A funny thing happened when the Europeans evaluated the same trial data that led to the approval of idelalisib in the US. They saw things differently....
Doctors and patients alike are quite interested in knowing the "package insert" for a medication. Essentially it contains the prescribing information on how to use the drug and for what conditions it is approved. This is enormously important because it often determines when an insurance company will have to pay for it to be used.
The US FDA and the European Commission on Medicinal Products look at new drugs independently. They look at all the safety of all the clinical trials and the efficacy and come to their own conclusions about when such a drug could / should be used.
The FDA took a very conservative view of the trial data and highlighted the risks and gave a fairly narrowly defined set of circumstances where the drug can be used.
In the US - the FDA has stated that it can be used in patients with CLL:
1) in combination with rituximab in patients who are not suitable for chemotherapy on account of other medical problems.
In Europe - idelalisib has been recommended for approval:
1) in combination with rituximab in patients who have had one prior line of therapy (sounds very similar to the information for ibrutinib)
2) in front line treatment for patients with 17P deletion or TP53 mutation.
2a) The best way to test for TP53 mutation linked here
2b) See my link for the new molecular markers
2c) There is a clinical trial in US utilizing idela/rtx in this same population that can be accessed through our network at these locations
The labeled indications for follicular lymphoma following two prior lines of therapy is quite similar.
The other key differences were regarding the safety of the drug. The US prescribing information highlights the risks of a variety of side effects. Things that happened to 1-2 patients (and may have due to entirely other medications) out of the 1000 treated prior to approval were listed as "black box" warnings. It appears that several of those will be stripped entirely from the European guidelines - will try to update link when it becomes available.
"package inserts" can be "living documents." They get updated as new clinical trials are released. For instance, the role for ibrutinib in patients with 17P was recently updated in the US. I expect that the package insert for both of these agents will continue to expand over time. I think the additional insight provided by our European colleagues shed new perspective on how and where we might think to use the drugs here in the US.
Thanks for reading.
Showing posts with label idelalisib. Show all posts
Showing posts with label idelalisib. Show all posts
Friday, September 19, 2014
Wednesday, July 23, 2014
Idelalisib / Zydelig approved
There is a new kid on the block!
First it was called CAL-101. It is common for a drug company to use letters from the name of the company. In this case, it was originally Calistoga Pharmaceuticals. The 101 part is a little more funny. I understand one of the early investors in the company was driving in Palo Alto California and turned from University Drive onto the 101 highway and decided to call the drug CAL-101. True? False? Not sure.
Then Gilead bought up the drug from Calistoga. Next step? Change the numbers. CAL-101 became GS-1101. GS = Gilead Science. Not sure where the extra "1" came from. Perhaps it was an effort to differentiate from GA-101 which became obinutuzumab before it became Gazyva.
Next step is to give the letter / number combo an actual name. In this case it was idelalisib. As difficult as that seems, it actually makes perfect sense.
Idelalisib (pronounced I-Dela-Lisib)
I=inhibit
Dela= delta isoform of PI3K
Lisib = that is the mandatory suffix of drugs that inhibit PI3K enzymes
I have heard this drug mispronounced so many ways that it is almost comical -I-del-isilib, I-dela-mab, etc. I think I would have chosen Ideltalisib if I were in control of all things as that would make a lot of sense (inhibit-delta-PI3K).
Every drug has two names (brand name vs generic name). You would be amazed how much effort goes into coming up with a name for a drug. You would also be amazed how often drug names begin with the letter "Z." Some sort of market research I don't know about I suppose. So idelalisib is now called Zydelig. I think this is a combo of the "z" and the "delta" but not sure I know where the "ig" comes from.
As if we were not already spoiled by approvals of the latest treatments for CLL including the addition of obinutuzumab and ibrutinib within the last 12 months, now we have yet another new agent that is simultaneously remarkably effective, well tolerated, and has proven to prolong survival for patients with CLL and show efficacy in hard to treat low grade lymphoma!
It has been an interesting race for approval between ibrutinib and idelalisib. These two drugs entered human clinical testing at nearly exactly the same time and in the grand cosmos of time and were approved nearly simultaneously in blinding speed. Idelalisib was the first to present randomized phase III study showing dramatically improved progression free survival (being alive and without progression) as well as improved overall survival against a control arm in CLL. I think ibrutinib ended up crossing the finish line first because they got the early papers published more quickly creating a strong buzz in the literature. Idelalisib was sold from Calistoga pharmaceuticals to Gilead pharmaceuticals midway through the development. This results in enormous changes on the development team that probably caused some regulatory delay while ibrutinib was held onto by Pharmacyclics all the way through development (sparing a joint venture with Jannsen).
We are lucky in NHL/CLL that we have discovered an entire new PATHWAY in which many of the enzymes make good targets for drugs. Since this pathway travels several key enzymes like Syk, BTK, PI3K, we will probably have a multitude of new drugs for these diseases. Indeed, there are several BTK inhibitors, several PI3K inhibitors, several Syk inhibitors all working their way through development.
What is so special about idelalisb?
I've had the opportunity to work with this drug quite a bit over the last several years all the way from the early phase I combination studies through helping the team at Calistoga write the main phase III protocols in relapsed disease. I would like to highlight two patients I have treated with the drug because they both illustrate something really remarkable.
The first patient came into my clinic shortly after I started in Eugene. He had some of the nastiest CLL I've ever seen. He presented with a white blood cell count of about 140 thousand, enormous lymph nodes, and red blood cells and platelets so low that I had to transfuse him weekly. Worse yet, all of his cells had the 17P deletion.
I started him on FCR but after two cycles he had made zero progress and indeed his transfusion requirement went up. I gave him campath and rituximab which at least cleared his marrow enough to stop transfusions but he still had big bulky nodes and was considered ineligible for transplant. From there we quickly cycled through R-ESHAP, R-Bendamustine, high dose steroids, revlimid and ofatumumab. Unfortunately that list of drugs took quite a toll on him and he was back to weekly transfusions.
We got him enrolled onto an idelalisib study and it was magic. His white blood cells shot up immediately (typical for these drugs), and his nodes shrank. His marrow began to "wake up" and we got him off of his transfusions again. Indeed, he went two and a half years almost completely normal taking only his idelalisib before his disease became problematic again. It was amazing to see him take advantage of the time this drug gave him - his life was completely changed by idelalisib in a way that was profoundly meaningful.
The second patient is an older gentleman with mantle cell lymphoma. He had a few lines of therapy before his MCL became a problem and we got him enrolled into the first ever clinical study of ibrutinib. He had several years of fantastic disease control on ibrutinib before he began having problems. He developed a cough and was short of breath. We found that one of his lungs had filled up with fluid from his lymphoma. We sent the sample for analysis and found that he had the BTK Cys481Ser mutation that inactivates ibrutinib. We were able to get him enrolled on an idelalisib study and that was over a year ago. His lungs cleared up, cough improved, fluid was dramatically reduced, etc.
Zydelig is approved in combination with rituximab for patients with relapsed CLL AND as a single agent (no rituximab) for patients with follicular lymphoma / small lymphocytic lymphoma who have become refractory to rituximab AND alkalating agents (bendamustine, chlorambucil, Cytoxan). Ongoing studies are likely to expand the circumstances where it is approved.
These are good times indeed!
Thanks for reading.
First it was called CAL-101. It is common for a drug company to use letters from the name of the company. In this case, it was originally Calistoga Pharmaceuticals. The 101 part is a little more funny. I understand one of the early investors in the company was driving in Palo Alto California and turned from University Drive onto the 101 highway and decided to call the drug CAL-101. True? False? Not sure.
Then Gilead bought up the drug from Calistoga. Next step? Change the numbers. CAL-101 became GS-1101. GS = Gilead Science. Not sure where the extra "1" came from. Perhaps it was an effort to differentiate from GA-101 which became obinutuzumab before it became Gazyva.
Next step is to give the letter / number combo an actual name. In this case it was idelalisib. As difficult as that seems, it actually makes perfect sense.
Idelalisib (pronounced I-Dela-Lisib)
I=inhibit
Dela= delta isoform of PI3K
Lisib = that is the mandatory suffix of drugs that inhibit PI3K enzymes
I have heard this drug mispronounced so many ways that it is almost comical -I-del-isilib, I-dela-mab, etc. I think I would have chosen Ideltalisib if I were in control of all things as that would make a lot of sense (inhibit-delta-PI3K).
Every drug has two names (brand name vs generic name). You would be amazed how much effort goes into coming up with a name for a drug. You would also be amazed how often drug names begin with the letter "Z." Some sort of market research I don't know about I suppose. So idelalisib is now called Zydelig. I think this is a combo of the "z" and the "delta" but not sure I know where the "ig" comes from.
As if we were not already spoiled by approvals of the latest treatments for CLL including the addition of obinutuzumab and ibrutinib within the last 12 months, now we have yet another new agent that is simultaneously remarkably effective, well tolerated, and has proven to prolong survival for patients with CLL and show efficacy in hard to treat low grade lymphoma!
It has been an interesting race for approval between ibrutinib and idelalisib. These two drugs entered human clinical testing at nearly exactly the same time and in the grand cosmos of time and were approved nearly simultaneously in blinding speed. Idelalisib was the first to present randomized phase III study showing dramatically improved progression free survival (being alive and without progression) as well as improved overall survival against a control arm in CLL. I think ibrutinib ended up crossing the finish line first because they got the early papers published more quickly creating a strong buzz in the literature. Idelalisib was sold from Calistoga pharmaceuticals to Gilead pharmaceuticals midway through the development. This results in enormous changes on the development team that probably caused some regulatory delay while ibrutinib was held onto by Pharmacyclics all the way through development (sparing a joint venture with Jannsen).
We are lucky in NHL/CLL that we have discovered an entire new PATHWAY in which many of the enzymes make good targets for drugs. Since this pathway travels several key enzymes like Syk, BTK, PI3K, we will probably have a multitude of new drugs for these diseases. Indeed, there are several BTK inhibitors, several PI3K inhibitors, several Syk inhibitors all working their way through development.
What is so special about idelalisb?
I've had the opportunity to work with this drug quite a bit over the last several years all the way from the early phase I combination studies through helping the team at Calistoga write the main phase III protocols in relapsed disease. I would like to highlight two patients I have treated with the drug because they both illustrate something really remarkable.
The first patient came into my clinic shortly after I started in Eugene. He had some of the nastiest CLL I've ever seen. He presented with a white blood cell count of about 140 thousand, enormous lymph nodes, and red blood cells and platelets so low that I had to transfuse him weekly. Worse yet, all of his cells had the 17P deletion.
I started him on FCR but after two cycles he had made zero progress and indeed his transfusion requirement went up. I gave him campath and rituximab which at least cleared his marrow enough to stop transfusions but he still had big bulky nodes and was considered ineligible for transplant. From there we quickly cycled through R-ESHAP, R-Bendamustine, high dose steroids, revlimid and ofatumumab. Unfortunately that list of drugs took quite a toll on him and he was back to weekly transfusions.
We got him enrolled onto an idelalisib study and it was magic. His white blood cells shot up immediately (typical for these drugs), and his nodes shrank. His marrow began to "wake up" and we got him off of his transfusions again. Indeed, he went two and a half years almost completely normal taking only his idelalisib before his disease became problematic again. It was amazing to see him take advantage of the time this drug gave him - his life was completely changed by idelalisib in a way that was profoundly meaningful.
The second patient is an older gentleman with mantle cell lymphoma. He had a few lines of therapy before his MCL became a problem and we got him enrolled into the first ever clinical study of ibrutinib. He had several years of fantastic disease control on ibrutinib before he began having problems. He developed a cough and was short of breath. We found that one of his lungs had filled up with fluid from his lymphoma. We sent the sample for analysis and found that he had the BTK Cys481Ser mutation that inactivates ibrutinib. We were able to get him enrolled on an idelalisib study and that was over a year ago. His lungs cleared up, cough improved, fluid was dramatically reduced, etc.
Zydelig is approved in combination with rituximab for patients with relapsed CLL AND as a single agent (no rituximab) for patients with follicular lymphoma / small lymphocytic lymphoma who have become refractory to rituximab AND alkalating agents (bendamustine, chlorambucil, Cytoxan). Ongoing studies are likely to expand the circumstances where it is approved.
These are good times indeed!
Thanks for reading.
Wednesday, January 22, 2014
Idelalisib prolongs survival in CLL
At 2PM today, our article entitled "Idelalisib and Rituximab in Relapsed CLL" was posted to the New England Journal of Medicine webpage. I blogged about "the race tightens" last October after a press release suggested this would be an important data set. Press releases, abstracts, ASH presentations are important, but nothing matches the importance of the full manuscript. The full article can be accessed here.
This study took patients who were considered inappropriate for traditional chemotherapy on the basis of bad kidney function (main way we get rid of fludarabine), poor marrow function, or lots of other medical conditions. It then randomized patients to either rituximab or rituximab in combination with idelalisib - one of the new BCR signal inhibitors.
Critics have argued that rituximab is considered inappropriate care for patients with CLL. In general I agree, but I think this study worked very hard to identify patients for whom this treatment might be appropriate. NCCN guidelines list rituximab as an appropriate therapy for patients with lots of medical problems. Patterns of care data sets indicate that it is commonly used in North America. Ofatumumab is another CD20 antibody that is approved for single agent (and our rituximab control arm did almost as well as ofatumumab in the study that led to its approval). You can argue this point endlessly but FDA standards point toward "commonly accepted standard" and I think you can make an argument that rituximab may be appropriate in selected circumstances and this trial worked hard to define when that might be.
Long story short - adding idelalisib to rituximab absolutely blows away rituximab alone.
The overall response rate >90% versus 4%, progression free survival and even OVERALL SURVIVAL favor the addition of idelalisib. Very few studies in CLL have EVER shown improvement in overall survival. In fact, we were not even trying to show that point in the study and were somewhat surprised the difference was so large. The data set also shows the relative ineffectiveness of rituximab when administered alone in previously treated CLL patients (improves WBC for 4-6 months, nodes shrink a little, then disease takes off).
This study will hopefully pave the way for idelalisib to be approved in CLL sometime in 2014. The drug has been granted "breakthrough" designation by the FDA for CLL and has a 9/11/14 decision date by the FDA in non hodgkins lymphoma
This study took patients who were considered inappropriate for traditional chemotherapy on the basis of bad kidney function (main way we get rid of fludarabine), poor marrow function, or lots of other medical conditions. It then randomized patients to either rituximab or rituximab in combination with idelalisib - one of the new BCR signal inhibitors.
Critics have argued that rituximab is considered inappropriate care for patients with CLL. In general I agree, but I think this study worked very hard to identify patients for whom this treatment might be appropriate. NCCN guidelines list rituximab as an appropriate therapy for patients with lots of medical problems. Patterns of care data sets indicate that it is commonly used in North America. Ofatumumab is another CD20 antibody that is approved for single agent (and our rituximab control arm did almost as well as ofatumumab in the study that led to its approval). You can argue this point endlessly but FDA standards point toward "commonly accepted standard" and I think you can make an argument that rituximab may be appropriate in selected circumstances and this trial worked hard to define when that might be.
Long story short - adding idelalisib to rituximab absolutely blows away rituximab alone.
The overall response rate >90% versus 4%, progression free survival and even OVERALL SURVIVAL favor the addition of idelalisib. Very few studies in CLL have EVER shown improvement in overall survival. In fact, we were not even trying to show that point in the study and were somewhat surprised the difference was so large. The data set also shows the relative ineffectiveness of rituximab when administered alone in previously treated CLL patients (improves WBC for 4-6 months, nodes shrink a little, then disease takes off).
This study will hopefully pave the way for idelalisib to be approved in CLL sometime in 2014. The drug has been granted "breakthrough" designation by the FDA for CLL and has a 9/11/14 decision date by the FDA in non hodgkins lymphoma
Wednesday, October 9, 2013
The race tightens
In case you missed it, Gilead put out a major press release today:
Gilead to Stop Phase 3 Study 116 of Idelalisib in Chronic Lymphocytic Leukemia Early Because of Positive Risk-Benefit
Idelalisib is a very promising experimental agent for both NHL and CLL. I've written about it quite a few times previously. In CLL there is overwhelming enthusiasm regarding the multitude of new drugs on the very near horizon.
Obinutuzumab is an exciting new antibody that has been granted "breakthrough status" with the FDA. Most readers will be familiar with Ibrutinib which carries the same FDA designation. Idelalisib is another important experimental new therapy but was not awarded the same breakthrough status and was therefore considered by some to be "third place" in the horse race of approval. This announcement will really give them a significant boost.
The FDA is charged with determining if a new therapy is both, "safe" and "effective." The absolute best way to do that is perform a randomized / blinded / controlled phase III study in which half of patients are given a "standard of care" and the other half are given the experimental treatment. If patients do better on the experimental treatment the drug can be approved.
It is fair to ask, "what is a standard of care?" Sometimes in CLL - particularly in elderly individuals it isn't exactly clear from any real source what is "standard." Is "standard" what is commonly done by doctors or is "standard" the most rigorously studied and published "treatment regimen." In CLL, single agent rituximab does not have the enthusiastic endorsement of many thought leaders, but if you look at what is done in practice it represents nearly 30% of the treatment offered to elderly individuals. Is single agent rituxan therefore a good control? That will be answered by the FDA.
Another way drugs may be approved is on the basis of an "accelerated approval" where a drug company identifies an "unmet medical need." This is a population of patients with a specific disease who have exhausted all of their therapies and lack any good remaining / approved options. If you can show that your new drug is active in this setting, the FDA can give you a "conditional approval." The "condition" is that your approval depends upon you then completing an appropriate randomized phase III study.
This route of approval can be perilous. A really promising breast cancer drug was rejected by the FDA while going down this road because it was felt that not every patient had truly exhausted every single approved drug. After the company then completed a randomized phase III study with the same drug, they got approval this year. Unfortunately nearly three years passed between these two events.
If anyone is following the story closely - here is where things stand:
Obinutuzumab conducted a randomized phase III trial in FRONTLINE ELDERLY patients with CLL. The antibody has some pretty significant advantages and the FDA has granted both "breakthrough status" and "priority review"
Ibrutinib submitted their application to the FDA on the basis of a non randomized study and the FDA has granted breakthrough status in the 17P deleted population. I am not participating in the subsequent randomized phase III studies with this molecule but there are quite a few of them and accrual has been brisk. Will it be approved in this smaller subgroup of patients or all patients with relapsed CLL? The FDA will soon tell.
Idelalisib had taken the single arm strategy in follicular lymphoma refractory to both rituximab and an alkalating agent chemotherapy. They had seemed a little behind in CLL but now this announcement gives them a lot of new momentum. They reported that a randomized phase III study in CLL had to be terminated early because the benefit of the experimental arm was so significant.
The study consisted of half patients getting single agent rituximab WITH a placebo while the other half got rituximab WITH idelalisib (CAL-101 or GS-1101). This strategy would only be appropriate for older individuals with medical reasons not to give chemotherapy.
It is always nice when a study stops early for positive results - but keep in mind that the DSMB (data safety monitoring board) is NOT the same group as the FDA. Now the study closes. It sounds like patients on the control arm will be allowed to receive idelalisib. This may minimize the magnitude of the benefit that would have occurred if the study were to continue. Other drugs have been stymied at the FDA under similar circumstances.
Can't wait to see how this all plays out.
Thanks for reading
Jeff
Gilead to Stop Phase 3 Study 116 of Idelalisib in Chronic Lymphocytic Leukemia Early Because of Positive Risk-Benefit
Idelalisib is a very promising experimental agent for both NHL and CLL. I've written about it quite a few times previously. In CLL there is overwhelming enthusiasm regarding the multitude of new drugs on the very near horizon.
Obinutuzumab is an exciting new antibody that has been granted "breakthrough status" with the FDA. Most readers will be familiar with Ibrutinib which carries the same FDA designation. Idelalisib is another important experimental new therapy but was not awarded the same breakthrough status and was therefore considered by some to be "third place" in the horse race of approval. This announcement will really give them a significant boost.
The FDA is charged with determining if a new therapy is both, "safe" and "effective." The absolute best way to do that is perform a randomized / blinded / controlled phase III study in which half of patients are given a "standard of care" and the other half are given the experimental treatment. If patients do better on the experimental treatment the drug can be approved.
It is fair to ask, "what is a standard of care?" Sometimes in CLL - particularly in elderly individuals it isn't exactly clear from any real source what is "standard." Is "standard" what is commonly done by doctors or is "standard" the most rigorously studied and published "treatment regimen." In CLL, single agent rituximab does not have the enthusiastic endorsement of many thought leaders, but if you look at what is done in practice it represents nearly 30% of the treatment offered to elderly individuals. Is single agent rituxan therefore a good control? That will be answered by the FDA.
Another way drugs may be approved is on the basis of an "accelerated approval" where a drug company identifies an "unmet medical need." This is a population of patients with a specific disease who have exhausted all of their therapies and lack any good remaining / approved options. If you can show that your new drug is active in this setting, the FDA can give you a "conditional approval." The "condition" is that your approval depends upon you then completing an appropriate randomized phase III study.
This route of approval can be perilous. A really promising breast cancer drug was rejected by the FDA while going down this road because it was felt that not every patient had truly exhausted every single approved drug. After the company then completed a randomized phase III study with the same drug, they got approval this year. Unfortunately nearly three years passed between these two events.
If anyone is following the story closely - here is where things stand:
Obinutuzumab conducted a randomized phase III trial in FRONTLINE ELDERLY patients with CLL. The antibody has some pretty significant advantages and the FDA has granted both "breakthrough status" and "priority review"
Ibrutinib submitted their application to the FDA on the basis of a non randomized study and the FDA has granted breakthrough status in the 17P deleted population. I am not participating in the subsequent randomized phase III studies with this molecule but there are quite a few of them and accrual has been brisk. Will it be approved in this smaller subgroup of patients or all patients with relapsed CLL? The FDA will soon tell.
Idelalisib had taken the single arm strategy in follicular lymphoma refractory to both rituximab and an alkalating agent chemotherapy. They had seemed a little behind in CLL but now this announcement gives them a lot of new momentum. They reported that a randomized phase III study in CLL had to be terminated early because the benefit of the experimental arm was so significant.
The study consisted of half patients getting single agent rituximab WITH a placebo while the other half got rituximab WITH idelalisib (CAL-101 or GS-1101). This strategy would only be appropriate for older individuals with medical reasons not to give chemotherapy.
It is always nice when a study stops early for positive results - but keep in mind that the DSMB (data safety monitoring board) is NOT the same group as the FDA. Now the study closes. It sounds like patients on the control arm will be allowed to receive idelalisib. This may minimize the magnitude of the benefit that would have occurred if the study were to continue. Other drugs have been stymied at the FDA under similar circumstances.
Can't wait to see how this all plays out.
Thanks for reading
Jeff
Wednesday, September 11, 2013
Video update from IWCLL
I had the chance to meet up with Andrew Schorr in Germany at the IWCLL meeting. We taped this interview to provide an overview of where the new CLL drugs may best fit into an individuals treatment plan. Hopefully it is a good summary for you and puts things into a more focused perspective.
Andrew does a great job collecting the voices of many experts and putting them into one place. If you haven't made a contribution to his efforts, you might want to think about doing so. We are lucky to have him out on the front lines.
I apologize for being a little long winded in response to his questions. So much exciting stuff to talk about, I had a hard time containing myself.
Andrew does a great job collecting the voices of many experts and putting them into one place. If you haven't made a contribution to his efforts, you might want to think about doing so. We are lucky to have him out on the front lines.
I apologize for being a little long winded in response to his questions. So much exciting stuff to talk about, I had a hard time containing myself.
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