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.
Haematological malignancies which include multiple myeloma (MM), acute myeloid leukaemia (AML), Myelodysplastic Syndromes (MDS) and certain lymphomas, are regulated in part by p300/CBP.
Multiple Myeloma (MM)
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 an in vivo 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.
Non-Hodgkin Lymphoma (NHL)
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common subtypes of non-Hodgkin lymphoma (NHL). NHL is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system. NHL usually starts in the lymph nodes or other lymph tissue but it can sometimes affect the skin.
A NHL is frequently characterised by having mutations and deletions in CBP and to a lesser extent, p300. Tumours that have these mutations may be more sensitive to inobrodib compared with their non-mutated counterparts, so there is a strong rationale for the therapeutic targeting of p300/CBP in NHL tumours, particularly those with loss of function CBP mutations.
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.
Inobrodib inhibits the proliferation of patient derived AML cells through cell cycle arrest and with an accompanying increase in markers of cell differentiation. Inobrodib may be of particular benefit in patients who have failed initial treatment, through targeting of aberrant self-renewal linked to disease relapse.
Prostate cancer is the most common form of malignancy in men and is the second leading cause of male cancer-related deaths. The prostate is a small gland in males that produces the seminal fluid that nourishes and transports sperm.
Initial treatments for advancing prostate cancer focus on reducing the levels of circulating male hormones (androgens) in the body which the tumour requires for growth. Over time however, the cancer cells are able to circumvent such treatments and can develop into the castration resistant form of the disease (CRPC). CRPC typically occurs when the cancer has spread past the prostate into the body and it is able to grow and spread even after treatments have been used to lower testosterone levels. Overall survival is typically less than 14 months.
Advancement of CRPC is characterised by the presence of functional but altered androgen receptors (ARs), which mediate the effects of male hormones. Current therapies are ineffective in reducing the activity of these altered receptors. Inobrodib works in a different way and lowers the levels and the function of ARs in prostate cancer cells, and importantly, of AR variants that arise as disease progresses. It is these variants that are thought to drive resistance to current therapeutic agents, such as Xtandi, Zytiga and Erleada. Inobrodib also affects other key oncogenes including MYC.
In an in vivo cancer xenograft model that is driven by AR variants (22Rv1), inobrodib anti-tumour effects are dose-dependent and can cause complete tumour stasis at a well-tolerated dose. Intriguingly, tumour stasis is maintained for a significant period after dosing cessation and when drug has completely cleared from the system. This suggests some kind of reprogramming of tumours with inobrodib. It also means that there is significant scope for different dosing schedules of inobrodib, as the first-in-class drug is used in patients.
As well as direct effects on AR protein levels, inobrodib affects downstream biomarkers of AR-inhibition and prostate cancer. In pre-clinical efficacy models, plasma Prostate Specific Antigen is profoundly reduced, corresponding with tumour growth inhibition. Other downstream genes are also affected including TMPRSS2 and MYC in tumours.
As the use of second-generation anti-hormonal drugs continues to increase, the numbers of patients that become resistant to them also continues to grow. This is now a recognised and significant population of high unmet need. Inobrodib is ideally positioned for these patients, either as a monotherapy or in combination with existing agents.
The development of tumours with specific molecular drivers has grown substantially in the past decade, with diagnosis cases per year in the UK averaging 55,000 with breast cancer, 48,000 with lung cancer and 42,000 with bowel cancer.
Paralogue lethality, particularly in bladder and certain lung cancers but also in NHL tumours, has a relatively high prevalence (up to 20%) in tumours causing a loss of function mutation in either p300 or CBP. There is pre-clinical evidence that the tumours are then dependent on the non-mutated paralogue, and thus sensitive to an inhibitor of both p300 and CBP.
The MYC transcription factor is a potent oncogene and demonstrated pan-cancer driver. Given that inobrodib is known to significantly impact MYC expression, tumours with MYC gene amplification or high gene expression are also being examined.
Several other mutations that are associated with sensitivity to targeting CBP and/or p300 in a more cancer-specific manner are also under investigation. Endometrial cancer develops in the uterus and is the 6th most common cancer in women. Endometrial cancers with mutations in ARID1A, a recurrently-mutated protein that regulates gene expression, may be sensitive to inhibition of p300.
Additionally, Adenoid Cystic Cancer is a relatively uncommon cancer typically found in the head and neck region. This cancer is almost universally associated with elevated expression of the MYB transcription factor, and this is thought to be important for tumour formation. Inhibition of p300/CBP can profoundly reduce expression of MYB, suggesting that inobrodib may benefit patients with this disease.