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