Inobrodib clinical development
Indications under Investigation
Inobrodib, through inhibiting p300/CBP, impacts certain key cancer drivers. It works specifically against some tumour types; it is not generally cytotoxic.
Multiple Myeloma (MM)
Haematological malignancies, and specifically (MM), are regulated in part by p300/CBP.
Multiple Myeloma (MM)
Hematological malignancies, and specifically (MM), are regulated in part by p300/CBP.
MM is a type of bone marrow cancer and often affects several areas of the body including the spine, the skull, the pelvis and hips. In MM, the IRF4 transcription factors play a central role in the development and progression of the disease.
In a pre-clinical xenograft model of multiple myeloma, inobrodib stops tumours growing and in some cases, causes them to regress. This is accompanied by a very significant reduction in the expression of the IRF4 and MYC transcription factors. Inobrodib may be of particular benefit in patients with multiple myeloma offering a more selective approach to targeting these key oncogenic drivers.
Initial clinical data presented at the American Society of Hematology (ASH), annual meeting 2022, showed that inobrodib as monotherapy, can offer clinical benefit to late stage, heavily pre-treated multiple myeloma patients.
Inobrodib can also be used in combination with existing drugs. In particular there is evidence that inhibiting p300/CBP can reignite susceptibility to the IMiD class of drugs (such as pomalidomide, lenalidomide). Clinical trials are currently investigating inobrodib in combination with other oral drugs, including pomalidomide and dexamethasone. Other rational combinations will be tested also, based on inobrodib’s mechanism of action and relative ease of use and tolerability.
Other Applications
Acute Myeloid Leukaemia (AML)
AML is an aggressive cancer of the myeloid cells which are responsible for functions such as fighting bacterial infections, defending the body against parasites and preventing the spread of tissue damage. AML is a rare type of cancer but the risk of developing it increases with age, most commonly in people over 75.
Patients with AML who have relapsed or are refractory to initial therapy and not deemed suitable for standard intensive treatment due to their age, currently have few remaining treatment options and these offer limited survival benefit and are often associated with an unfavourable safety profile.
P300/CBP interacts with many different oncogenes or fusion proteins to regulate target genes that are involved in the self-renewal of haematopoetic stem and progenitor cells, and growth of leukaemic cancers.
Lymphomas
Peripheral T cell lymphomas (PTCL) are a type of blood cancer that originates from immune cells called T lymphocytes. Certain PTCL are driven by the transcription factors IRF4, MYC, or GATA3, whose expression depends on p300/CBP.
Diffuse large B-cell lymphoma (DLBCL) is another type of lymphoma that has recurrent mutations or deletions in CBP which may render them more responsive to inobrodib.
Targeted Tumors
The development of tumours with specific molecular drivers has grown substantially in the past decade. It may be possible to use inobrodib to treat tumours with particular mutations, such as a loss of function mutation in either p300 or CBP.
Tumours that are no longer susceptible to certain drugs may also benefit from inobrodib. As well is for treating haematological malignancies, there is pre-clinical evidence that solid tumours resistant to KRAS inhibitors and immune checkpoint inhibitors may be re-sensitised when treated with inobrodib.
Solid Tumours
P300/CBP inhibition may also have a role in treating certain solid tumour cancers. Prostate cancer is the most common form of malignancy in men and is the second leading cause of male cancer-related deaths. Data from patients with late stage, metastatic castration resistant prostate cancer has shown that inobrodib can impact key drivers MYC and the androgen receptor (AR). It can also be combined with existing drugs, such as enzalutamide and daralutamide.