FDA Denies Approval for Bispecific (For Now)

The FDA has denied approval for the bispecific Odronextamab -- for now. In giving the denial, the FDA pointed to problems in the trial, rather than concerns about its safety or effectiveness. 

Some background: Odronextamab is a bispecific, meaning that it works in two parts. It is a monoclonal antibody, like Rituxan. (I keep referring back to Rituxan when I talk about monoclonal antibodies, because it's been around for so long and is so widely used in Follicualr Lymphoma that I assume most readers know what it is.) In fact, it attaches to CD20, the same protein on the surface of B cells that Rituxan attaches to. But as a bispecific, Odronextamab also attaches to a T cell, an immune cell that can help kill off the cancer cell when it comes in close contact with it. If you've been reading the blog for the last year or two, you know that bispecifics are one of those treatments that tend to get oncologists very excited.

Odronextamab (which was known as REGN1979 before it got its official name) was granted accelerated review last October by the FDA. As you may know, accelerated review means the FDA will look at a smaller set of data (maybe from a phase 2 trial instead of a larger phase 3 trial) and make a decision in a shorter amount of time (usually about 6 months instead of about 10 months). They usually grant this faster review because the treatment will provide something that is not currently available to patients, and it will help a larger number of people if they can get access to it sooner.

However, accelerated review is also provisional review. Approval will allow the maker of the treatment to make it available, but they also have to keep up their clinical trials and submit data to show that it really is as safe and effective as it seems in that shorter amount of time. 

For Odronextamab, the original application was based on data from phase 1 and phase 2 trials. The results from those trials were strong. In phase 2 trial, patients with Follicular Lymphoma had an Overall Response of 82% and a Complete Response of 75%. The treatment was durable, with a median duration of response of 20.5 months and median Progression Free Survival was 20 months. Safety was decent, though 100% of the 131 patients with FL experienced side effects, with 78% of them experiencing grade 3 (serious) side effects, including Cytokine Release Syndrome (in over 50% of patients in the trial), low blood cell counts, diarrhea, fever, and joint pain. 

Importantly, the denial of the application is based on numbers of patients, not on concerns about safety or effectiveness. Basically, the FDA wants to see how the treatment works in more patients. They aren't denying the application forever, just until more data can be collected.

Of course, that's not what the maker of Odronextamab wanted to hear. There are actually two types of trials required, one focused on dosing (making sure the optimal amount of the treatment is given) and the other focusing on confirming the results f the earlier trials. The company behind Odronextamab says it is actively recruiting patients for these trials and is working with the FDA to have a new schedule later this year.

A couple of things seem significant to me.

First, this seems like a clear signal that the FDA really is getting more serious about accelerated approvals. With problems coming up after a quick approval, the agency wants to make sure treatments are safe and effective. In this case, they don't seem to be switching to an emphasis on Overall Survival, with all of the complications that would come with it (as William and Peter pointed out in their comments to my post earlier this month). They don't necessarily want new or different data here, just more of it. That seems like a reasonable approach.

Second, this confirms the importance of clinical trials, and patient participation in them. New treatments can't be approved without large trials, and large trials need willing patients. As you meet with your oncologist, add that question to your conversation -- are there clinical trials that would be appropriate for me, if and when I need treatment again? It's important to know what might come next for you, and important to all of us that new treatments have the data that they need to be approved (or not approved, which is just as important).

I'm sure there will be updates about Odronextamab in the very near future -- maybe as soon as a couple of months from now at the ASCO conference. But we'll definitely hear something by the end of the year about what the plans are for trying to get permanent approval.