Constellation Article sourced by Cabel

Posted on RVX by Cabel Apr 1 2019

I’ve reposted an article posted about Constellation Pharmaceutical by Cabel on RVX on Apr 1,2019 because it applies to Zenith. Thanks for the find Cabel.

They are testing their small molecule CPI-1205 that is an EZH2 inhibitor in patients with mCRPC patients in combination with abiraterone or enzalutamide.

From a business POV this looks like a competitor to zen3694 and they are at phase ll. From a science POV would this be considered a competitor?

What we’ve seen from the zen3694 mCRPC trial is that zen3694 has very strong results in a few patients but not others. So it seems the breakthrough is to identify patient targets ahead of treatment that it will be most effective in so they can be targeted (this might even allow for market size projections) and I think this is the program (translational biology) outlined on p17 of the Zenith presentation.

In the article at paragraphs 10 & 11 the CSO points out that this is a challenge for all oncology drugs. It would be fantastic if Zenith can narrow in on some of the filters for zen3694. Might be a bit of a breakthrough and create much bigger interest at Pfizer and some other companies that have 1 or more of the 25+ drugs that zen3694 enhances.

Looks like it is a big challenge not just for Zenith. Any thoughts re implications for Zenith? At the end of the day I guess oncologists can just stick with the broad brush approach because if it helps 20% of patients have significantly extended lives it probably is very valuable to Pfizer and others.

Following is the part of the article.

Thanks again cabel.

GLTA

Toinv

cabel

News article on epigenetics

posted on Apr 02, 2019 07:30AM

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Ran into this news article on epigenetics in my news feed:

https://www.genengnews.com/insights/epigenetic-therapies-return-cells-to-the-straight-and-narrow/

Whether they are partially or fully differentiated, individual cells within multicellular organisms must confront life’s big questions: Who am I? Why am I here? Where am I going? Cells that forget the right answers may succumb to dysfunction and contribute to neurodegenerative, autoimmune, or metabolic disease—or cancer. In the case of cancer, cells may lose themselves in sketchy identities, deviant metabolism, and wanton proliferation, as well as metastatic corruption.

A cell’s fate, be it wholesome or debased, is determined by epigenetics, that is, by patterns of gene expression. Fortunately, normal patterns may be distinguished from aberrant patterns by technologies that interrogate epigenetic factors and monitor epigenetic changes. Even better, if these technologies detect aberrant gene expression, they may prompt pharmacological interventions.

Pharmacological interventions that aim to reverse aberrant gene expression are becoming increasingly specific—and successful. For example, therapeutics are targeting epigenetic regulators of different types, including the so-called writers, readers, and erasers of epigenetic marks. These regulators figure prominently in a growing number of medically relevant cellular pathways.

Epigenetic regulators are subject to modulation by a growing number of epigenetic therapies, some of which have already been approved by the FDA. Other epigenetic therapies are at various stages of preclinical and clinical development.

Selectively inhibiting epigenetic regulators with small molecules “When a handful of eager young scientists and I founded our company 11 years ago, our core mission was to identify and develop small molecules that inhibit chromatin regulators,” says Patrick Trojer, PhD, chief scientific officer at Constellation Pharmaceuticals. By inhibiting chromatin regulators, small-molecule drugs may, he emphasizes, “manipulate gene expression programs in cancer cells and immune cells.”

Constellation built an integrated epigenetics platform that can validate therapeutic targets and deliver drug candidates that can address unmet clinical needs for malignancies characterized by aberrant gene expression. “After a decade of effort,” Trojer continues, “we are gratified to have two drugs close to achieving clinical proof of concept.” The first targets a bromodomain and extraterminal domain (BET) protein, an epigenetic reader. The second targets the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), an enzyme that functions as an epigenetic writer. Both drugs are in Phase II clinical trials.

“We are testing our BET inhibitor CPI-0610 in patients with myelofibrosis as a monotherapy or in combination with ruxolitinib,” specifies Trojer. CPI-0610 is being evaluated in MANIFEST, a global study, for its ability to modify, alone or in combination with ruxolitinib, the underlying disease process of myelofibrosis. Positive results would include improvements in hematopoietic function, reductions in spleen volume, and amelioration of patient symptoms. Presentations of interim data may be delivered in the second quarter of the year, and another update may be available in the second half of the year.

The second compound in Phase II clinical trials is CPI-1205, a small-molecule EZH2 inhibitor. “We are exploring CPI-1205 as a second-line drug in a Phase II U.S.-only clinical trial called ProSTAR for patients with metastatic castration-resistant prostate cancer,” informs Trojer. Patients who progressed while on enzalutamide or abiraterone acetate, which block the androgen receptor signaling pathway, are moved to the other of these two first-line drugs and combined with CPI-1205. “We expect to present Phase Ib data at a medical meeting in the second quarter and an interim data update of our Phase II study in the second half of this year,” continues Trojer.

Constellation is also working on a second-generation EZH2 inhibitor, CPI-0209, currently in IND-enabling studies. This molecule is substantially differentiated from first-generation EZH2 inhibitors in its comprehensive target engagement and long duration of action, and a Phase I clinical trial using CPI-0209 for solid tumors is expected to start in mid-2019.

“The biggest challenge in taking full advantage of epigenetics as a target space in oncology is still translational biology,” declares Trojer. This challenge, the translation of basic science findings into the clinic, is common to both epigenetic therapies and traditional oncology drugs. It reflects the impossibility of predicting a priori which patients will respond to a particular drug.

“None of the novel oncology drugs works in unselected patient populations across the community,” Trojer points out. “This has complicated drug development in oncology.”

About two years ago, Constellation made a significant investment to build strong translational capabilities to facilitate the identification of predictive biomarkers and to help select and enrich patient populations in clinical trials. Such strategies are ideally positioned to help identify new mechanisms to enter the market.

etc

Happy Easter

GLTA

Toinv