On 18 June, the US Food and Drug Administration (FDA) gave accelerated approval to Epizyme’s EZH2 inhibitor Tazverik (tazemetostat) for relapsed or refractory follicular lymphoma, marking the drug’s second approval in less than six months; the first was for epithelioid sarcoma, a rare disease until then without an approved treatment. The agency’s two green lights in quick succession for this first-in-class EZH2 inhibitor presage more specific epigenetic agents to come for cancer.. Tazverik “is the tip of the iceberg,” says Robert Copeland, Epizyme’s founding CSO and now president and CSO of Accent Therapeutics.

Mutations in either a chromatin remodeling complex or in EZH2 itself can sensitize tumors to EZH2 inhibitors like Tazverik. Reprinted with permission from K. H. Kim and C. W. M. Roberts, Nat. Med. 22, 128–134 (2016).

Tazverik works by inhibiting EZH2, short for enhancer of zeste homolog 2. It is part of a histone methyltransferase complex, responsible for the trimethylation of lysine 27 on histone H3. One of its biological effects is to temporarily silence genes involved in the differentiation of B cells and their exit from the germinal centers in lymph nodes. When the EZH2 gene is mutated, making its function irreversible, B cells are unable to exit and become cancerous, as happens in follicular lymphoma. In a phase 2 trial in relapsed or refractory follicular lymphoma, 31 of 45 patients with mutated EZH2 in their tumors had an objective response to Tazverik, whereas 19 of 54 individuals with non-mutated EZH2 tumors responded. The responses in individuals with EZH2-mutant tumors lasted for about a year, and the response rate was higher than for two phosphatidylinositol-3-OH kinase (PI3K) inhibitors previously approved for this indication, with considerably less toxicity. “That [efficacy] speaks to the power of the biology at play,” says Ari Melnick, a cancer researcher at the Weill Cornell Medical College. “It’s hard to have a strong impact on patients at that stage.”

Although the FDA’s approval for relapsed or refractory cases was expected, the agency issued a surprisingly expansive label, says Yaron Werber, a biotech analyst at Cowen. It approved the drug for patients with EZH2-mutant lymphomas who have failed two previous therapies, but also for adults “who have no satisfactory alternative treatment options,” regardless of mutation status. This gives hematologists wide discretion. Werber forecasts worldwide Tazverik sales peaking at $959 million in 2032.

Scientists have been developing epigenetic agents for cancer for several decades. Many researchers consider DNA methylation and histone deacetylation just as important as gene mutations in turning off genes, either by blocking transcription factor binding to promoters or by causing chromatin structure to become more compact and inaccessible. But thus far small molecules targeting epigenetic targets haven’t met early expectations: they are approved in only a few indications, have limited efficacy and are generally quite toxic.

The first wave of epigenetic small-molecule drugs included the DNA methylation inhibitor Vidaza (5-azacytidine) and Dacogen (decitabine), approved for myelodysplastic syndrome and some leukemias in 2004 and 2006, respectively. Soon after, two so-called global ‘histone eraser’ drugs targeting the histone deacetylase (HDAC) inhibitors — Zolinza (vorinostat) and Istodax (romidepsin) — were approved for cutaneous T-cell lymphoma. But Zolinza and Istodax are not very specific epigenetic drugs. “They really target thousands of proteins,” says Melnick. “There’s no evidence that HDAC inhibitors carry out their antitumor function through any effect on epigenetic regulation.”

The second wave of approvals included three new HDAC inhibitors. The FDA approved Beleodaq (belinostat) and Farydak (panobinostat) in 2014 and 2015, for peripheral T cell lymphoma (PTCL) and myeloma, respectively, and the Chinese FDA approved Epidaza (chidamide) for PTCL in 2015. These agents were generally more potent their predecessors, but not necessarily more specific.

The third and newest wave of epigenetic drugs targets lysine and arginine residues on histones and is exemplified by EZH2 inhibitors like Tazverik. Post-translational modifications of specific lysines in the exposed tails of certain histones have dramatic effects on cell fate. For example, the histone mark targeted by Tazverik is crucial for the proper timing of cell differentiation, and too much of this mark can lead to cancer. “Compared with HDAC inhibitors, for example, [EZH2] is a much cleaner target,” says Melnick. “And that’s exciting per se, because we can really get a sense of how impactful epigenetic therapy can be.”

Companies first directed their attention to EZH2 because it’s overexpressed in several solid tumors, mainly prostate cancer. But in 2010 heterozygous EZH2 mutations were identified in germinal center lymphomas, including follicular lymphomas. Epizyme found that the EZH2-activating mutations and the wild-type allele cooperatively drive these tumors by together adding three methyl groups to a particular histone lysine residue. “The lymphoma data seemed solid as a rock, and that’s what we pursued,” says Copeland.

Other companies, including GlaxoSmithKline, Constellation, Daiichi Sankyo and Pfizer, jumped in with their own EZH2 inhibitors (Table 1). Epizyme remains the leader and is now testing Tazverik in a variety of combinations in both solid tumors and blood cancers. “Tazemetostat holds potential as a ‘pipeline in a molecule,’” says Epizyme chief medical officer Shefali Agarwal.

Table 1 Selected EZH2 inhibitors in clinical development
Full size table

The June FDA approval only hints at the drug’s usefulness, Melnick suggests. The optimal duration and number of cycles for the therapy have not been defined, and many combinations are possible. Other epigenetic marks “might need to be targeted as well to maximally yield a therapeutic effect,” says Melnick.

Epizyme seized another completely different EZH2 inhibitor opportunity in 2010 to treat rhabdoid tumors. These rare and lethal childhood cancers lose INI1 gene expression. The INI1 protein is part of a protein complex whose function is to slide nucleosomes apart (a nucleosome is a length of DNA wrapped around histones) so transcription factors can bind DNA and transcription can take place. In that year, Charles Roberts, then at the Dana-Farber Cancer Institute, reported that when INI1 is lost, cells respond by boosting EZH2, which suppresses the expression of genes vital for cell differentiation. With hyperactive EZH2, cells are unable to differentiate and remain in a stem-cell-like state. Rhabdoid cancer is the result. Knocking down EZH2 completely blocks tumor formation. This is an example of synthetic lethality — a genetic deletion setting the conditions for an otherwise innocuous intervention to kill cells.

Epizyme immediately noticed. “As soon as we published it, they [Epizyme] tried it in their rhabdoid tumor cell lines,” recalls Roberts. “Works great. Then they called, and I went over and gave a lecture … that’s how they got interested.” (Roberts says he has never taken any funds from Epizyme.) An Epizyme trial in adults with rhabdoid-like tumors lacking INI1 showed good results in epithelioid sarcoma, an aggressive soft tissue cancer. (Pediatric rhabdoid tumor trials are ongoing.) Epizyme later launched a pivotal phase 2 adult epithelioid sarcoma trial. In it, 9 of 62 patients taking Tazverik achieved an objective response, including one complete response. FDA approval followed. Pediatric trial data reported at the American Society of Clinical Oncology annual meeting in June were similar (17% of patients responded). The many non-responders puzzle Roberts, now at St. Jude Children’s Research Hospital, because those patients’ tumors, too, lack INI1 and have hyperactive EZH2. “Why doesn’t every single tumor just melt away?” Roberts asks. He is now looking into possible resistance mechanisms, which may have to do with the negative consequences of knocking down EZH2 at certain sites in the genome.

EZH2 drug resistance in lymphoma is also a puzzle. Later-stage tumors, under the pressure of therapy, may develop clones that can tolerate the loss of EZH2, says Melnick. As a result, Epizyme is now supporting an investigator-sponsored clinical trial to test Tazverik together with chemotherapy as frontline treatment for lymphoma.

How to best combine EZH2 inhibitors with other drugs, however, is unknown. Several companies are combining with standard androgen signaling inhibitors in prostate cancer, in part based on the ability of EZH2 inhibitors to reverse resistance to antiandrogen drugs in cells. A series of recent papers have also implicated EZH2 mutation and overexpression in immune dysfunction, including impaired antigen presentation and skewing of the T cell response. That’s part of the rationale for a new trial at MD Anderson Cancer Center, combining the Daiichi Sankyo dual EZH1/EZH2 inhibitor valemetostat with the immune checkpoint blocker Yervoy (ipilimumab) in bladder, renal and prostate cancer.

There is also room for improvement in the drugs themselves. Constellation Pharmaceuticals began EZH2 drug discovery back around 2009. “This was by far not a trivial undertaking, not for us and not for anyone in the field,” says CSO Patrick Trojer. Like other methyltransferases, EZH2 obtains the methyl group from the compound S-adenosylmethionine (SAM), and most EZH2 inhibitors block EZH2 by out-competing SAM for binding, thus preventing transfer of the methyl group to the histone substrate. These EZH2 inhibitors all contain the same core motif, which binds the SAM pocket and is critical for drug potency. But the core also impairs drug solubility. GlaxoSmithKline dropped its EZH2 inhibitor in 2017 after phase 1 due to short plasma half-life. Companies including Epizyme optimized their compounds with good results, but many continue to fashion new ones with better properties. Constellation recently scrapped phase 3 plans for its EZH2 inhibitor, instead prioritizing a second-generation compound with “best in class potential,” says Trojer, because it stays bound to its target for much longer time.

The upshot of Tazverik’s lymphoma approval is that it should boost company and investor interest in epigenetics. But there are pitfalls. BET bromodomain inhibitors, which target ‘reader’ proteins that recognize histone marks, are a good example. There are specificity issues when targeting histone readers. “My impression of these compounds is that they are somewhat unselective and toxic to cells,” says Melnick. Single-agent clinical trial results overall have been disappointing. Overinterpretation of preclinical experiments using high drug concentrations may be one reason, says Trojer.

Constellation’s BET bromodomain inhibitor program is moving forward because the company eventually found a tumor type, myelofibrosis, highly sensitive to the drug. But Constellation has now decided to advance only those agents underpinned by a biomarker-driven hypothesis. “Epigenetics is a complicated area, and you can do clinical development for years without really getting good traction,” says Trojer. “And so we said to ourselves, let’s not do this again.”

Tazverik’s careful development sets an important precedent. “There are tons of [epigenetic] targets out there,” says Melnick, “but not a great understanding of how they are working.” He laments a common “hit and run” mentality: “Find some drug that works and then make a big claim about epigenetic therapy. But we can’t do it that way. We have to do consistent, methodical analyses of these systems to get a sense of where the true vulnerability lies.”