Jeff Kutok, MD, PhD, Chief Scientific Officer, Epizyme, discusses preclinical data that validates the therapeutic rational for targeting SETD2, a histone methyltransferase, in high-risk t(4;14) multiple myeloma (MM), the data of which were presented at the EHA2021 Virtual Congress.

Transcript

My name is Jeff Kutok. I'm the chief scientific officer at Epizyme. I'm excited to talk to you today about our new preclinical data supporting the therapeutic rationale for inhibiting the epigenetic target, SETD2, in multiple myeloma.

First, I wanted to provide a little insight into our approach at Epizyme that led to this work. Epizyme's a leader within the field of epigenetics and with a focus on the discovery and the development of novel therapeutics, most notably our novel first-in-class EZH2 inhibitor, Tazverik.

We have an experienced team and a proprietary platform that allows us for building a deep pipeline of novel drugs across multiple targets of the epigenetic class.

I thought it'd be helpful to explain what we mean when we talk about epigenetics. Epigenetics refers to the broad regulatory system that controls gene expression without altering the sequence of the genes themselves.

The genes are composed of DNA, and in nature, the DNA is wrapped around a core of proteins known as histones. Together, the DNA and the histone proteins form a complex known as chromatin. That's the basic structural component of chromosomes.

Gene regulation is determined by that chromatin structure. The dynamics of the chromatin structure are regulated through multiple mechanisms by chromatin-modifying proteins.

Some chromatin-modifying proteins, like EZH2 and SETD2, place chemical groups on specific sites on the histone that affect the chromatin structures. It's the where, when, how, such chromatin structural changes occur that determine which genes are turned on or turned off in a cell at any particular time.

When the function of these chromatin-modifying proteins is altered, the program of gene expression is changed in a way that can lead to disease, including cancer.

The focus of the work that were presented at the EHA meeting was on SETD2, which is a histone methyltransferase that plays multiple roles in key cellular processes.

Its enzymatic activity adds the third, or the final methyl chemical group, on the tail of histone H3 at the 36 lysine position. For short, we call that H3K36.

It's this activity of SETD2 that forms these trimethylated H3K36 marks on the chromatin that directs a variety of important functions, including gene expression, transcriptional regulation, even DNA damage repair.

To get back to your question regarding what led us to this research, our initial insight into the potential for SETD2 inhibition in cancer came from research in multiple myeloma, particularly multiple myeloma with a specific genetic mutation called the 4;14 chromosomal translocation, which is associated with very poor outcomes and survival rates.

The 4;14 translocation is a result of a genetic accident or mutation that involves the breaking and rejoining, or translocating, of specific regions on chromosome 4 with those on 14. That's how it gets its t(4;14) name.

The mutation brings the immunoglobulin heavy-chain enhancer elements on chromosome 14 near MMSET gene on chromosome 4, driving high levels of MMSET overexpression. MMSET, like SETD2, is also a histone methyltransferase. It adds one or two methyl groups to histones on that H3K36 before SETD2 can add that final methyl group.

Extensive research and evidence has confirmed that it's the high levels of MMSET in the 4;14 myeloma that's a key factor in its pathogenesis, therefore makes MMSET a great target for this disease.

However, attempts to target MMSET have been unsuccessful to date. Given SETD2's role immediately downstream of MMSET in this pathway, we were investigating, is there a dependency on SETD2 4;14 multiple myeloma cell growth and survival?

If so, our hypothesis was that inhibiting SETD2 would lead to tumor cell death. This hypothesis is the basis of our research that was presented at EHA.

The aim of the preclinical research, again, was to further understand, is there a dependency SETD2 for t(4;14) myeloma cell growth as well as, more broadly in multiple myeloma, to characterize our potent and selective small molecule SETD2 inhibitor in this setting?

The results provided four key findings that I'll summarize.

The first is that our SETD2 inhibitor exhibited potent in vitro cell growth inhibition in a large panel of 4;14 myeloma cell lines.

The second was that the pharmacokinetic profile of our SETD2 inhibitor supported in vivo use, and we saw potent inhibition of tumor growth in our preclinical models of 4;14 myeloma.

Third, in vitro synergy was observed with our SETD2 inhibitor in combination with multiple myeloma standard of care therapies and emerging therapies in myeloma and supports a rationale to combine a SETD2 inhibitor with other multiple myeloma therapies.

Lastly, we were surprised to see that both vitro and in vivo antiproliferative activity was also demonstrated in non-t(4;14) multiple myeloma cell lines, suggesting potentially broader applicability of a SETD2 inhibitor in other forms of myeloma, as well as other B cell malignancies.

Overall, this is, to our knowledge, the first preclinical data to show successful targeting of the underlying oncogenic mechanism driven by MMSET overexpression in the t(4;14) multiple myeloma, and it's the first demonstration of a SETD2 as an oncogenic driver in multiple myeloma.

We feel that there's a considerable unmet need for patients with the high-risk t(4;14) myeloma. This accounts for about 15 to 20 percent of all cases of myeloma. The work validates that targeting SETD2 with a small molecule inhibitor in multiple myeloma could be of a potential therapeutic value.

We believe that it could present a promising option for patients with the 4;14 myeloma, either as a monotherapy or in combination with approved standard of care, or even emerging investigational therapies.

Overall, it suggests that further investigation of SETD2 is also warranted in myeloma without the 4;14 mutation as well as other B cell malignancies.

The data are the basis for moving our SETD2 inhibitor program forward. We're on track for our planned IND submission in the middle of 2021 this year and plan to initiate a first-in-human clinical trial by the year end.

In addition, we plan to further expand our research into the molecular mechanisms of action of SETD2 inhibition in a variety of tumor types to better understand the potential of this approach in both myeloma and B-cell malignancies.

This will be done either through our own research at Epizyme or through collaborations with academic researchers who've taken an interest in the target.

I'd like to add that to the best of our knowledge, there were no other SETD2 targeted programs in development, but we know that this has been an undruggable pathway of interest in epigenetic research for some time.

The data provide further proof that epigenetic modulators may be able to be used to reach difficult targets in oncology, both precisely and selectively.

We have an incredibly rich pipeline of discovery programs targeting several classes of epigenetic modulators at Epizyme, including histone methyltransferase inhibitors, which is the class that EZH2 and SETD2 belong to, but also histone acetyltransferase and helicase inhibitor programs.

We have a world-class team with passion for scientific innovation and commitment to developing novel therapeutics. We're interested in developing novel therapies for patients living with cancer. We're prepared to deliver on this ambition.

I look forward to sharing our developments throughout the remainder of this year and beyond with you.