Next generation proteasome inhibitors

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Published: 16 Jul 2010
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Dr Keith Stewart - Mayo Clinic, Arizona, USA
Dr Stewart discusses results of Phase I and Phase II trials of carfilzomib, a next generation proteasome inhibitor, which has a different binding structure to bortezomib.

This interview is supported by an unrestricted educational grant from Novartis Oncology.

15th Congress of the European Hematology Association (EHA), 10—13 June, 2010, Barcelona

Interview with Dr Keith Stewart (Mayo Clinic, Arizona, USA )

Next generation proteasome inhibitors
You’re going to talk about second, third generation proteasome inhibitors at this meeting in Barcelona.

I’m going to talk about Carfilzomib, it’s a new class of proteasome inhibitor.  It has a different binding structure to the proteasome as compared to Bortezomib, which is the sort of primary drug.  The result of that different structure is it binds irreversibly to the proteasome and has sustained deeper and probably more specific proteasome inhibition. 

Is that going to do you any harm being irreversible?

The concern when we started the trials of the drug was that we didn’t know if these were good or bad things.  It may mean it’s more toxic and less efficient because it’s more specific or it could be the opposite and I think fortunately it’s the opposite, so it appears to be less toxic and probably as effective, or slightly more.

Any neuropathy?

Well, I shouldn’t say zero; it is minimal.

So how do you explain that?

Well, we think that it probably shows that the neuropathy from Bortezomib is off target.

It’s not related to the proteasome inhibition?

We don’t think so any more because even in animal studies Carfilzomib, they both inhibit the proteasome very efficiently yet Carfilzomib, with animal studies and in man, does not appear to be associated with the severe neuropathy that one can see with Bortezomib.

Have you done Phase I and Phase II trials?

Phase I we did; that established a safe dose and showed that you could give this drug with effectiveness.  The response rates in Phase I myeloma trials were in the 20% range. And then subsequently Phase II trials were done both in Bortezomib resistant and in Bortezomib naïve patients.  What we’ll present at this meeting is the Bortezomib naïve population primarily.  The response rate in the Bortezomib resistant population is about 13% partial response, 20% clinical benefit, so it’s not dramatic but there are some patients who will still respond.   The primary benefit seems to be or the primary most effective data is in Bortezomib naïve patients where we will show that the response rate is 55% partial response or better which is probably the highest ever for a single agent in myeloma.

Is the next stop combination treatments?

Combination’s already underway.  Carfilzomib plus Revlimid plus Dexamethasone is a poster at this meeting; safe, looks effective.  An international randomised Phase III trial for registration purposes, is starting within the next month in a large number of countries, recruiting 700 patients. 

What’s the standard arm?

The standard arm is Revlimid plus low dose Dexamethasone , which is a standard for relapse versus Carfilzomib plus Revlimid and low dose Dexamethasone plus Revlimid.  The drug has now moved into the newly diagnosed patient arena with some investigator sponsored trials in newly diagnosed patients combined with Revlimid or with cyclophosphamide.

What else is new in myeloma?

Pomalidomide is new.  Pomalidomide is a third generation thalidomide.  It has a  chemical structure related to Revlimid and Thalidomide; it is also profoundly active with about 50% response rate in early stage and 30%, even in patients who are refractory to Revlimid, which is very interesting, so probably a more potent drug than we currently have available but with a side effect profile that looks somewhat like Revlimid.