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Roche’s GA101 (obinutuzumab): Engineering an antibody to beat Rituxan

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

Survival rates for people with B-cell driven blood cancers, such as non-Hodgkin’s Lymphoma and chronic lymphocytic leukemia, have vastly improved in the last decade thanks to the introduction of Rituxan, marketed by Biogen Idec and Genentech. But the drug, a chimeric monoclonal antibody targeting CD-20, a protein that sits on the surface of B-cells, has its limitations: not all patients respond at first, and others become resistant to the drug over time.

As a result, companies are tinkering with the sugar molecules that decorate antibodies in hopes of coming up with a drug that binds better to its target and, ultimately, is more effective at battling cancer. At the American Society of Clinical Oncology annual meeting, held earlier this year in Chicago, Roche offered Phase III data showing its glycoengineered antibody GA-101 worked better than Rituxan at delaying the progression of CLL. If all goes well with FDA, the drug could be approved by the end of the year.

BACKGROUND:

Although the CD20 antigen is expressed on both normal and malignant cells, it has proven to be a useful target therapeutically.  Rituximab, ofatumumab and most of the anti-CD20 antibodies in earlier development are Type I monoclonal antibodies, which means that they have good complement-dependent cytotoxicity (CDC) and Ab-dependent cell mediated cytotoxicity (ADCC), but are weak inducers of direct cell death.

In contrast to Type I monoclonal antibodies, next generation monoclonals are increasingly Type II, such as GA101 (obinutuzumab) in CLL and NHL and mogamulizumab (anti-CCR4), for T-cell leukemias and lymphomas.  They have little CDC activity, but are much more effective at inducing ADCC and also direct cell death, at least based on in vitro studies performed to date.

How does glycoengineering make a difference?

Glycoengineering is the term used to refer to manipulation of sugar molecules to improve the binding of monoclonal antibodies with immune effector cells, thereby increasing ADCC.

Obinutuzumab is a very different molecule from rituximab, in that it is a novel compound in its own right (originally developed by scientists at Glycart before being bought by Genentech).  It is not a biosimilar of rituximab.  It is also a glycoengineered molecule designed specifically to improve efficacy through greater affinity to the Fc receptor, thereby increasing ADCC activity.GA101

The overall intent with the development of obinutuzumab was to significantly improve efficacy over rituximab and Type I monoclonal antibodies in B-cell malignancies using glycoengineering techniques.

At the recent ASCO annual meeting, data from a phase III trial was presented to evaluate rituximab or obinutuzumab in combination with the chemotherapy chlorambucil versus chlorambucil alone in newly diagnosed CLL.  Patients elderly and had co-existing co-morbidities, excluding them from standard chemotherapy with fludarabine and cyclophosphamide (FC).

This two part trial sought to compare both combinations to the chemotherapy initially, and then against each other in a head-to-head comparison once the survival data matured in the second phase.  Data from the first phase of the study was reported at this meeting.

What did the results show?

When looking at the response rates, both obinutuzumab and rituximab combinations had a higher overall response rate (ORR) than chemotherapy alone (75.5% and 65.9% vs. 30.2% and 30.0%).  Importantly, the combinations had a great proportion of complete responses (CR) i.e. 22.2% and 8.3% compared to 0% in the chlorambucil arms.

Minimal residual disease (MRD), a measure of the number of leukemia cells remaining in the blood, was 31.1% in the peripheral blood of the obinutuzumab combination compared with 0% in the chemotherapy arm.  Corresponding values in the rituximab and chlorambucil arms were 2.0% and 0%, respectively.

Median progression-free survival (PFS) i.e. the length of time during which people lived without their disease worsening for the obinutuzumab plus chlorambucil arm were impressively higher than chemotherapy alone.  PFS was more than doubled (23 months compared to 10.9 months, HR=0.14, p <.0001) when compared to chlorambucil alone.  The corresponding outcome data for the rituximab combination were 15.7 versus 10.8 months for chlorambucil alone (HR=0.32, p <.0001).

Since ASCO, Roche have announced that the FDA granted Priority Review for obinutuzumab in CLL (in addition to the Breakthrough Designation already received in May, when the company filed a new drug application for obinutuzumab), meaning that the PDUFA date is set as December 20th.  In addition, the Data Monitoring Committee decided that the interim data analysis was sufficient to meet the primary endpoint of the trial, ahead of schedule.  The data confirms that obinutuzumab was superior to rituximab in terms of the disease worsening (PFS).  The full data will be presented at ASH in December, when overall survival data (ie did the patients live longer) may be available.

The adverse event profiles were slightly different between the monoclonal antibodies.  Patients in the obinutuzumab arm experienced more infusion site reactions, and a slightly higher degree of myelosuppression (thrombocytopenia and neutropenia), but lower infection rates.

Overall findings

The study demonstrated that both obinutuzumab and rituximab were more beneficial to elderly patients living with CLL and co-existing medical conditions than chemotherapy alone.  The final head to head analysis of the two combinations will be available once the second stage of the study has mature data.  Based on the progress to date, the signs are very encouraging that the chemical engineering behind the development of obinutuzumab may potentially have produced a superior compound to rituximab for treatment of B-cell malignancies.

Should the mature outcome data show a positive survival advantage in obinutuzumab’s favour over rituximab, we may well see similar glycoengineering techniques applied to other monoclonal antibodies in the near future, potentially leading to further improvement in outcomes.

 

Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA

Bookmark this page now, folks. On Wednesday, April 10, I will be here, liveblogging the public debut of five drug candidates’ structures. The “First Time Disclosures” Session at the ACS National Meeting in New Orleans runs from 2PM-4:55PM Central time. I am not able to conjure up a permalink to the session program, so here’s a screengrab instead.
NOLAblog-program
1:20PM I’m in hall R02, where the session’s set to begin in about 40 minutes. Found a seat with a power outlet nearby, so I’m good to go!
2:29PM
IMG_3813
BMS-906024
Company: Bristol-Myers Squibb
Meant to treat: cancers including breast, lung, colon, and leukemia
Mode of action: pan-Notch inhibitor
Medicinal chemistry tidbit: The BMS team used an oxidative enolate heterocoupling en route to the candidate– a procedure from Phil Baran’s lab at Scripps Research Institute. JACS 130, 11546
Status in the pipeline: Phase I
Relevant documents: WO 2012/129353
3:02PM
IMG_3810
LGX818
Company: Novartis Institutes for Biomedical Research and Genomics Institute of the Novartis Research Foundation
Meant to treat: melanoma with a specific mutation in B-RAF kinase: V600E
Mode of action: selective mutant B-RAF kinase inhibitor
Status in the pipeline: Phase Ib/II
Relevant documents: WO 2011/023773 ; WO 2011/025927
3:47PM
IMG_3812
AZD5423
Company: AstraZeneca
Meant to treat: respiratory diseases, in particular chronic obstructive pulmonary disease
Mode of action: non-steroidal glucocorticoid receptor modulators
Medicinal chemistry tidbit: This compound originated in part from a collaboration with Bayer Pharma.
Status in the pipeline: Phase II
Relevant documents: WO 2011/061527 ; WO 2010/008341 ; WO 2009/142568
4:17PM
IMG_3811
Birinapant (formerly known as TL32711)
Company: TetraLogic Pharmaceuticals
Meant to treat: cancer
Mode of action: blocks the inhibitor of apoptosis proteins to reinstate cancer cell death
Status in the pipeline: Phase II
Relevant documents: US 8,283,372
5:00PM
IMG_3814
MGL-3196 (previously VIA-3196)
Company: Madrigal Pharmaceuticals, acquired from VIA Pharmaceuticals, licensed from Roche
Meant to treat: high cholesterol/high triglycerides
Mode of action: mimics thyroid hormone, targeted to thyroid hormone receptor beta in the liver
Medicinal chemistry tidbit: this molecule was discovered at Roche’s now-shuttered Nutley site.
Status in the pipeline: completed Phase I trials
Relevant documents: WO 2007/009913 ; WO 2009/037172

And that’s it, folks! Watch the April 22nd issue of C&EN for more on this session.

New Targets in Advanced Prostate Cancer

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

Much hullabaloo has been in the medical news over the past year over new options for the treatment of metastatic castrate resistant prostate cancer (CRPC). FDA approval for two new drugs, abiraterone acetate (J&J’s Zytiga) and enzalutamide (Astellas/Medivation’s Xtandi), has meant a sharp focus on drugs that target the androgen receptor. But at the the American Society of Clinical Oncology Genitourinary (ASCO GU) symposium, held last month in Orlando, intriguing data on new targets for CRPC emerged.

Zytiga and Xtandi target the androgen receptor (AR) in very different ways, but the overall effect is similar, in that they can effectively reduce the levels of prostatic serum antigen (PSA), which is reactivated in tumors with advanced disease. Zytiga acts high up in the steroidogenic pathway and one side effect associated with monotherapy is the development of mineralcorticosteroid effects, leading to over stimulation of the adrenal glands and hypokalaemia.  This toxicity must therefore managed with concomitant prednisone therapy. Xtandi, meanwhile, more directly targets the androgen receptor, which tends to be amplified in advanced prostate cancer. The drug doesn’t have same effect on cortisol production as Zytiga, and can therefore be taken without steroids.

The androgen receptor isn’t the only valid target in CRPC, however.  Aldo-keto reductase 1C3 (AK1C3), an enzyme that can facilitate androstenedione conversion to testosterone, is also over-expressed in advanced prostate cancer. Several new agents in early development appear to specifically target AK1C3. At ASCO GU, a couple of abstract particularly caught my eye and are worth highlighting here:

1) Bertrand Tombal et al., presented the initial data on Xtandi monotherapy in advanced prostate cancer in the hormone-naive setting, that is prior to CRPC.  Traditionally, Androgen Deprivation Therapy (ADT) is given to patients with high risk disease.  In the US, LHRH antagonists are used first-line, followed by AR antagonists such as bicalutamide, giving a basis for the rationale testing Xtandi, which is a more complete antagonist of the AR than bicalutamide.

In this trial, the single arm design sought to determine whether not enzalutamide would have activity in patients who had not received standard ADT therapy. The waterfall plots in this study (n=67) were impressive. The results showed that:

a) Ninety-three percent of study participants experienced a ≥80% PSA decrease at week 25.

b) Median change in PSA was -99.6% (range -100% to -86.5%).

In other words, most of the men in this trial responded well to Xtandi, suggesting that a randomized trial is well worth pursuing next.

You can read more about the specifics of this new development and what Dr Tombal had to say here.

2) Ramesh Narayanan et al., presented an intriguing poster on a new preclinical compound from GTX Inc that specifically targets AK1C3. The results demonstrated some nice inhibitory activity of AKR1C3, with reduced androgen signaling and CRPC tumour growth. It is important to selectively inhibit C3 and not the C1 and C2 isoforms, since the latter are involved in production of the sex hormones.  Inhibition of C1 and C2 is also counter-productive because it can increase the androgenic signal and deprive ERβ of its ligand. To date, the challenge has been to develop a C3 isoform specific inhibitor, making GTX-560 a compound that may be worthwhile watching out for in the clinic.

Recently, Adeniji et al., (2011) observed that, “AKR1C3 plays a pivotal role in prostate tumor androgen biosynthesis, inhibitors of this enzyme have the potential to be superior to abiraterone acetate, a CYP17/20 hydroxylase/lyase inhibitor.”

Clearly, this is a promising development in CRPC, however, it is early days yet and we will have to wait and see how the clinical trials progress with this new agent.

New developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 2

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

In my last post on The Haystack, we discussed the phase III data from the Abraxane MPACT trial in advanced pancreatic cancer that was presented at the recent ASCO GI meeting in San Francisco. Two other late-stage studies in pancreatic cancer caught my eye—fresh data for AB Science’s kinase inhibitor masitinib and Sanofi’s multidrug pill S1.

Masitinib is an oral tyrosine kinase inhibitor from AB Science that targets KIT, PDGFR, FGFR3 and has shown activity in gastrointestinal stromal tumours (GIST). A different version of the drug (Masivet, Kinavet) is also approved in France and the US for the treatment of a dog mast cell (skin) cancers, which are also known to be KIT-driven.

S1 is multidrug pill from Sanofi and Taiho that consists of tegafur (a prodrug of 5FU), gimeracil (5-chloro-2,4 dihydropyridine, CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) enzyme, and oteracil (potassium oxonate, Oxo), which reduces gastrointestinal toxicity. Previous Japanese studies have demonstrated effectiveness of this agent in gastric and colorectal cancers, so a big unaswered question is whether it is effective in pancreatic cancer.

So what was interesting about the latest data at this meeting?

At the ASCO GI conference in 2009, French oncologist Emmanuel Mitry presented data from a small Phase II study of the effect of combining masitinib and Eli Lilly’s Gemzar in advanced pancreatic cancer. The study had just 22 patients, but the median overall survival of 7.1 months in was not a large improvement over what is often seen with the standard of care, Gemzar given alone, or with a combination of Gemzar and Genentech’s Tarceva. Over the years, many combination therapies based on Gemzar have failed to show superiority over single agent therapy. It’s both a high unmet medical need and a high barrier to beat.  Thus, the phase III data for the combination of masitnib and Gemzar was highly anticipated at this year’s ASCO GI meeting.

Gael Deplanque and colleagues compared masitinib plus Gemzar to Gemzar plus placebo.  Although the overall trial results for median overall survival were slightly higher than in the phase II study, they were not significant (7.7 versus 7.0 months, P=0.74; HR=0.90).

Some promising data was observed, however, in a subset of the population identified by a profile of biomarkers that the authors vaguely described as, “a specific deleterious genomic biomarker (GBM) consisting of a limited number of genes.” No other details on the actual genes or biomarkers were was provided, but the subset was described as having an improved MOS to 11.0 months compared to the Gemzar and placebo arm.

They also noted that patients with high pain, who usually do poorly on standard chemotherapy, also saw improvement with the masitinib combination. AB Science might have found a particularly aggressive subset that respond to masitinib, in which case, a biomarker would be useful in selecting those patients most likely to respond, as opposed to a catch-all approach where everyone is treated regardless of the predictive value.

AB Science has asked European regulatory authorities for approval, but the Phase III data will not be sufficient for US approval. The company will need to validate the biomarker panel in a large-scale randomized study, and a new phase III trial is now recruiting patients. The outcome of that study won’t be known for awhile, but the hope is for more insight into how to choose the right patients to respond to masitinib in combination with Gemzar.

The other compound featuring late-stage results in pancreatic cancer was Sanofi’s S1. The compound is interesting, but so far its development has been limited to Asian patients, particularly people of Japanese origin. Studies in caucasians have not seen any benefit over standard 5FU therapy.

Katsuhiko Uesaka, medical deputy director at Shizuoka Cancer Center Hospital in Japan, presented encouraging data for the use of S1 as adjuvant therapy in combination with Gemzar after surgical resection (relevant in stage I-III pancreatic cancer). They compared S1 and Gemzar in a head to head non-inferiority trial (with 385 patients. In the interim analysis reported at this year’s ASCO GI meeting, the hazard ratio for S-1 to Gemzar was 0.56, while the 2-year survival rates were 53% for Gemzar and 70% for S-1. The percentage of serious side effects were similar to previously reported studies with Gemzar and S-1, including fatigue (4.7/5.4), anorexia (5.8/8.0), leukopenia (38.7/8.6), thrombocytopenia (9.4/4.3), anemia (17.3/13.4), and elevated AST (5.2/1.1).

Overall, the authors concluded that S-1 adjuvant chemotherapy was shown to be as good as, perhaps even better than Gemzar, even suggesting that S-1 could be considered the new standard treatment for resected pancreatic cancer. It should be noted, however, that this data is only applicable to patients of Japanese origin since no caucasian data was included in this analysis.

 

New Developments in Advanced Pancreatic Cancer from ASCO GI 2013 – Part 1

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

The cancer research conference season kicked off in earnest in 2013 with the American Society of Clinical Oncology (ASCO)’s Gastrointestinal Symposium, held in San Francisco in late January. Some of the most anticipated data to be presented at ASCO GI was for drugs that treat pancreatic cancer, with three drugs—Celgene’s Abraxane, AB Science’s masitinib, and Sanofi’s S1, generating the most interest.

With this post, we’ll take a closer look at the most advanced of the three agents, Abraxane, which generated encouraging results in a Phase III study. Later this week, we’ll tackle masitinib and S1.

Abraxane is a nanoparticle albumin-bound form of the breast cancer drug paclitaxel, and is designed to improve the activity of the active ingredient. Abraxane is already approved in the US for advanced breast and lung cancers, and recently showed signs of activity in metastatic melanoma.

At ASCO GI, Daniel Von Hoff, director of the Translational Genomics Research Institute, presented data from a randomized phase III study called MPACT that compared the effects of Lilly’s Gemzar, the current standard of care, to a once weekly combination of Gemzar and Abraxane in patients with metastatic adenocarcinoma of the pancreas. With 861 patients, this was a large global study that sought to determine whether the combination would outdo the regulatory standard of care.

A note on the trial design: Although this study uses Gemzar as the standard of care, in practice, many leading oncologists prescribe FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) for advanced pancreatic patients. But because FOLFIRINOX is generic, and is not formally approved by FDA for advanced pancreatic cancer, Phase III studies tend to match new drug candidates up against Gemzar.

As Hedy Kindler, director of gastrointestinal oncology at the University of Chicago, explained, FOLFIRINOX is widely used because the regimen has “the higher response rate, and that has the longer median survival.”

However, FOLFIRINOX also has unpleasant side effects, and in private practice settings, oncologists prefer to use less toxic combinations based on Gemzar—namely, Gemzar alone, GemOx (with oxaliplatin), or GemErlotinib (with Tarceva, an EGFR TKI). To provide context, FOLFIRINOX typically has an improved survival of approximately 11 months, while gemcitabine or gemcitabine plus erlotinib elicit a 6-7 month improvement in median overall survival (MOS).  Erlotinib added 12 days of extra survival over gemcitabine alone, but unfortunately we have no way of selecting those advanced pancreatic patients most likely to respond to EGFR therapy.

Celgene is exploring the combination of Abraxane and Gemzar based on preclinical work that suggests Abraxane can knock out the protective stroma surrounding the tumor, thereby providing better penetration of the tumor.  The phase II data led to a promising 12.2 months improvement in median overall survival.

In general, results from randomized phase III trials tends to be lower than that reported in the smaller studies. This is exactly what happened in the MPACT trial, with the Abraxane combination showing a MOS of 8.7 months versus 6.7 months for Gemzar alone, a highly statistical significant finding (P<0.000015). The hazard ratio (HR) was 0.72, suggesting that the combination gave a 28% reduction in the risk of death versus gemcitabine.

Kindler is eager to use and learn more about the combination and notes that it will be another option for oncologists rather than a new standard of care.

This is encouraging data and met the primary endpoint. Celgene is expected to file for approval for Abraxane in advanced pancreatic adenocarcinoma in the second half of the year. Data on a previously identified biomarker (SPARC expression) was not yet available and is expected to be presented at the annual ASCO meeting in June.  The audience at the GI meeting were clearly expecting survival to be higher in those patients with high SPARC expression, but we will see what happens.

Advanced pancreatic cancer is a particularly devastating disease – the incidence and prevalence are approximately equal, with patients typically having a year of life left.  The symptoms are vague and insidious plus there are no useful screening approaches approved for earlier detection, so the emergence of potential biomarkers for selecting patients most likely to respond to Abraxane or Tarceva in combination with gemcitabine would be a most welcome advance, especially given the toxicities associated with FOLFIRINOX.

 

 

#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation.

However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months.

At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them?

An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research–this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic.

One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone.

Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent. Continue reading →

#ASCO12 Data Digest: Combating Resistance in Lung Cancer

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog.

The American Society of Clinical Oncology (ASCO) meeting, held in Chicago earlier this month, brought some fascinating presentations on progress in two very tough to treat cancer types, lung cancer and advanced melanoma. This week, we’ll take a look at some of the data that emerged out of ASCO on small molecules that could overcome the limitations of existing therapies.

Treatment for lung cancer and melanoma has commonalities. Small molecule kinase inhibitors targeting a particular aberration driving the tumor have been approved for both types of cancer. But in each case, tumors eventually develop resistance to those kinase inhibitors, usually after about 6 to 9 months of treatment. Researchers are now trying to pinpoint the mechanism that tumor cells use to overcome the activity of kinase inhibitors, and then design new compounds or combinations of drugs that can improve patient outcomes.

Today we’ll focus on advances in non-small cell lung cancer (NSCLC). ASCO brought data from several new agents—most notably, Boehringer Ingelheim’s afatinib, AstraZeneca’s selumetinib, and Novartis’ LDK378—as well as new combinations of existing drugs.

First, some background on the current treatment paradigm in NSCLC: To date, scientists have identified several key protein receptors—EGFR, KRAS, and ALK—as drivers of the disease. Patients with a mutation in EGFR can take Genentech’s Tarceva (erlotinib) or AstraZeneca’s Iressa (gefitinib), but only after undergoing four cycles of chemotherapy. Although Tarceva was approved based on its ability to shrink tumors, it only prolongs survival in NSCLC patients by one month (12 months Tarceva vs. 11 months for placebo). Meanwhile, people who have the anaplastic lymphoma kinase (ALK-ELM4) translocation, can receive Pfizer’s Xalkori (crizotinib), which was approved in the U.S. in 2011.

Unfortunately, people with the KRAS mutation, which is considered mutually exclusive with EGFR, do not benefit from either additional chemotherapy or EGFR inhibitors. New therapies are desperately needed, since prognosis tends to be rather poor.

At ASCO this year, clinicians reported new data that answered some key questions about how best to treat people with these particular mutations: Continue reading →

Epizyme & Celgene to Develop Epigenetics-Based Cancer Drugs

Cambridge, Mass.-based Epizyme has scored $90 million upfront as part of a broad cancer drug development pact with Celgene. The deal adds to a spate of lucrative pacts to find compounds to modulate epigenetic targets, or enzymes that control gene expression without altering the underlying DNA.

As we wrote in last week’s cover story, DNA carries the instructions for assembling all of life’s essential building blocks, but epigenetics dictates how and when that DNA is put to work. Recently, companies have made significant process in understanding the complex biology behind epigenetic processes, while also figuring out how to design compounds that can potently block epigenetic enzymes. With the science and business rationale for pursuing epigenetic targets dovetailing, big pharma and big biotech alike are forging deep ties with the handful of companies with expertise in the field.

Under the three-year deal announced today, Celgene has the right to opt-in to the ex-U.S. rights for any unencumbered histone methyl transferase program at Epizyme. Eisai currently has the rights to Epizyme’s EZH2 inhibitor, while GlaxoSmithKline has a deep collaboration with Epizyme against undisclosed targets that would be excluded from today’s pact with Celgene.

Epizyme says the partnership makes sense because Celgene shares “our vision in oncology and epigenetics,” says Epizyme’s president and CEO Robert J. Gould. “That’s been a fundamental bedrock of our partnering strategy–to partner with people who share our enthusiasm for this space.”

Indeed, Celgene has long played in the epigenetics space, boasting two of the four currently marketed drugs that act on epigenetic targets. However, Celgene’s drugs, Istadax and Vidaza, hit first-generation epigenetic targets. Epizyme’s activities, meanwhile, center on one of the next waves of epigenetic targets: a family of enzymes called histone methyltransferases (HMTs). Of the 96 members of that family, Epizyme has identified roughly 20 HMTs for which there is a clear link to a specific form of cancer, Gould says.  To date, the company has two compounds—the EZH2 inhibitor partnered with Eisai, and a DOT1L inhibitor—in preclinical studies. (Check out last week’s cover story on epigenetics for more on how Epizyme went about discovering those two compounds.)

Celgene is kicking off the pact by opting into the inhibitor of DOT1L, an HMT that is implicated in mixed lineage leukemia, a rare subtype of the blood cancer that the Leukemia and Lymphoma Society says affects about 1,500 new patients in the U.S. each year.

With each program thereafter that Celgene buys into, Epizyme could score up to $160 million in milestone payments.

The cash influx, coupled with the U.S. rights to the programs, “positions us nicely to maintain our independence, but also control our own future as a company,” Gould says. “We now have the runway to go pretty far with these programs.”

That independence is important aspect of Epizyme’s strategy of commercializing its cancer therapies in the U.S., a goal Gould says is attainable because HMT inhibitors will be used in highly specific, genetically-defined patient populations.

The Celgene deal also broadens Epizyme’s scientific horizons, Gould says. “This expands the depth of research we can do around histone methyl transferases specifically…but also gives us the opportunity to imagine what other approaches we might take that might be synergistic or additive to the HMT family.”

Gould is quick to note that in the near term, the company is focused on HMTs “until we prove these compounds are effective in these patients with genetically-defined cancer.”

Between its deals with GSK, Eisai, and Celgene, and its burgeoning pipeline, Epizyme will need to expand its operations. The current headcount stands at about 48, but Gould notes that going forward the small biotech will need to grow out its clinical development organization and, more modestly, its basic research activities.