A year after its launch as the first and only FDA-approved EZH2 inhibitor via accelerated approval, Epizyme’s first marketed drug Tazverik® (tazemetostat) failed to meet analyst expectations. The methyltransferase inhibitor, indicated for two rare cancers, forms of epithelioid sarcoma (ES) and follicular lymphoma (FL), finished 2020 with $11.47 million in sales, well short of a Wall Street consensus forecast of $35 million in first-year sales made in February, a month before COVID-19 led to lockdowns nationwide.

The pandemic impeded company outreach to physicians and patients, Epizyme contends, while pointing to several silver linings amid the proverbial clouds: Net revenue rose 31% in the fourth quarter compared with Q3, with new physician “accounts” prescribing Tazverik jumping by more than 50% quarter-over-quarter.

Another reason for optimism, Epizyme says, is the company’s clinical efforts to expand Tazverik’s label. Epizyme is preparing to begin the Phase III randomization portion of its EZH-302 trial (NCT04224493) assessing tazemetostat and R2 (lenalidomide and rituximab) in second-line FL following positive Phase Ib safety run-in results in 13 patients.

The company has begun enrollment in the Phase II efficacy portion of the EZH-1101 trial (NCT04179864) assessing tazemetostat with standard-of-care treatments (enzalutamide or abiraterone) in castration-resistant prostate cancer, after a Phase Ib safety run-in study showed seven of 21 patients having a PSA response of ≥50%, with an eighth having ≥35%. Tazemetostat is also in Phase II development for several other solid tumor indications, including front-line epithelioid sarcoma and INI1-negative tumors, as well as front-line diffuse large B-cell lymphoma (DLBCL).

Epizyme recently detailed its development strategy and pipeline priorities over the next five years during a “Strategic Vision Call.” Those priorities include launching two signal-finding “basket” studies in the second half of 2021 to evaluate tazemetostat safety and efficacy across multiple new types of blood and solid tumors; and advancing to the clinic its SETD2 inhibitor program starting with an IND filing this year, with at least five clinical programs including SETD2 planned over five years.

“Some investors may be concerned about the aggressive expansion efforts into multiple tumor types, which will significantly increase operating expenses and also may provide a distraction from the more pressing need to improve the ongoing launch,” cautioned Andrew Berens, MD, managing director, targeted oncology and a senior research analyst with SVB Leerink, in a March 3 research note.

However, Michael J. Yee, equity analyst with Jefferies, sounded more optimistic: “The pipeline could be interesting and we will be following this (though it’s early) as a potential next leg of growth.” This year, he added, Tazverik’s launch remains important as the pipeline is mostly in early phases.

GEN Edge learned more about Epizyme’s five-year vision, and its recent clinical developments and plans, in interviews with three company executives: Shefali Agarwal, MD, MPH, executive vice president, chief medical & development officer; Jeffery Kutok, MD, PhD, CSO; and Vicki Vakiener, chief commercial officer. (The interviews were lightly edited for space and clarity).

Shefali Agarwal, MD, MPH, executive vice president, chief medical & development officer

Shefali Agarwal, MD, MPH, executive vice president, chief medical & development officer

GEN Edge: Epizyme is studying earlier lines of treatment with tazemetostat in epithelioid sarcoma (ES) and follicular lymphoma (FL) “by exploring various combinations with standard of care therapies.” Is tazemetostat viewed as more of a combination drug vs monotherapy?

Agarwal: Given the nature of cancer diagnoses and disease progression, the most common trajectory for any novel agent is to first demonstrate efficacy and tolerability as a monotherapy, and then move to combination therapy studies to evaluate agents with current standards of care.

Following our FDA approvals last year, our next goal is to bring tazemetostat into earlier lines of therapy in both ES and FL through our ongoing and planned development programs. Given the efficacy and tolerability demonstrated in our Phase II trials, combined with low discontinuation rates, we believe tazemetostat has the potential to be explored in combination with other agents. Based on the feedback from physicians, we believe tazemetostat can become an important backbone of therapy in the relapsed/refractory FL setting.

We plan to build on tazemetostat’s pipeline drug potential by evaluating tazemetostat in additional solid tumors and hematological malignancies. Due to its novel mechanism, its durable responses, generally well-tolerated safety profile, and an oral administration, we believe tazemetostat has the potential to be positioned as both a monotherapy and a combination agent that patients can take over an extended period.

Our ongoing and planned clinical trials evaluating tazemetostat in combinations and in earlier lines of therapy will read out a steady flow of data over the next five years. We have given serious consideration to innovative and efficient approaches to developing tazemetostat across a range of tumor types.

GEN Edge: Epizyme is preparing to commence the Phase III randomization portion of the EZH-302 trial assessing the combination of tazemetostat + R2 (lenalidomide and rituximab) in FL. What were the early safety and activity findings that proved positive enough for Epizyme to advance the study to Phase III?

Agarwal: We are in the process of reviewing our early data with the FDA and initiating the Phase III portion of the trial. We are encouraged, given the design of the study, biological hypothesis, and characteristics of tazemetostat regarding safety and activity.

GEN Edge: Tazemetostat is also being studied in prostate cancer with standard of care treatments (enzalutamide or abiraterone) in the Phase Ib safety run-in portion of the EZH-1101 trial. What factors help explain a key finding: Seven out of 21 patients had a PSA response of ≥50%; one additional patient had a PSA response of ≥35%?

Agarwal: We are excited about the potential for targeting EZH2 within a number of solid tumors, starting with castration-resistant prostate cancer. EZH2 inhibition has been shown to have the potential to play an important role in the treatment of patients with metastatic prostate cancer. EZH2 has been shown to cooperate with the androgen receptor during oncogenic transformation, leading to epigenetic silencing of many tumor suppressors and regulators of differentiation. Non-clinical combination experiments based on models have shown that EZH2 inhibition can re-sensitize both prostate culture cells and xenograft tumor models to androgen-signaling inhibitor therapy.

While the data we showed during the Vision call was preliminary, as there are still patients ongoing and being followed up on, a summary of preliminary safety findings suggests that the side effect profile across the cohorts are low, and combined rates of Grade 3 or higher adverse event are low.  Further, no new safety signals were observed in combining tazemetostat with ENZA or tazemetostat with ABI and prednisolone.

We are encouraged to see that 7 out of 21 patients had a PSA response of greater than 50% and another had a PSA decrease of greater than 35% (PSA by PCWG3 criteria, which is the gold standard for detection of early signs of clinical activity). We’ve also seen preliminary evidence of radiographic improvement in the trial in a patient who had a PSA response, which is a confirmed partial response after receiving tazemetostat and enzalutamide in the Phase Ia portion of the EZH-1101 trial.

Based on these encouraging preliminary data, we have decided to move to the Phase II efficacy portion of the study. We look forward to sharing further data readouts on this ongoing program.

GEN Edge: Is ARV7 status another factor? Epizyme noted that all responses were in ARV7 negative patients using the EPIC platform, considered more rigorous in detecting ARV7 status.

Agarwal: We used the EPIC platform, which is more accurate in detecting ARV7 positivity, hence we expect a low false positive rate in patients with ARV7. We recruited only one ARV7 positive patient into this small safety study, and 85–90% of prostate cancer patients are ARV7 negative.

We believe based on the emerging data that EZH2 inhibition has the potential to play an important role in the treatment of patients with metastatic prostate cancer. EZH2 has been shown to cooperate with the androgen receptor during oncogenic transformation, leading to epigenetic silencing of many tumor suppressors and regulators of differentiation. Moderate to high EZH2 expression was associated with worse failure-free survival.

GEN Edge: Epizyme has reported that six of the PSA50 responses were in the tazemetostat + enzalutamide cohort and one was in the tazemetostat + abiraterone/prednisone cohort. How fair is it to conclude that TAZ is more effective with enzalutamide vs. tazemetostat + abiraterone/prednisone?

Agarwal: It would be premature for us to draw conclusions between the two arms at this point in time since the trial is ongoing and we are currently enrolling the Phase II efficacy portion of the trial.

We are moving forward with enzalutamide in the Phase II portion of the study based on the preliminary Phase Ib results and the fact that enzalutamide is widely used in prostate cancer, either before or after ABI and the preliminary activity observed. We look forward to presenting further data from the Phase Ib portion of the study at a medical meeting in 2021.

GEN Edge: Epizyme said it will launch “basket” trials assessing tazemetostat across multiple new types of heme and solid tumors in the second half of this year. Why use a basket trial approach?

Agarwal: Using signal finding studies, like basket trials, allow us to look at multiple types of hematological and solid tumors to find signals, and once we have a signal, decide if we ought to move into larger trials that may be able to support registration. These basket trials are also adaptive, and allow us to add additional cohorts, or modify our patient populations as we view the data.

With this approach, we can study multiple combinations with standard of care therapies and new mechanisms of action to maximize the potential of tazemetostat.

This type of trial may shorten clinical development timelines if signals are identified in areas of large unmet medical need where there could be registrational opportunities based off smaller, single arm studies. We will continue to evaluate as data become available.

GEN Edge: On what types of tumors, both solid and blood, will tazemetostat be evaluated?

Agarwal: These studies will be U.S.-based trials with the goal of first understanding the safety of these combinations and then to generate important proof-of-concept data. It is important to note that we are basing the designs of the heme and solid basket trials on preclinical results we have generated thus far or that have been published externally, providing scientific rationale for each indication. These trial designs will be using a Bayesian method to generate data and understand the signal of proof-of-concept using efficacy and biomarkers.

The hematological malignancies we plan to study include combinations with relevant standard of care therapies in a basket trial include FL, diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma and multiple myeloma. The solid tumor basket trial will be conducted in combinations with relevant standard of care therapies in small cell lung cancer, prostate cancer, and ovarian cancer.

GEN Edge: Epizyme has referred to Tazverik/tazemetostat as a “pipeline in a drug,” How so?  To what extent is this mainly or more properly viewed as a cancer pipeline in a drug? Are any indications beyond oncology contemplated?

Agarwal: At this time, our focus has been oncology. However, we continue to evaluate our development plans based on scientific rationale.

There is clear scientific rationale to further the development of tazemetostat in both hematological malignancies and solid tumors and we have developed an expansive clinical development program to evolve tazemetostat’s potential into a number of new indications.

Through Epizyme’s leading epigenetic research, our understanding of EZH2 continues to evolve. EZH2 expression has been shown to lead to epigenetic silencing of many downstream tumor suppressors and regulators of differentiation.

Jeffery Kutok, MD, PhD, CSO

Jeffery Kutok, MD, PhD, CSO

GEN Edge: Epizyme’s platform includes clinical and discovery programs targeting several classes of epigenetic modulators—do those indeed include the PRMT 5 and PRMT 1 clinical programs?

Kutok: The pipeline slide that was shared during the Vision call includes preclinical programs only. Our PRMT 5 and PRMT 1 methyltransferase inhibitors are licensed to GlaxoSmithKline (GSK), and all research support by Epizyme has been completed. GSK is responsible for subsequent research, development, and commercialization of each program.

GEN Edge: What other types of modulators is the company targeting?

Kutok: Epizyme is well positioned to continue to expand on the success of tazemetostat as well as to identify and develop the next generation of targeted epigenetic medicines. Through our CRISPR platform we have a cutting-edge approach to target identification and validation. In addition, we have a highly efficient, target focused chemical library that we have extensively cross screened against multiple targets and target classes, and repeatedly shown that it can provide novel starting points within these target classes.

Our experience in the biology of epigenetics, together with this platform, has led to an incredibly rich pipeline of discovery programs targeting several classes of epigenetic modulators including histone methyltransferase inhibitors, which is the class that tazemetostat belongs to, as well as histone acetyltransferase and helicase inhibitor programs.

Our goal is to advance many of these programs into clinical trials in the next several years. We’ll be sharing more details about these in the future as the data evolve.

GEN Edge: Why is Epizyme targeting SETD2? How is SETD2 inhibition believed to fight cancer? What sort of preclinical data has this generated to date?

Kutok: Like EZH2, which tazemetostat targets, SETD2 is a histone methyltransferase that plays multiple key roles in cellular processes. Its enzymatic activity adds the third or final methyl chemical group on the tail of histone H3 at the 36th lysine position (H3K36). Trimethylated H3K36 is a key mark in the chromatin that directs important functions involved in genomic integrity and stability, including transcriptional regulation and gene expression, DNA damage repair, and RNA splicing regulation.

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 t(4;14) chromosomal translocation, which is associated with very poor survival rates.

t(4;14) is the result of a genetic mutation that involves breaking and re-joining or translocating of specific regions on chromosomes 4 with those on 14. This mutation brings the immunoglobulin gene enhancer elements on chromosome 14 near the MMSET gene on chromosome 4 driving MMSET overexpression.

MMSET is a histone methyl transferase that works upstream of SETD2 and is responsible for putting either one or two methyl groups on H3K36. The 4;14 translocation, therefore, leads to over-expression of MMSET, resulting in high levels of the dimethylated substrate for SETD2, and SETD2, in turn, produces high levels of tri-methylated H3K36.

Given SETD2’s role in this pathway, we are investigating if there is a dependency on SETD2 for t4;14 myeloma cell growth and survival, and if so, our hypothesis is that inhibiting SETD2 will lead to tumor cell death. Our preclinical in vitro and in vivo studies with our novel potent and selective oral SETD2 inhibitor confirm that this is the case in the t(4;14) myeloma as well as other myeloma cell lines without the t(4;14).

GEN Edge: What other potential for SETD2 has Epizyme explored?

Kutok: We have also explored the potential for SETD2 in other B-cell malignancies. This has included extensively profiling our inhibitor in in vitro and in vivo lymphoma panels, which suggest suppression of diffuse large B cell lymphoma tumor growth with SETD2 inhibition. We are working on identifying the genetic basis for these effects in DLBCL.

We previously presented work outlining the in vitro effects of our SETD2 in the t(4;14) myeloma cell lines at ASH in 2018. We expect that the data shared on the Vision call will be presented at a medical congress later this year. Our SETD2 inhibitor program is currently in the IND-enabling phase, with a planned IND filing later this year.

GEN Edge: Epizyme has cited high risk t (4;14) multiple myeloma and other B-cell malignancies such as large-cell lymphoma as areas where SETD2 inhibition has shown promise. Can those be expected to be among indications once this starts clinical trials?

Kutok: It would be premature to speculate about the clinical program as we are currently in the late stages of IND-enabling activities, but we are a science-driven company and our clinical development plans have always followed the science.

GEN Edge: Epizyme has envisioned clinical trials for other discovery programs over the next several years. Can any of these programs be expected to launch this year?

Kutok: We have 11 pipeline programs in progress that are in all stages of development. As these programs evolve, further guidance and information will be provided accordingly.

Vicki Vakiener, chief commercial officer

Vicki Vakiener, Chief Commercial Officer

GEN Edge: Epizyme’s launch of Tazverik last year did not meet analyst projections. How much of that is due to COVID-19 and how much is it other factors, such as provider acceptance and payer reimbursement?

Vakiener: We have experienced two specific challenges related to COVID-19. First, as follicular lymphoma is an indolent cancer, patient visits have been down, and we have also seen new starts on any medication for these patients is down 30–40% vs. pre-COVID-19 levels.

The second factor is access to providers. We launched Tazverik for FL almost entirely virtually. The metrics we reported in our 4Q call indicate that we are gaining traction in both physicians using Tazverik and the share of new patient starts has been increasing since launch. We are confident that Tazverik can become a backbone of therapy in treating patients with FL. From a payer perspective, Tazverik has coverage consistent with the label with >90% of insured lives.

GEN Edge: To the extent that COVID-19 was a factor in 2020, how much is the re-emergence from lockdown in much of the United States expected to stoke demand for Tazverik in 2021?

Vakiener: We are seeing positive signs of our commercial execution and novel approaches to tackle the challenges created by COVID-19. Our hope is that once broad vaccination is fully deployed across the United States, patients will come back to live, in-office visits and our field team’s access will also increase.

GEN Edge: How much has the COVID-19-impacted 2020 launch compelled Epizyme to pursue the expansion programs for TAZ?

Vakiener: The plans we rolled out during the Vision Call align to the tazemetostat clinical development strategy we’ve been describing for some time now. On the call, we described our decision to move forward into the next stages on trials that started last year and that we successfully enrolled despite the COVID-19 challenges.

GEN Edge: How is Epizyme working to win providers and payers over to Tazverik going forward?

Vakiener: We have deployed a mix of marketing programs that have focused on peer-to-peer education, medical education programming as well as engaging with patients through educational advocacy. From a payer perspective, we have more than 90% of insured lives covered and the payers are generally covering Tazverik consistent with the label.

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