approve the drug for the indication of patients with moderate to severely active psoriatic arthritis. The real problem was in whether or not to include the X-ray data. One of the studies was a twenty four week study, one was a fifty two week study that actually had, an x-ray outcome. The sponsor said that the study was not done to get an x-ray indication but instead to prove that patients were not getting worse radiographically while their joints were improving clinically. And in fact, that's what was seen.
Patients did not worsen, but what they saw in placebo and actively treated patients with tofacitinib at five or ten milligrams BID that there was no advantage to the drug, and that basically the problem was that patients in this trial didn't progress very much at all, and that could be a function of getting patients in trials these days or doing x-ray outcomes. The question is, should this be a caveat and a feature for doctors to look at or should it be in the label? I think that the panelists expressed the opinion the x-ray data should not be in the label because they did not do a trial that proved whether it does work or doesn't work, and the findings that they have shouldn't be construed as an endorsement for no change because really nobody changed in the trial including the placebo populations. So that's it for this week at roomnow.com. Be sure to go to the website.
You can download slides from our daily downloads section. Right now we have featured slides on the biosimilar survey that we conducted or three months ago. And obviously there are other downloads as well. Tune in, go to the website to get these links and other news from roomnow.com. See you next week.
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