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.