“Not just another immune-modulary drug”

These are the words that Dana Farber’s Dr. Paul Richardson uses to introduce us to a new class of drugs called CelMoDs. CelMoD is scientific shorthand for ‘Cereblon E3 ligase modulator’, and, believe it or not, just about all of us multiple myeloma patients have already been pretty heavily involved with this Cereblon E3-beast while we have been treated with Revlimid, Pomalyst or Thalomid. The Myeloma Crowd posted an article nearly two years ago indicating that medical science was paying more attention to Cereblon as a direct target to further build on future treatment options for multiple myeloma.

What exactly is this ‘Cereblon E3 ligase’ ? Picture a linked grouping (a ligase) of a handful of proteins. At one end is the protein cereblon and at the other end is the enzyme E3 (also known as ubiquitin). Separate from this group are myeloma cells. It has been shown in the past that four proteins are over-expressed in multiple myeloma cells (Ikaros, Aiolos, c-Myc and IRF4), compared to normal plasma cells. The same paper referenced in the previous sentence also suggests that the over-expression of the last two proteins may be the direct result of the overexpression of Ikaros and Aiolos. 

When we take a dose of Revlimid or Pomalyst, the drug binds itself to the cereblon part of the strung together ligase. Ikaros and Aiolos (in or on our myeloma cells) gets knocked down by the molecules of our Revlimid or Pomalyst and results in the cell-death of our myeloma cells. The interesting thing to know is that other drugs we are familiar with (Velcade, melphalan and dexamethasone) will not even touch those same proteins, making the cancerous ‘cell killing’ properties of Revlimid, Pomalyst and Thalomid not only very unique, but also very potent in their method of action. Research has also revealed that the extent of the knock-down of Ikaros and Aiolos is ‘concentration dependent’. This means that a higher dose of either drug degrades these two proteins more aggressively than a lower dose. This is why, when we start our myeloma treatment, we take high(er) doses of either drug – when we are dealing with high concentrations of cancerous plasma cells – compared to ‘maintenance treatment’, where we can get by with low(er) doses. Research has also shown that Pomalyst is more potent than Revlimid.

So, what is the big deal now with this new CelMoD ? The compound CC-92480 also latches on to cereblon and also degrades the proteins Ikaros and Aiolos but does so more rapidly and more aggressively than Revlimid/Pomalyst. It will therefor be ideally suited for, not only relapsed myeloma, myeloma that has become resistant to any of the other immunomodulators, but also for ‘high risk myeloma’. For example, myeloma that has become resistant to other immunomodulators expresses between 40-70 % less cereblon, making these cells a less productive target for Revlimid/Pomalyst. In addition, the speed and efficiency of this novel compound lead to dramatically improved potency and breadth of activity on a whole host of proteins on or in myeloma cells that were previously untouched by either Revlimid or Pomalyst. And, to top things off, CC-92480 enhanced the cell-killing activity of dexamethasone. AND … the drug is a ‘pill’ (as opposed to injection or infusion). 

Summary results of a 76-patient Phase I study were presented at the most recent ASCO forum. Remember, again, that Phase I studies are geared towards making sure that the drug is safe in humans and to also find out what the maximal tolerated doses will be that can be safely used in the later phases of the clinical program. I encourage you to read the article referenced in this last link. It is written in plain English and provides some insights as to the efficacy in humans seen so far.

Dr. Richardson, mentioned in the opening paragraph, states, “If you look at maximum-tolerated dose, which was 1 mg, the response rate jumped to 40% in patients who got 10 out of 14 days across each month. If you looked at the recommended phase 2 dose, our overall response rate just for CC-92480 combined with dexamethasone jumped to 55%, which is very encouraging.”

Some other points that may be of interest:

• So far, 11 patients have received the highest dose given at the ‘optimal’ dosing schedule. “Of the seven triple-class refractory patients in this group, five patients had responses, with one patient achieving complete remission, one achieving very good partial remission, two achieving partial remission and one achieving minimal response.”
• “Of the 37% of patients with extramedullary disease who received the 1 mg dose, the researchers observed two very good partial responses, one complete remission and two partial responses. That is compelling and reflects the tissue penetrated I mentioned before. If this proves sustained, this is an important advance for our patients – and the platform is just a pill, 3 weeks on and 1 week off.’’
• The side effect profile can be summarized as follows:
  • One third of the 76 patients enrolled in this Phase I study are still on the study drug
  • No deaths were reported during the study
  • No patients discontinued treatment due to toxicities
  • “Neutropenia, thrombocytopenia and pneumonitis were manageable with dose-reduction schedule change and treatment-emergent adverse events were low 
  • Overall, there were four cases of mild peripheral neuropathy and one case and is of deep vein thrombosis
  • About one-third of patients had significant infections and about 15% had pneumonia, which is typical for this population [of MM patients]”

Let us hope this compound succeeds in the later phases of its clinical program and that we can look forward as another potent weapon in the fight against our disease. We will still have to wait several years before we may see this drug in clinical practice, but it may me well worth the wait. This one has the potential to be ‘a biggie’ for us !