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FTY720 passes first hurdle in US approval
FDA Advisory Committee Unanimously Recommends Approval of Novartis Investigational Treatment FTY720 to Treat Relapsing Remitting MS
-- Committee voted in favor of approval of FTY720 (fingolimod [now Gilenia]), as treatment in relapsing remitting multiple sclerosis, affirming the drugs positive benefit/risk profile
-- FTY720, potentially first in a new class of MS therapy, represents a significant advance as an efficacious oral treatment for people with relapsing remitting MS
-- Committee recommended post marketing collection of additional safety data and evaluation of a lower dose
The committee evaluated data from the largest clinical trial program ever submitted to the FDA as part of an MS new drug application. This study data provided evidence of superior efficacy of FTY720 over one of the most commonly prescribed treatments, interferon beta-1a IM (Avonex®), and to placebo, in reducing relapses and brain lesions (a measure of disease activity) (1,2). In addition, the two-year placebo-controlled study showed FTY720 significantly delayed disability progression.
The FDA granted FTY720 priority review status in February 2010, reducing the standard 10-month review to six months. In May, the FDA extended the priority review period by three months to September 2010.
from http://www.prnewswire.com/news-releases/fda-advisory-committee-unanimously-recommends-approval-of-novartis-investigational-treatment-fty720-to-treat-relapsing-remitting-ms-96104399.html
So I guess now we wait to see what happens in September.
sho
So this is a promising first step, but the
-- Committee voted in favor of approval of FTY720 (fingolimod [now Gilenia]), as treatment in relapsing remitting multiple sclerosis, affirming the drugs positive benefit/risk profile
-- FTY720, potentially first in a new class of MS therapy, represents a significant advance as an efficacious oral treatment for people with relapsing remitting MS
-- Committee recommended post marketing collection of additional safety data and evaluation of a lower dose
The committee evaluated data from the largest clinical trial program ever submitted to the FDA as part of an MS new drug application. This study data provided evidence of superior efficacy of FTY720 over one of the most commonly prescribed treatments, interferon beta-1a IM (Avonex®), and to placebo, in reducing relapses and brain lesions (a measure of disease activity) (1,2). In addition, the two-year placebo-controlled study showed FTY720 significantly delayed disability progression.
The FDA granted FTY720 priority review status in February 2010, reducing the standard 10-month review to six months. In May, the FDA extended the priority review period by three months to September 2010.
from http://www.prnewswire.com/news-releases/fda-advisory-committee-unanimously-recommends-approval-of-novartis-investigational-treatment-fty720-to-treat-relapsing-remitting-ms-96104399.html
So I guess now we wait to see what happens in September.
sho
So this is a promising first step, but the
Thanks so much for taking the time to do such a wonderful write up on your experience with FTY720 and other oral drugs for MS.
I agree with you that if and when these drugs come available, we have to really look at our personal circumstances and make this decision carefully with our doctor's.
The more I am learning about the oral drugs and knowing my personal health history, I am not as gung-ho about jumping on the bandwagon.
Again, I appreciate your putting your thoughts down on this very important subject..
Julie
I agree with you that if and when these drugs come available, we have to really look at our personal circumstances and make this decision carefully with our doctor's.
The more I am learning about the oral drugs and knowing my personal health history, I am not as gung-ho about jumping on the bandwagon.
Again, I appreciate your putting your thoughts down on this very important subject..
Julie
All very interesting to somone who is going for medical screening for another oral drug this week in UK. Hope I have my eyes open as wide as posible before I jump...but still feel a little scared of what is ahead. Will start my journal about drug trial soon.
Sarah
Sarah
Here is an interesting article on cladribine, that also talks about what is measured in MS clinical trials:
http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1629
"Freedom from any disease activity, including relapse, disability progression, or MRI progression, was experienced by 44.3% of patients treated with a high-dose of cladribine, and 43% of patients randomized to a low-dose regimen compared with 16% of placebo patients ...
"'Disease activity-free outcome is a composite efficacy parameter that may become the gold standard for measuring remission,' [Gavin Giovannoni] said.
"'We are looking for more sensitive disease outcomes in MS trials,' Patricia Coyle, MD, of the State University of New York at Stony Brook, told MedPage Today.
"'I think freedom from disease activity is a very appealing primary outcome in future relapsing trials to replace attack rate,' which, she said, is 'way down, even in placebo arms.' She said there were multiple reasons for the decline in attack rate, including earlier treatment.
"That success has made it more difficult to assess disease modifying drugs. The appeal of freedom from disease activity as an endpoint, Coyle said, 'is that first, it is a composite outcome, combining clinical and MRI activity, and second, it is setting the bar higher. It's a much more demanding outcome, but it is a very reasonable one' ...
"The new results were from the recently published CLARITY study, a phase III trial of oral cladribine versus placebo. The primary endpoints in that study indicated cladribine's ability to reduce the relapse rate by more than 50%, MRI lesions by up to 88%, and the risk for three-month disability progression by more than 30%...
"Freedom from disease activity was defined as having no relapse, no sustained three-month disease progression, and an absence of T1 gadolinium-enhancing lesions and active T2 lesions over the course of the trial."
Freedom from disease activity sounds intriguing as a measurement. On the other hand, I think I would've met the qualifications for being free from disease activity during the FTY720 trial since I had no radiological changes and I don't think they would say I had progressed since my EDSS did not change by more than half a point and didn't ever get higher than it was when I started the trial. Nevertheless, I am clearly worse off than I was when I started the trial. However, it is also not really clear that I have RRMS or that I even had it when I started the trial and they really only seem to be proposing this measure for RRMS.
sho
http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1629
"Freedom from any disease activity, including relapse, disability progression, or MRI progression, was experienced by 44.3% of patients treated with a high-dose of cladribine, and 43% of patients randomized to a low-dose regimen compared with 16% of placebo patients ...
"'Disease activity-free outcome is a composite efficacy parameter that may become the gold standard for measuring remission,' [Gavin Giovannoni] said.
"'We are looking for more sensitive disease outcomes in MS trials,' Patricia Coyle, MD, of the State University of New York at Stony Brook, told MedPage Today.
"'I think freedom from disease activity is a very appealing primary outcome in future relapsing trials to replace attack rate,' which, she said, is 'way down, even in placebo arms.' She said there were multiple reasons for the decline in attack rate, including earlier treatment.
"That success has made it more difficult to assess disease modifying drugs. The appeal of freedom from disease activity as an endpoint, Coyle said, 'is that first, it is a composite outcome, combining clinical and MRI activity, and second, it is setting the bar higher. It's a much more demanding outcome, but it is a very reasonable one' ...
"The new results were from the recently published CLARITY study, a phase III trial of oral cladribine versus placebo. The primary endpoints in that study indicated cladribine's ability to reduce the relapse rate by more than 50%, MRI lesions by up to 88%, and the risk for three-month disability progression by more than 30%...
"Freedom from disease activity was defined as having no relapse, no sustained three-month disease progression, and an absence of T1 gadolinium-enhancing lesions and active T2 lesions over the course of the trial."
Freedom from disease activity sounds intriguing as a measurement. On the other hand, I think I would've met the qualifications for being free from disease activity during the FTY720 trial since I had no radiological changes and I don't think they would say I had progressed since my EDSS did not change by more than half a point and didn't ever get higher than it was when I started the trial. Nevertheless, I am clearly worse off than I was when I started the trial. However, it is also not really clear that I have RRMS or that I even had it when I started the trial and they really only seem to be proposing this measure for RRMS.
sho
That's a hard question. I was on the real drug in the FTY720 trial for 18 months and it had no discernible effect so far as I could tell. I didn't get any side effects, but I continued to gradually get worse over the long run (which is basically what I was doing before I started the FTY720).
That doesn't mean it didn't do anything, though. It seems like a lot of these drugs only prove themselves statistically over large numbers of people and it's not always obvious to the individual. Plus no one can say what might've happened if I hadn't been on the drug. There's also the problem of responders and non-responders, which you have with any MS drug. Some people seem to have had very good experiences with FTY720 and even had some improvement. For myself, I don't think I will try to go back on it if it comes to market. The benefits, if any, were minimal so I don't think they outweigh the risks of the unknown.
All of the DMDs target the immune system and associated inflammation in some way, which is why they are thought not to be effective in progressive MS. They don't even know for sure what the role of the autoimmune response is in MS or whether it is the fundamental mechanism that drives MS. Since I don't seem to have much acute inflammation, several neuros have told me that they don't think the standard CRAB drugs will help me. Even though FTY720 is being investigated primarily for its effects on the immune system, my neuro did think that the fact that FTY720 is thought to have some neuroprotective effects or even possibly the ability to perform neural repair to some degree meant that it might be more likely to help me. It didn't seem to, but they are doing a PPMS trial with FTY720 and I am very interested to see what the results of that will be.
Here is how I understand the general trade-offs between the current CRAB drugs and the new oral meds in general.
COST: both will probably continue to be insanely expensive so I'd say this is a wash
CONVENIENCE: Oral meds win hands down. Taking a pill once a day is way easier than managing the injectables (temperature control, carrying them around) plus having to actually inject yourself. The CRAB drugs also have a lot of side effects that, even though they are not dangerous, are unpleasant, like the flu-like symptoms of the interferons or the injection site problems with Copaxone (apparently, they have actually been studying a lower dose of Copaxone which seems to maintain the drug's effectiveness while cutting down on the welting and dimpling)
SHORT-TERM SAFETY: CRABs have not been shown to have any serious side effects that can't be prevented or reversed by reasonable monitoring (liver enzymes, depression) and don't seem to have ever killed anyone. The oral meds have a sketchier safety profile. Two people have died of infections in FTY720 trials, albeit on higher doses than the one that the FDA is being asked to approve. Since the newer drugs are immunosuppressants (the CRABs are immunomodulatory so they change the immune system without suppressing it), they are inherently more dangerous. For FTY720 side effects, the Accelerated Cure blog (http://msnews.acceleratedcure.org/node/3597) gives the examples of "cardiac problems, an eye disorder called macular edema, and impaired lung function." There is also some info on the FDA website at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm214668.htm from the recent meeting.
LONG-TERM SAFETY: CRABs have been in use for 10-15 years and haven't thus far turned out to be ticking time bombs. It is unknown whether the oral DMDs will have a worse safety profile if they are used for a longer period of time or if they make changes (like increasing the risk for cancer) that will only become apparent of over time. In wider, long-term use, FTY720 may also make people vulnerable to PML, like Tysabri does. It hasn't happened yet, but no one can rule out the possibility. FTY720 also does some weird thing to mouse lungs. They are not sure if it does the same to human lungs or what the significance of this change is.
You can get very different info depending on who you talk to. Even in the trial, I got very different impressions of the safety profile of FTY720 from my neuro and the neuro in change of the trial. You'd think they might stick to some party line, but no. And no one can know what the long-term safety profile is.
EFFECTIVENESS: Oral meds, in order to get approved, have to show that they are significantly more effective than the current CRAB drugs. Thus far, the ones that are close to approval do seem to be significantly better at the standard measurements of number of clinical relapses and MRI changes. I'm not sure you can say much that is definitive about progression in the short amount of time that these trials have run, but that also seems promising.
So the bottom line seems to be that on balance, the oral DMDs are both more effective and more dangerous. They also have more unknowns.
It seems like with almost everything related to MS, it's impossible to know what the right choice is. You can research and learn as much as you can and you can evaluate your choices against your priorities, but in the end, you just have to make a choice, close your eyes and jump.
So I guess everybody has to look at their own situation and make their own choice. If you're seriously interested in oral DMDs, in addition to FTY720, it seems likely that Cladribine will come to market soonish so it would probably pay off to research both.
sho
That doesn't mean it didn't do anything, though. It seems like a lot of these drugs only prove themselves statistically over large numbers of people and it's not always obvious to the individual. Plus no one can say what might've happened if I hadn't been on the drug. There's also the problem of responders and non-responders, which you have with any MS drug. Some people seem to have had very good experiences with FTY720 and even had some improvement. For myself, I don't think I will try to go back on it if it comes to market. The benefits, if any, were minimal so I don't think they outweigh the risks of the unknown.
All of the DMDs target the immune system and associated inflammation in some way, which is why they are thought not to be effective in progressive MS. They don't even know for sure what the role of the autoimmune response is in MS or whether it is the fundamental mechanism that drives MS. Since I don't seem to have much acute inflammation, several neuros have told me that they don't think the standard CRAB drugs will help me. Even though FTY720 is being investigated primarily for its effects on the immune system, my neuro did think that the fact that FTY720 is thought to have some neuroprotective effects or even possibly the ability to perform neural repair to some degree meant that it might be more likely to help me. It didn't seem to, but they are doing a PPMS trial with FTY720 and I am very interested to see what the results of that will be.
Here is how I understand the general trade-offs between the current CRAB drugs and the new oral meds in general.
COST: both will probably continue to be insanely expensive so I'd say this is a wash
CONVENIENCE: Oral meds win hands down. Taking a pill once a day is way easier than managing the injectables (temperature control, carrying them around) plus having to actually inject yourself. The CRAB drugs also have a lot of side effects that, even though they are not dangerous, are unpleasant, like the flu-like symptoms of the interferons or the injection site problems with Copaxone (apparently, they have actually been studying a lower dose of Copaxone which seems to maintain the drug's effectiveness while cutting down on the welting and dimpling)
SHORT-TERM SAFETY: CRABs have not been shown to have any serious side effects that can't be prevented or reversed by reasonable monitoring (liver enzymes, depression) and don't seem to have ever killed anyone. The oral meds have a sketchier safety profile. Two people have died of infections in FTY720 trials, albeit on higher doses than the one that the FDA is being asked to approve. Since the newer drugs are immunosuppressants (the CRABs are immunomodulatory so they change the immune system without suppressing it), they are inherently more dangerous. For FTY720 side effects, the Accelerated Cure blog (http://msnews.acceleratedcure.org/node/3597) gives the examples of "cardiac problems, an eye disorder called macular edema, and impaired lung function." There is also some info on the FDA website at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/ucm214668.htm from the recent meeting.
LONG-TERM SAFETY: CRABs have been in use for 10-15 years and haven't thus far turned out to be ticking time bombs. It is unknown whether the oral DMDs will have a worse safety profile if they are used for a longer period of time or if they make changes (like increasing the risk for cancer) that will only become apparent of over time. In wider, long-term use, FTY720 may also make people vulnerable to PML, like Tysabri does. It hasn't happened yet, but no one can rule out the possibility. FTY720 also does some weird thing to mouse lungs. They are not sure if it does the same to human lungs or what the significance of this change is.
You can get very different info depending on who you talk to. Even in the trial, I got very different impressions of the safety profile of FTY720 from my neuro and the neuro in change of the trial. You'd think they might stick to some party line, but no. And no one can know what the long-term safety profile is.
EFFECTIVENESS: Oral meds, in order to get approved, have to show that they are significantly more effective than the current CRAB drugs. Thus far, the ones that are close to approval do seem to be significantly better at the standard measurements of number of clinical relapses and MRI changes. I'm not sure you can say much that is definitive about progression in the short amount of time that these trials have run, but that also seems promising.
So the bottom line seems to be that on balance, the oral DMDs are both more effective and more dangerous. They also have more unknowns.
It seems like with almost everything related to MS, it's impossible to know what the right choice is. You can research and learn as much as you can and you can evaluate your choices against your priorities, but in the end, you just have to make a choice, close your eyes and jump.
So I guess everybody has to look at their own situation and make their own choice. If you're seriously interested in oral DMDs, in addition to FTY720, it seems likely that Cladribine will come to market soonish so it would probably pay off to research both.
sho
I do hope that everything stays positive with this....would be so nice to see shots as a thing of the past....like the bee stings!
Addi
Addi
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