The 2014 annual report highlighted CC-122 as part of the next-generation drugs, CELMoDs, including CC-122 and CC220, based on more advanced understanding of the role of Cereblon with IMiDs:
Last year we established the first three Thematic Centers of Excellence (TCoE) in protein homeostasis, epigenetics and immuno-oncology. These are important areas of medicine that provide significant long-term opportunity. We intend to create new TCoE’s in additional areas of research in which we have scientific strength and unique competitive advantages. • Protein Homeostasis: With our enhanced insights on cereblon, the target protein for REVLIMID® and POMALYST®/ IMNOVID®, we are redefining the therapeutic potential of protein homeostasis. We are developing next-generation drugs, called CELMoDs™ (Cereblon E3 Ligase Modulation Drugs), designed with novel chemistry and differentiated properties that potentially enable us to address a broader range of diseases. We have two CELMoDs in clinical development—CC-122 and CC-220—and expect to advance a third one into human testing over the next 12 months.
Next generation of Cereblon Modulatory drugs: CC-122 (a PPMTM Pleiotropic Pathway Modifier) and CC-220 represent novel compounds that are in phase I clinical trials for hematological and solid tumor cancers and inflammation and immunology diseases. They have been differentiated from previous compounds (such as Thalidomide, Lenalidomide and Pomalidomide) and have been developed based on our scientific understanding of Cereblon-mediated protein homeostasis.
Excerpt from ASH2014 post re Cereblon:
It is remarkable that Revlimid received its first approved indication with MDS 5q- on 28Dec2005, yet there are still lessons to be learned about the mechanism of action. Several abstracts about Cereblon as an important factor with the IMiDs caught my attention at ASCO2012, but it was deemed too early to reach major conclusions at the time. A peer-reviewed publication appeared in Nature Structural & Molecular Biology on 10Aug2014 “Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs” (http://www.nature.com/nsmb/journal/v21/n9/full/nsmb.2874.html), which describes how IMiDs directly bind Cereblon and promote recruitment of two members of the Ikaros zinc finger protein family, Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex. At ASH2014, 29 abstracts involving Cereblon were selected including plenary presentation “Lenalidomide Induces Ubiquitination and Degradation of CSNK1A! in MDS with Del(5q). During Celgene’s excellent, informative Sunday Analyst Event, 2 of 5 highlighted abstracts describing key Multiple Myeloma (MM) abstracts important for the future of MM treatments involved Cereblon (abstracts #420, 639). Slide 50 shows a diagram IMiDs interaction with Cereblon and its impact on a complex network of effects that can be mapped to create designer IMiDs with deeper molecular biology insights.
Five open trials for CC-122 are found on clinicaltrials.gov:
Rank | Status | Study |
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1 | Not yet recruiting | A Phase 1/2, Open-label, Dose Finding Study to Evaluate CC-122 in Combination With Rituximab, Ibrutinib and Obinutuzumab in Subjects With Relapsed/Refractory CLL/SLLCondition: | Leukemia, Lymphocytic, Chronic, B-Cell |
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Interventions: | Drug: CC-122; Drug: Rituximab; Drug: Ibrutinib; Drug: Obinutuzumab |
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2 | Recruiting | Study of CC-122 to Evaluate the Safety, Tolerability, and Effectiveness for Patients With Advanced Solid Tumors, Non-Hodgkin's Lymphoma, or Multiple MyelomaConditions: | Solid Tumors; Non-Hodgkin's Lymphoma; Multiple Myeloma; Glioblastoma Multiforme; Oligodendroglioma; Hepatocellular Carcinoma; Diffuse Large B-cell Lymphoma; Mantle Cell Lymphoma |
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Intervention: | Drug: CC-122 |
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3 | Recruiting | Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell LymphomaCondition: | Lymphoma, Large B-Cell, Diffuse |
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Interventions: | Drug: CC-122; Drug: CC-223; Drug: Rituximab; Drug: CC-292 |
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4 | Recruiting | Safety and Efficacy Study of CC-122 Combined With Sorafenib for Primary Liver CancerCondition: | Carcinoma, Hepatocellular |
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Interventions: | Drug: CC-122; Drug: Sorafenib |
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5 | Recruiting | A Phase 1b Open-label Study to Evaluate the Safety and Efficacy of CC-122 With Obinutuzumab (GA101) in Relapsed/Refractory DLBCL and iNHL.Conditions: | Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin |
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Interventions: | Drug: Obinutuzumab; Drug: CC-122 |
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The first formal mention of the pleiotropic pathway modifier program came in the 3May2007 1Q2007 earnings PR and also mentioned during the ASCO2007 Analyst Event. Here is an excerpt from the PR:
To support clinical development and to advance global regulatory filings the Company increased R&D investments in multiple international clinical programs evaluating REVLIMID® and other IMIDs® across a broad range of hematological cancers with unmet medical needs including: multiple myeloma, myelodysplastic syndromes, chronic lymphocyte leukemia, non-Hodgkin's lymphoma, myelofibrosis and hemoglobinopathies. For the first quarter period of 2007, the Company incurred adjusted R&D expenses of $77.0 million. These R&D expenditures support ongoing clinical progress in multiple proprietary development programs for REVLIMID and THALOMID®; for other IMiDs compounds such as CC-4047, CC-11006, CC-10015, CC-13097 and CC-15965; for our lead anti- inflammatory compounds CC-10004 and CC-11050; our pleiotropic pathway modifier program; as well as our kinase and ligase inhibitor programs and placental- derived stem cell program. On a GAAP basis, R&D expenses were $79.6 million for the first quarter period of 2007.
As an historical reference, CC-4047 became Pomalidomide/Omnivid, CC-10004 Otezla/Apremilast.