Hi masila, I'm afraid I can't provide a link because it is a research note. I have extracted the summary and a few RVX relevant sections and copied below. But note that this is a general piece of research on epigenetics and it has a strong bias towards cancer. RVX is basically the only reference to non-cancer indications. The note also discusses other epigenetic MOAs unrelated to BET inhibition. At the bottom I have copied a table which shows the BET Bromodomain inhibitor clinical trials.

Epigenetic Drugs. The Next Big Big Thing?

Immunotherapy’s new best friend.

 Summary and Investment Conclusion — Epigenetic breakthroughs are quietly creating a tool box of powerful drugs to treat cancer and many other potential indications. Importantly, epigenetic drugs may materially increase the percentage of patients likely to experience profound increases in survival in response toimmunotherapy. We conservatively estimate the oncology indications alone to generate $10bn by 2025. GSK, Celgene, Epizyme and Otsuka are among potential near term beneficiaries. Novartis recent hiring of a distinguished epigeneticist as new head of research suggests heavy future investment. We prefer Novartis, AZN in EU, LLY and BMY in the US and Otsuka and Ono in Japan (all BUY rated).

 Epigenetic drugs can “turn off” cancer related genes — While cancer causing DNA mutations are irreversible, epigenetic drugs can turn off cancer associated genes by controlling the decoding of cancer related DNA. Key epigenetic drug classes include DNMT inhibitors (DNMTi) such as Otsuka’s SGI110 and Celgene’s oral cc-486, HDAC inhibitors (HDACi) such as Syndax’s entinostat, EZH2 inhibitors such as Epizyme’s tazemetostat and GSK’126, BRD4 inhibitors such as GSK’762 and LSD1 inhibitors such as Roche/ Oryzon’s RG6016 and GSK’552.

 Immunotherapy’s new best friend. Several epigenetic drug classes may materially broaden and deepen the efficacy of cancer immunotherapies, such as PD1 antibodies. Low dose inhibitors of DNMT may improve immune priming by triggering the transcription of repressed viruses long embedded in the human genome. Separately, inhibitors of EZH2, HDAC and FAK improve the tumor microenvironment through suppression of inhibitory immune cells. While decades of immunotherapy research (The Beginning of the End for Cancer) materially pre-date epigenetics, powerful diagnostic assays for the genome and the epigenome will rapidly drive development of novel epigenetic drugs.

 We anticipate 5 waves of epigenetic commercial success, examples include

(i) mono or combination epigenetic therapy in subgroups NHL (lymphoma) and SCLC (lung cancer), (ii) overcoming acquired resistance to oral cancer drugs such as Sprycel and Tarceva with BRD4i to inhibit c-myc cancer oncogene, (iii) eliminate cancer stem cells prevent disease relapse, (iv) broaden and deepen response to cancer immunotherapy through better epigenetic priming and enhanced tumor microenvironment (v) use in non-cancer indications, such as BRD4i in PAH and HIV.

 What’s Next? We anticipate the several novel epigenetic agents to move into phase II/III registration trials in 2016. We anticipate phase I data in AML (leukemia) to be presented at ASH in December, Ph I data from GSK’s BRDi, LSD1i in solid tumours to be presented at AACR or ASCO in 2016 and BMY’s trial with entinostat/ aza priming in NSCLC (lung cancer) to be presented mid-2016.

BRD4 inhibitors have potential efficacy outside oncology including PAH, CVD,

autoimmune disease and seizures. Pulmonary Arterial Hypertension (PAH) is associated with decreased microRNA-204 expression effected through BRD4 activation. BRD4 inhibition entirely reversed a mouse model of PAH, restoring mitochondrial membrane potential and increased cells spare respiratory capacity. It has also been demonstrated that BRD4 inhibition reduces seizure rate in an epilepsy model. Given the limited treatment options, we anticipate clinical development in these indications in the near future.

Epigenetic processes triggered by a selective BRD4-BD2 inhibitor resulted in the elevation of ApoA1 expression, the domain protein in HDL. Pool analysis of the two Ph II studies suggested a 77% relative risk reduction in MACE in those patients with diabetes. The BRD4i has been subject to over 1,000 patients with acceptable adverse events profile with reversible liver enzyme elevations. A 2,400 patient Ph III study called ‘BETonMACE’ has been planned to start in 4Q2015, with primary endpoint being a 30% reduction in MACE events. Early studies have also claimed synergistic effects of combining the BRD4i with Crestor, making the asset of value to AstraZeneca. Given the failure of the Lilly’s CETPi evacetrapib, there remains a need for a cost-effective cholesterol drug that can compete with high-cost anti-PCSK9s.

BRD4 inhibitors also have potential utility for auto-immune disease due to their depletion of CD4 and CD8 lymphocytes coupled with the demonstrated reduction in their DNA damage sensing response to radiotherapy.

BRD4 Backgrounder. BRD4 is a member of the bromodomain and extraterminal (BET) subfamily of human bromodomain proteins, which includes BRDT, BRD2, BRD3, and BRD4. Each of these domains have two sub-domains BD1 and BD2, which can be targets of BET inhibitors. More details on bromodomains and their mechanisms can be found on pages 46 and 47. These proteins associate with acetylated chromatin and facilitate transcription. The oncogene myc, an important driver in in many cancers has proved undruggable through small molecules. Inhibition of the transcriptional co-activator BRD4 through BRD4 inhibitors selective inhibition of the myc oncogene, over-expressed directly in multiple myeloma but also associated with super enhancers related to myc activation in numerous other tumors types including ALL, mCRPC, SCLC, AML, GBM and ALL. Myc amplification is unsurprisingly being explored a potential a biomarker in clinical trial.

In addition to the histone writers and erasers, there is one additional class of proteins that act as readers that recognize the histone codes and can deliver nucleosome, histone, or DNA-modifying enzymes. Writers and erasers involve chemical interaction with histones and has been the focus of 1st generation epigenetic drugs, readers on the other hand involve in protein-protein interactions and have more complex, functionally diverse and higher hierarchical roles. By ‘reading’, the histone readers are able to determine the functional outcome of post-translational modifications. Histone readers can contain one or more protein domains which are capable of sensing the constant flux of covalent modifications achieved by writers and erasers. These domains include the bromodomains, PHD domains, TUDOR domains, SET domains and CHROMO domains. The BET family of bromodomains has received most attention in the epigenetic community. Of the BET family members, the function of BRD4 has been most thoroughly studied. BRD4 has two sub-domains BRD4-BD1 and BRD4-BD2, it is thought that these regulates RNA-pol II-mediated elongation and transcription by directly interacting with the P-TEFb. Additionally, recent literature has shown direct BRD4 interactions with other transcription factors, such as GATA-1, Twist protein, NF-κB, and p53, across a range of cancer types. These interactions occur via bromodomain-dependent and -independent mechanisms. Thus, in a cancer contextspecific manner, BRD4 serves as a node between disease-relevant transcription factors and the transcriptional machinery. As Figure 73 illustrates, at enhancer and promoter regions, the combinatorial interactions among acetylated histones, transcription factors, nuclear proteins, and the transcriptional machinery allow BRD4 to mediate translation of the epigenetic code into RNA synthesis. Therapeutic targeting of histone readers is an emerging area of drug discovery that has been gathering momentum, with most of the excitement stemming from oncology applications. As discussed earlier in this report, BRD4 activating mutations are rare. NUT midline carcinoma involves the translocation of the BRD4 with NUT genes. BET inhibitors have shown remarkable responses in this rare tumor. BRD4 is also thought to be needed for the expression of Myc and other ‘tumor driving’ oncogenes including multiple myeloma and AML. As shown in Figures 6 and 74 the biopharmaceutical industry is actively looking at this space with multiple pre-clinical licensing deals in recent years and the initiation of multiple clinical-stage BET inhibitors.

As discussed previously, early signs of clinical efficacy and the pace of trial expansions are encouraging. However, a significant risk to the BRD4 thesis lies in the safety profile of these compounds. While the remarkable anti-cancer activity of BRD4 inhibitors has provided much excitement in some settings, there are also potential liabilities against inflicting damage to non-malignant tissues. Unlike other targeted therapies, BRD4 isn’t exclusively expressed in tumours; rather, BRD4 is ubiquitously expressed in all tissues. It has been shown that BRD4-depleted animals displayed epidermal hyperplasia, alopecia, suppression of normal hematopoiesis, and marked intestinal defects. However, all phenotypes can be reversed through restoring normal BRD4 levels, suggesting that unintended consequences of BRD4 inhibition could be managed through dosing optimisation. We will gain more clarity following the reporting of ongoing clinical trials.

Key questions with BRD4

Numerous pre-clinical safety signals. Animal data has highlighted several potential concerns with a variety of increased adverse events in different animal models. These include higher rates of post natal death, reduced growth rates, development abnormalities including hyperplasia of the skin, alopecia organ stress and memory loss in mice. Additional findings include depletion of CD4 and CD8 T cells, weight gain, sensitivity to radiation induced GI damage. Despite the animal data, we assume that BRD4i have shown themselves to be well tolerated in humans given the expanding clinical trials.

BRD4 may reduce cancer risk in some indications. Although BRD4 inhibition has shown activity across multiple animal models, BRD4 is protective formalignancy in breast and lung underlining the importance of molecular characterisation of both cancer and patient genotype. In addition, we note the BRDi driven depletion of CD4 and CD8 T cells which could obviate the clinical benefit of immunotherapy and potentially increase the risk of secondary malignancies. Finally, animal models have indicated the rapid emergence of resistance to BRD4 mechanisms likely necessitating the need for combination therapy with HDACi or other agents, potentially increasing the toxicity burden for the patients.

Figure 33. Ongoing BET Bromodomain inhibitor clinical trials

ABBV-075 AbbVie Phase I BET Solid tumors, lymphoma 2016 (NCT02391480)

GS-5829 Gilead Phase I BET Solid tumors, DLBCL 2017 (NCT02392611)

BAY1238097 Bayer Phase I BRD4 Solid tumors, lymphoma 2017 (NCT02369029)

INCB54329 Incyte Phase I / II BRD2/3/4 Solid tumors, lymphoma 2017 (NCT02431260)

BMS-986158 BMY Phase I / II BET TNBC, SCLC, Ovarian cancer 2018 (NCT02419417)

TEN-010 Tensha Therapeutics Phase I BRD4 Solid Tumors; Hematologic malignancies 2016 (NCT01987362)

RVX-208 Resverlogix Phase II BRD4 Cardiovascular disease, Diabetes 2015 (NCT01067820)

OTX-015; OTX-008 Merck/ OncoEthix Phase I BRD4 Acute Leukemia; Solid tumors 2015 (NCT01713582)

CPI-0610 Consteflation Phase I BRD4 ALL, MM, MDS 2015 (NCT02158858)

GSK525762 GSK Phase I BRD4 NMC, Myc amplified solid tumor, lymphomas 2017 (NCT01943851)