Epizyme, Inc. (NASDAQ:EPZM)
32nd Annual JPMorgan Healthcare Conference Call
January 16, 2014 3:00 PM ET
Robert J. Gould Ph.D. – President and CEO
Good morning everyone, thank you for joining us. It is my pleasure to introduce Epizyme. Speaking on behalf of Epizyme will be CEO, Dr. Robert Gould. I just like to remind everyone that the breakout session will take place in the Olympic Room which is just down the hall and right around the corner. So with that turn it over to you.
Robert J. Gould
Thank you very much. It is my pleasure to present to you today the progress that Epizyme has made in the last year and hope we anticipate looking forward to in 2014. Epizyme is a biopharmaceutical company creating personalized therapeutics for patients with genetically-defined cancers. We create proprietary first-in-class small molecule inhibitors of a number of a class of enzymes called histone methyltransferases. This family of enzymes comprises 96 members and these enzymes control gene expression through a phenomenon called Epigenetics.
When these enzymes are misregulated or genetically altered they can be the direct drivers of a variety of both solid and hematologic malignancies as well as other diseases. We currently have two programs that are in clinical development for these genetically-defined cancers. The first molecule goes by the name EPZ-5676 and it is an inhibitor of an enzyme called DOT1L, one of the histone methyltransferases. The second program that’s in clinical development is a net compound EPZ-6438, which is an inhibitor of an enzyme called EZH2. We are very excited that in the last year in 2013, we were able to demonstrate objective responses in our first clinical trial in the Phase I dose escalation study. These two programs are generated by a product platform that we put together a number of years ago, that creates a pipeline of novel personalized therapeutic programs and continues to be a productive source of novel chemical entities for us as inhibitors of these enzymes. All of the intellectual property at Epizyme is generated in-house and our earliest composition of matter patents expire in 2032. We’ve developed therapeutic collaborations with Celgene, Eisai and GSK over the last few years.
And importantly companion diagnostic collaboration with Abbott and Roche to facilitate the identification of patients with the genetic alterations that are driving their diseases. In 2013 we completed enrollment of the Phase I dose escalation stage of EPZ-5676 a DOT1L inhibitor. We achieved a $25 million proof-of-concept milestone in our – from our partner Celgene. As we saw objective responses in the target patient population a form of leukemia called mixed lineage leukemia in which there is a chromosomal rearrangement.
We also identified a potential expansion indication in 2013, a form of leukemia called MLL-PTD. In our EZH2 program compound EPZ-6438 we achieved a $6 million Phase I study initiation milestone from our partner Eisai and it also identified a new potential expansion indication in a solid tumors in which there is deficiencies of a protein called INI1. In our GSK collaboration we achieved a 4 million mile, $4 million development candidate milestone for one of our GSK targets.
5676 and 6438 have strong patent protection, composition of matter patents were granted last year for those two compounds as well as two other granted patents last year. And we continue our scientific leadership in this field of HMT or histone methyltransferases. During 2013, we had a successful IPO which raised $89 million and we finished our 2013 with cash and receivables or receivables of approximately $145 million, this puts us in a robust position through 2015. This is important to us because during the next few years we intend to move our two lead programs, DOT1L for acute leukemias, and EZH2 for non-Hodgkin lymphoma and solid tumors forward through clinical development, as well as continuing the preclinical development of our three targets that are partnered with GSK as well as novel histone methyltransferase targets in our platform.
Key events in 2014 include five clinical proof-of-concept programs as well as clinical data disclosure for major medical conferences. Three of those proof-of-concept programs will be in the DOT1L arena an adult study with mixed lineage leukemia, a pediatric study in which there is a similarly a genetic alteration driving that pediatric leukemia and an adult form of leukemia called MLL-PTD. EZH2 program we will have two plan proof-of-concept programs, a study in a genetically defined subset of non-Hodgkin lymphoma and synovial sarcoma in which there is a genetic drivers due to deficiency of a protein called INI1.
As I have mentioned these HMT target class that we are working in regulates gene expression by the addition of methyl groups and hence the name histone methyltransferases. This transfer of these methyl groups control gene expression and when misregulated, when the enzymes are misregulated, gene expression is misregulated and disease can result. Out of the 96 enzymes we’ve identified 20 that we prioritized based on their oncogenic mechanism and based on the demonstration that they appear to be drivers of a variety of hematologic and solid malignancies. This early focus on patients with genetically-defined cancers enables us to have a very focused clinical development strategy.
Two of our programs are currently in the dose escalation phase in which we determine safety, tolerability and pharmacokinetic parameters. The DOT1L program has moved to an expansion phase, which gives us an initial assessment of therapeutic effect, as we study only patients with the genetically-defined cancers as identified with companion diagnostic.
From there we intend to move into registration studies based on the data obtained in the expansion cohort results and again identifying patients using the companion diagnostic, so we can have a highly focused clinical development strategy. The DOT1L inhibitor 5676 is a first-in-class small molecule inhibitor of the HMT DOT1L. This enzyme DOT1L is the driving oncogene in acute leukemias, in which there is a chromosomal rearrangement of a gene called MLL. Late in 2013, we achieved objective responses in a Phase I dose escalation study which we were treating MLL-rearranged patients and exciting step forward for us in that program.
Importantly for the hypothesis we’ve seen anti-leukemic effect in cancers with MLL genetic alterations, but no effects in cancers without MLL genetic alterations. Again consistent with the chromosomal rearrangement within MLL driving the cancer.
The primary indication for this program is MLL-rearranged leukemia, a genetically defined subset of both AML as well as ALL and we intent to expand into a another genetically defined subset of AML, MLL-PTD. Enrolment was completed in the dose escalation phase of this program and we are currently enrolling in the MLL-r expansions phase are treating only patients with the MLL rearrangement. Epizyme is partnered with Celgene in this program, but we have been able to retain a 100% of our U.S. development and commercialization rights.
This overall survival for patients with MLL-r or MLL-PTD is low. In the adult populations median survival is about nine months and five-year survival is 20% or less and similarly in the pediatric population. There are existing diagnostic tests for these patients and therefore we can leverage the existing diagnostic test to identify these patients. And to insure that we focus our clinical development on the patients that have the genetic alterations.
DOT1L is the driving oncogene although the chromosomal translocation is within a protein called MLL because MLL, the MLL-fusion protein that’s created during the chromosomal translocation aberrantly recruits an otherwise normal enzyme called DOT1L to an abnormal place and the chromosome or it should not be. When it goes to that place in the chromosome it transfers methyl groups which lead to transcriptional changes, controlling gene expression inappropriately and the results in phenotypic changes result in the cancer that shows up as a mixed lineage leukemia. We can selectively kill cells that have those chromosomal translocations by targeting this misregulated enzyme DOT1L shown on the left of this panel are MLL-rearranged cells which in a dosing time dependent manner or selectively killed by the clinical development candidate 5676 or as other leukemic cells shown on the right hand side without the MLL-rearrangement do not or not affected and do not or not killed by 5676. This despite the fact that the enzyme is inhabited in both places as seen by degrees in a methyl mark their particular product of this enzyme called H3K79. This is important for us because we can use this H3K79 methyl mark to determine that we are in fact inhibiting the enzyme in our clinical trials.
If one take cells with that MLL-rearrangement embeds them into new grafts in a xenograft model allow the tumor to grow and then initiate treatment either with vehicle or two different doses of 5676 at 35 or 70 milligrams per kilo in these patients. Treat the animals for 21 days as indicated with the dosing period bar and tumor is eliminated from these animals. If one then discontinues treatment, but continue to follow the animals, no tumor grow back – grows back in the highest dose that’s shown here at 70 milligrams per kilo. We therefore have durable in vivo efficacy in animal models, dose exposure and time dependent effects and importantly sustained tumor aggressions again importantly seen at well tolerated doses.
In these preclinical models we see both differentiation of genes, as well as a differentiation of cells, as well as a apoptosis. Shown in the right hand side here, right hand panel here is differentiation effects that are seen when one treats MLL-rearranged cells evidence - morphologic evidence of maturation as well as upregulation of cell markers like CD14. Once these cells begin to differentiate because they are misregulated generic elements they then go on to apoptosis and die. And this is the mechanism of death that we’ve seen both in vitro as well as in vivo in animals.
So I’ve mentioned we have completed the dose escalation phase with 5676 in 2013. This clinical program enrolled patients with advanced hematologic malignancies including, but not limited to the patients with MLL-r rearrangement. It followed a 21-day on, seven-day off IV administration in these patients with continued – continuous IV administration at six sites assessing safety, pharmacokinetics and pharmacodynamic. We are currently in an expansion phase in which only MLL-r patients are being treated with uninterrupted administration and it increase the number of sites both in the U.S. and Europe up to 12. This expansion phase will provide the initial assessment of efficacy in the MLL-r patients.
In the Phase I program as of December 2013 we saw a favorable safety profile with 5676 and evidence of anti-leukemic activity. These patients are a heavily pretreated population, what we saw no dose limiting toxicities when they were receiving 5676, no drug related treatment discontinuations and no dose toxicity relationship. We did however see nicely dose proportional exposure, dose and time dependent reduction in the methyl mark and importantly objected responses observed in two patients in cohort 4 receiving a 54 milligram per meter square per day dose.
Cohort 5 this clinical protocol is continuing with patients receiving 80 milligrams per meter squared per day so called cohort 5. We’ve also began an expansion cohort restricted to MLL-r or MLL-PTD patients that was initiated last year in the starting dose and expansion cohort will be 90 milligrams square grams per meter squared per day with uninterrupted continuous IV infusion. With the objective responses observed in cohort-4 were an important step forward for us, because that triggered a $25 million milestone payment from Celgene as well as continuing to provide robust biological support for the continued clinical development of this compound. Consistent with the preclinical data, we saw differentiation effects among patients with the MLL-rearrangement we saw leukocytosis, maturation of leukemic blast in the bone marrow and evidenced that that maturation of leukemic blast were releasing neutrophils into the peripheral blood again consistent with the underlining biologically hypothesis.
Switching now to our EZH2 program EPZ-6438, this is a first-in-class small molecule inhibitor of the enzyme EZH2, a methyltransferase that is misregulated both in mutant-bearing non-Hodgkin lymphoma patients as well as in solid tumors with the deficiency in a protein called INI1. In 2014 we anticipate to have continuing our Phase I dose escalation study that is ongoing and gated on completion of that dose escalation study initiating two proof-of concept programs. One in the EZH2 mutant-bearing non-Hodgkin lymphoma patients and one in synovial sarcomas patients, patients that have a deficiency in protein called INI1. This program is partnered with Eisai where Epizyme has retained 50% of the U.S. development and commercialization rights in this program.
Thus EZH2 inhibition has the ability to potentially treat two different genetically defined cancers. Cancers that are driven by INI1 deficiency and cancers that are driven by change of function mutations within EZH2. 6438 selectively kills cells that have the EZH2 mutant that shown on the left hand side here. Time and concentration dependent killing of EZH2 mutant cells with an associated inhibition in the methyl mark and no effect on non-mutant lymphoma cells as shown in the right hand panel. 6438 also has a potent and durable effect targeting EZH2 mutant cells in a mutant lymphoma xenograft model.
This compound is dosed BID orally and causes time and dose dependent ablation of tumors that are sustained, show sustained tumor regression in well tolerated doses, Similarly synovial sarcoma is a soft tissue sarcoma that is sensitive to EZH2 inhibition as shown in this data on this slide. EPZ-6438 selectively kills mutant cells in-vitro on the right hand panel and has no effect on cells in the left hand panel. However, there is a complete and sustained regression of mutant xenograft animals in these INI1-deficient tumors and another tumor type called a malignant rhabdoid tumor, a deadly childhood cancer.
EPZ-6438 is currently in a Phase-I dose escalation study and advanced hematologic and solid tumors that was initiated in June of last year. This study is progressing well, we’ve seen no dosage limiting toxicities to date and we anticipate at 2014 completion, gated on that data from that dose escalation study, we planned to start two Phase II proof-of-concept studies in 2014. EZH2 mutated germinal-center non-Hodgkin lymphoma study and a synovial sarcoma study. As I have already mentioned, the intellectual protection is robust, 5676 had an issued patent in 2013 that will expire in 2032 as did EPZ-6438.
Collaborations have been an important business driver for us and overly approximately six years of Epizyme’s history. We generated a $164 million in non-equity. Our funding all being able to significantly retain U.S. rights. As I’ve mentioned we retained all of the U.S. rights on the DOT1L program which has partnered ex-US with Celgene. We’ve been able to retain half of our U.S. rights on EZH2 program, which has partnered ex-US with Eisai and Eisai also having the other half of the U.S. rights. Our partnership with GSK has been an important mechanism for us to build our platform, re-proceeds $38 million to date in that program achieved a development candidate milestone late last year indicating the ability of our platform to continue to produce high quality molecules for the continued treatment of patients with genetically-defined cancers.
As we look ahead to 2014 we’ll be presenting the clinical data from the EPZ-5676 Phase I dose escalation study as well as the MLL-r rearrange stage and upon completion and analysis to Phase I dose escalation studies from 6438. We have five planned proof-of-concept programs ongoing in 2000 that we anticipate have ongoing in 2014. Three 5676 MLL-rearranged leukemia, a pediatric study in MLL-rearranged leukemia and an adult study in mixed lineage leukemia with partial tandem duplication PTD.
Two programs in the 6438, the program are anticipated to initiate next in 2014. Genetically-defined subset of germinal-center B-cell lymphomas and synovial sarcoma. We are in a strong financial position building on our $89 million IPO race in 2013. We finished 2013 with approximately $145 million in cash or receivables, which funds the company through 2015, and enables us to continue to aggressively move forward not only our clinical development programs, but also our basic research programs as we continue to produce high value assets as inhibitors of histone methyltransferases.
So I thank you very much for your time.
[No Q&A session for this event]
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