Epizyme Inc (NASDAQ:EPZM)
UBS Global Healthcare Conference Call
May 21, 2014 10:00 AM ET
Robert J. Gould – Chief Executive Officer
Matt M. Roden – UBS Securities LLC
Matt M. Roden – UBS Securities LLC
Good morning. My name is Matt Roden, I’m the biotechnology analyst here at UBS. And I am pleased to introduce our next speaker it’s Robert Gould, Chief Executive Officer of Epizyme. Robert has served in that role since 2010 and he was a Director since 2008. Prior to joining Epizyme, Robert served as Director of Novel Therapeutics at The Broad Institute of MIT and Harvard. And before that he was at Merck for solid 10-year. I think in – the last role as Vice President of Licensing and External Research in Merck.
So, we are pleased to have you with us and we are looking-forward to hearing the latest update on Epizyme. Robert?
Robert J. Gould
Thanks, Matt. Well, thank you, Matt and thank you to UBS for the invitation, and thank you to each one of you for taking the time to hear the Epizyme story. I’m very pleased to have this opportunity to give you an update on where Epizyme stands in the first half of 2014 and what we can look forward to in the future.
For those of you who don’t know Epizyme, we are a biopharmaceutical company creating personalized therapeutics for patients with genetically-defined cancers. And very specifically we make small molecule inhibitors that are discovered by the scientists at Epizyme, the target – one of a family of enzymes called histone methyltransferases or HMTs for short. This is a large family of enzymes, 96-members within the human genome comprised this family of enzymes, and a controlled gene expression via phenomenon called epigenetics and they control that by transferring small chemical groups called methyl groups on to proteins called histones hence the name histone methyltransferases.
And because of the critical role that they play in driving gene expression, when these enzymes are misregulated through genetic alterations within the enzyme itself or within associated regulatory proteins. That misregulation of the enzyme leads to misregulated gene expression and that misregulated gene expression can be the driver for a variety of hematologic and solid malignancies as well as in another diseases, but Epizyme is chosen to focus on the cancers in which histone methyltransferases are the driving mutations.
We have two such clinical programs currently and genetically-defined cancers; a compound called EPZ-5676, which is an inhibitor of one of these HMTs, and HMT called DOT1L. And during dose escalation phase this – the development of 5676, we are very pleased to see objective responses in patients that have the genetic alteration.
Second program that’s in the clinic is for a different an inhibitor of the different HMT, this compound 6438 inhibits an HMT called EZH2. The Phase 1 dose escalation is currently ongoing in this program, where we’re targeting NHL patients with specific genetic alterations. But these two programs are only the tip of a product platform is generating a pipeline of novel personalized therapeutic programs within this family of enzymes, within the HMTs. Our intellectual property is robust, we have composition of matter patents around our two lead programs 5676 and 6438 that expire in 2032.
And we have therapeutic collaborations with Celgene, Eisai, and GSK that have been an important source not only revenue for the company, but also validation of our approach and recognition of the uniqueness of our product platforms, because of the criticality of addressing patients with genetically-defined cancers, we also have companion diagnostic collaborations with Abbott and Roche. Abbott around the DOT1L program and Roche molecular around the EZH2 program.
In 2013 and 2014 to date we’ve advanced our clinical program 5676 significantly, we achieved a $25 million proof-of-concept milestone with Celgene for achieving objective responses in the dose escalation phase of that program. And we initiated a Phase 1 expansion study specifically in patients that have genetic alterations. This is a leukemia population that has chromosomal translocation, leukemia is known as MLL-r or MLL-PTD.
And additionally we started a Phase 1 study in pediatric MLL-r patients. The form of leukemia were treating occurs in two age populations, in adult population and in pediatric population and we’re very pleased based on the safety profile that we’ve seen to date with 5676 to initiate the pediatric trial.
We have an ongoing EZH2 Phase 1 dose escalation study and again in 2013 we achieved $6 million initiation milestone with Eisai in that program. We have three programs that are partnered with GSK and over the last since December we’ve achieved $10 million in milestones across those three programs with the three GSK targets. And as I’ve mentioned we’ve advanced our intellectual property position with U.S. patents that have been issued this year on 5676 and 6438 as well as therapeutic and diagnostic claims around the EZH2 programs.
We anticipate that we’ll finish 2014 with more than a $170 million in cash this cash runway extends us through at least mid 2016 and that does not consider any additional milestones from any of our three partners. More importantly than the time that it extends through our ability to do proof-of-concept trials in our two programs that are currently in the clinic.
So let me turn now and explain a little bit more about this class of enzymes and then why we chose to focus initially on the two HMTs DOT1L and EZH2. So in this within that nucleus of your cell is the DNA that it encodes the proteins that make up life. And that control of gene expression is regulated by the addition of small chemical groups on to protein called histones as depicted in this cartoon. The addition of methyl groups is a particularly important regulatory system controlling gene expression.
And when HMTs are misregulated it results in misregulated gene expression and that misregulated gene expression can result in disease. This is a highly regulated system in the human cell, there is 96 members of these enzymes that can add specific methyl groups to very particular residues within the nucleus of the cell. And we prioritize 20 of those 96 is being important based on their oncogenic mechanisms.
Two of those as I’ve mentioned already, in clinical development for acute leukemias and for non-Hodgkin lymphoma or a solid tumor population deficient in another protein called INI1. And I will explain the biological rational for that in a subsequent slide. But as I’ve mentioned the three GSK targets have all achieved significant milestones in 2013 and 2014. As they move through pre-clinical development towards clinical development, the development candidate milestone and target number one in 2013 and lead candidate milestones in 2014 for targets two and three.
And then behind these five programs are additional solid tumor programs and hematologic malignancies programs that are product of our platform that we have generated over the last six years.
In 2014, as we look forward to the second half of this year we anticipate having five clinical proof-of-concept programs ongoing. The MLL-r adult population in which we have completed the dose escalation and intend to show proof-of-concept data in the second half of 2014, as well as the pediatric population in this form of leukemia where we initiated the Phase 1b proof-of-concept study about two weeks ago.
Additionally, we moved into a new leukemia population in 2014 and population called MLL-PTD where PTD stands for partial tandem duplication. And again we are actively enrolling patients in that Phase 1 proof-of-concept study in that population. Epizyme has a 100% of the U.S. commercial rights for the DOT1L program. And our partner Celgene has ex-US rights. In EZH2 program, we intend to complete our dose escalation phase of the program this year and disclose that data in the second half of this year.
And then gated on successful completion of that dose escalation component of the program, initiate two proof-of-concept studies in the second half of this year, one in non-Hodgkin lymphoma population and the other in a Synovial Sarcoma population. Eisai is our partner on this program and we have an option on 50% of the U.S. rights.
The DOT1L program – in the DOT1L program 5676 is the first-in-class small molecule inhibitor of the enzyme DOT1L. This enzyme DOT1L is a driving oncogene in acute leukemias that have genetic alterations within MLL whether they are chromosomal translocation in which case the disease is called MLL-r, or partial tandem duplication within the MLL gene in which case the disease is called MLL-PTD.
We are very pleased to see objective responses in the Phase 1 dose escalation study of this program. The Phase 1 dose escalation included patients with rearrangement wasn’t limited to those and entry of patients with rearrangement we saw objective responses.
We saw those objective responses specifically in cancers with the genetic alteration and no affect either pre-clinically or in the clinical studies in cancers without the MLL rearrangement. And so that represents our primary indication with MLL rearranged leukemia, which is a genetically-defined subset of AML and ALL. We currently have designed a two stage Phase 1 study that is ongoing. The dose escalation phase was completed in 2013, we are currently in an expansion stage which we expect completion in 2014. And we initiated a pediatric style enrolling patients between the ages of three months and 18 years, in 2014 to evaluate safety PK and PD and also to enable preliminary assessment of efficacy in that program.
With our partner Celgene, we have an ongoing joint global clinical development strategy to move this program forward aggressively. In MLL-r, this represents about 5% to 10% of the AML and ALL population, it involves a reciprocal translocation and chromosomal 11q23. It’s about 5% to 10% of the acute leukemias and that represents an incident of about 4,900 patients in major market. The incidence and the prevalence is virtually identical in this population, because as you can see in the lower left corner the survival curves for patients with these chromosomal translocations is quite poor.
Current standard of care for leukemia patients includes diagnostic evaluation for these chromosomal translocations either by Cytogenetics or by FISH. And we’re in partnership with Abbott to move the FISH diagnostics forward as an improved diagnostic.
In the case of MLL-PTD again it’s about half the population of the MLL-r – MLL-r again incidence and prevalence are virtually identical, and these patients are easily detected in a PCR based diagnostic, which is currently run as a research test.
The chromosomal translocation that drives this disease, creates a novel fusion protein that recruits the otherwise normal enzyme DOT1L and that recruit of DOT1L results in transcriptional changes as a result of hyper-methylation that results in a Phenotypic changes that show up as acute leukemias.
Selective inhibitors of DOT1L decrease the target methyl mark that is the subject of this HMT, so called H3K79. And this becomes a useful marker for us in clinical study to access our degree of inhibition of the enzyme. When you inhibit the enzyme as shown on the left hand panel here in cell lines it results in dose and time-dependent depth of the MLL-rearranged cell, but no affect on non-MLL-rearranged cell speaking not only to the criticality of DOT1L in the MLL-rearranged cells but also the specificity of 5676 in only killing MLL-rearranged cells.
That affect in vitro as seen in Xenograft models in new graph in which tumors are allowed to grow. Animals are dosed for 21 days intravenous linked with 5676. And in a dose dependent way one can achieve complete ablation of the tumor in these Xenograft models discontinuing the drug at day 21 in the higher dose in which tumors eliminated results in sustained tumor regressions at well-tolerated doses.
And so in this inhibition of DOT1L we see both differentiation in apoptosis occurring in these pre-clinical models co-instant with the reduction in methylation and the reduction in target genes we see upregulation of differentiation markers as well as morphologic evidence of maturation and induction in apoptosis markers like annexin. Again consistent with DOT1L being a critical regulator of both maturation or differentiation as well as apoptosis in these cells.
So in the Phase 1 adult program we completed enrollment in patients with advanced hematologic malignancies including MLL-r patients we followed a 21-day on/7-day off administration in those patients.
On a case-by-case basis we were able to move uninterrupted administration and as the standard for a Phase 1 dose escalation study we looked at safety tolerability pharmacokinetics that is dose and exposure measurements of 5676 as well as inhibition of the methyl mark as a pharmacodynamic readout of engagement of the enzyme.
We’re currently in the expansion phase of this program that is currently enrolling only MLL-r or MLL-PTD patients with uninterrupted administration the safety profile seen in the dose escalation place was clean and so we move to uninterrupted administration. And actually increased the number of sites up to 12 sites at both U.S. and Europe where we have sites in the Netherlands and Germany. We’ll not only obtain assessment of safety and tolerability in this expansion phase, but also early assessment of efficacy in the rearranged and PTD patients.
In the Phase I adult study as I’ve mentioned this was a 21-day on/7-day off schedule with no dose limiting toxicity seen, no drug related treatment discontinuations. We saw dose proportional exposure, dose and time-dependent reduction in the methyl mark and objective responses seen in two patients receiving 54 milligrams per meter squared per day.
We completed that dose escalation phase with an additional cohort at 80 milligrams per meter squared per day. And then in December moved to an expansion cohort with the starting dose of 90 milligrams per meter squared per day, the two significant changes from the dose escalation phase are restricting the patients population to those with MLL-r or PTD and moving to uninterrupted continuous intravenous infusion in that population. We take advantage of the fact that these patients all have center line that have been previously been installed, they are treated on an outpatient basis wearing a pump on the belt that has a concept that plugs in with the drug in it.
The pediatric study was just initiated a couple of weeks ago, we will be treating pediatric patients between three months and 18 years of age with MLL-r via continuous IV infusion for 28 days of a 28 day cycle. And again outcome measures in this study will be safety, tolerability and preliminary assessment of efficacy.
In our second clinical program EZH2, this is a program targeting an HMT called EZH2, which is a histone methyltransferases it translates to different methyl mark so called K27, which becomes our pharmacodynamic readout. And in non-hodgkin lymphoma patients there are point mutations within the active site of the EZH2 enzyme. The result in change of function that a variety of labs including our own have shown are the driver mutations in non-hodgkin lymphoma very specifically in NHL patients of germinal-center origin.
Additionally, what we have discovered over the last year is that there is a different complex so called SWI/SNF complex, which deficiency and a protein called INI1 leads to a dependence upon EZH2 for continued survival. This INI1 deficiency shows up in a variety of solid tumors like synovial sarcoma in which there is a chromosomal translocation between chromosomes X and 18 or a dilution in the case of a solid tumor called MRT.
So we have a first-in-class small molecule inhibitor of EZH2 that inhibits the HMT that’s through driving oncogene in NHL in solid tumors. So we’ll be focusing initially on the EZH2 mutant-bearing NHL patients, very specifically the germinal center origin NHL population as well as in the synovial sarcoma population.
In 2014, we have an ongoing dose escalation study in patients with advanced solid tumors or B cell lymphomas and gated to completion of that dose escalation, we currently anticipate initiating two proof-of-concept programs in 2014. EZH2 NHL patients, mutant-bearing NHL patients and synovial sarcoma patients. We retain half of the U.S. development and commercialization rights on an opt in basis with our partner Eisai owing the rest of the world.
6438 is potent selective orally bioavailable compound, that’s specifically inhibits the relevant methyl mark and then leads to specific killing. In ASH this past year, we’re very pleased to see present data that showed in this program by combining EZH2 with glucocorticoid receptor agonists or B cell signaling pathway modulators, we’re able to extend the pharmacological activity, not only the NHL cells to contain them point mutation, but to all germinal center derived NHL cells, that is both mutant cells as well as wild-type EZH2 cells.
And as – we would expect for a driver mutation profound and sustained in vivo efficacy in animal models, this shows the selective killing on the left side of EZH2 mutant cells, and on the right side non-mutant lymphomas cells and in the bottom the reduction in the relevant methyl mark, which becomes our biomarker for assessment of target engagement in the clinic.
As we’ve seen with the DOT1L inhibitor now using lymphoma Xenograft model 6438 leads to dose and time-dependent inhibition of tumor growth in nude mice, now treated for 28 days twice daily orally. In separate studies, once the tumor is abolished at day 28, the animals were followed for an additional 60 days, up to a total of 90 days, without drug therapy and no tumor grew back. So again durable in vivo efficacy that was dose exposure and time-dependent and led to sustained regressions and well-tolerated doses.
Similarly, 6438 shows effects in INI1-deficient tumors, here illustrated with synovial sarcoma but also seen in malignant rhabdoid tumors. Synovial Sarcoma is a soft tissue sarcoma of adolescents and young adults that has a chromosomal translocation so called SSX-SS18. And what you see in the left hand panel our SSX-SS18 fusion negative cells unaffected by 6438 and in the right hand panel fusion positive cells that have dose and time-dependent inhibition of growth.
In malignant rhabdoid tumor a deadly childhood cancer caused by a deficiency or mutation within INI1 again leading to a misregulated or dependents upon EZH2 activity, this tumor shows in children less than two years of age with event-free survival of less than 20% particularly tragic tumor as current therapy is chemotherapy and radiation. As you can imagine in children of two years of age receiving chemo and radiation there are significant treatment related morbidity in these children.
And again on the left hand panel selective killing of cells with INI1 mutation, INI1 also called SMARCB1 and complete and sustained regression of mutant MRT xenograft in these animals, again this complete ablation of the tumor in the xenograft studies with no tumor growing back. So in this program we have an ongoing Phase 1 dose escalation that was initiated in June of last year, we expect completion this year and we’ll be presenting the data in the second half of this year. Gated on the data from that dose escalation, we anticipate starting two Phase 2 proof-of-concept studies in 2014, studies in germinal center NHL patients; both DLBCL as well as follicular lymphoma. And synovial sarcoma initiated in parallel with the NHL studies.
As I’ve mentioned we have robust composition of matter claims for our therapeutic candidates expiring in 2032 as well as diagnostic patents and treatment patents that begin to expire in 2031, but a broad IP position all discovered within Epizyme covering both platform as well as therapeutic candidates.
Our collaborations have been important business drivers for us to date over the six years of the company we brought in $178 million in non-equity funding with significant retained U.S. rights, ex-U.S. rights with Celgene, half of the U.S. rights around DOT1L, half of the U.S. rights with Eisai and $48 million to date in three GSK targets.
So in 2014 we will be finishing our Phase 1 clinical studies initiating clinical studies in the pediatric populations in May, which we’ve achieved. Have ongoing Phase 1 dose escalation studies in 6438 that we expect to complete this year and present the data in the second half of this year. And then two proof-of-concept studies one in non-hodgkin lymphoma patients and one in INI1-deficient tumors like synovial sarcoma.
I thank you for your time and your attention. And I think the breakout room is across the hall. So thank you.
[No Q&A session for this event]