In conversation with Dr. Isaac Ciechanover

Dr. Isaac Ciechanover

Dr. Isaac Ciechanover

As president and CEO of Atara Biotherapeutics (NASDAQ:ATRA), Dr. Isaac Ciechanover has spent the past 20 years working with entrepreneurs and life sciences organizations to advance medicine through innovation and technology. He was a former partner in the life sciences practice at Kleiner Perkins Caufield & Byers and spent a decade as Celgene’s executive director of business development, spearheading venture capital, licensing and M&A activities with an aggregate transaction value of more than $6.7-billion. Dr. Ciechanover started Atara for personal reasons when his mother, Atara Ciechanover, for whom the company is named, was sick with ovarian cancer and there were no new therapies to treat the disease. Mrs. Ciechanover passed away in 2012. In this interview with, Dr. Ciechanover discusses the company’s clinical programs that target unique pathways and may pause or reverse patients’ underlying diseases.

Let’s start with a brief history of the company.

In August 2012, Amgen and Kleiner Perkins created Atara to focus on innovative therapies for the treatment of cancer, kidney disease and other illnesses. Kleiner Perkins initially financed Atara, and we received licenses to seven molecules from Amgen. Our research is based on groundbreaking discoveries regarding the potential ability of activin, myostatin and other growth factors to change the course of disease progression in patient populations where there have been few innovations and limited therapeutic options for patients.

Could you outline your technology platform?

We have two platforms: one for the development of molecularly targeted molecules and a second for the development of “off-the-shelf,” targeted T-cells. In molecular-targeting, we are developing biologics that target two proteins—myostatin and activin— that are members of the Transforming Growth Factor-Beta (TGF-β) protein superfamily. Myostatin and activin play roles in the growth and maintenance of muscle and many other body tissues. We have two clinical stage product candidates in this space: PINTA 745 and STM 434. We licensed these two molecules from Amgen several years ago.

In T-cell targeting, we recently entered into an exclusive option agreement with Memorial Sloan Kettering Cancer Center (MSK) through which we have the right to acquire the exclusive, worldwide rights to three clinical stage T-cell product candidates pursuant to a negotiated form of license. The three T-cell product candidates are Epstein-Barr virus (EBV)-targeted cytotoxic T lymphocytes (CTLs), cytomegalovirus (CMV)-targeted CTLs, and Wilms Tumor 1 (WT1)-targeted CTLs. Each product candidate is designed to kill particular types of virally infected or malignant cells.

What’s your lead program currently?

PINTA 745 is a peptide-antibody combination that binds to and blocks myostatin, a growth factor in the TGF-β pathway. We are studying whether it can reverse protein-energy wasting in dialysis patients with end-stage renal disease. It is estimated that 250,000 dialysis patients in the U.S. suffer from protein-energy wasting and that these patients have been shown to die in the first year at a rate three times faster than the rest of the dialysis population. PINTA 745 is the only agent that we know of in development for patients with this condition.

Representative Example of the Observed Reduction in Size

Representative Example of the Observed Reduction in Size

What makes PINTA 745 so special?

It has anti-inflammatory properties that, to our knowledge, differentiate it from the other anti-myostatin programs out there. Preliminary evidence of safety and efficacy with 745 has already been published in a peer-reviewed journal, and the molecule was well tolerated in this clinical study.

What’s the clinical status of PINTA 745?

We are in a Phase 2 clinical trial at six clinical sites in the U.S. Planned enrollment is 48 patients, with 36 patients on the drug and 12 on placebo. We expect to unblind the data in the fourth quarter of 2015.


What kind of molecule is STM 434?

STM 434 is a soluble receptor fused to part of an antibody that is designed to block the growth factor, Activin A, and other ligands of the Activin Type IIB receptor. STM 434 is being studied in patients with ovarian cancer and other advanced solid tumors. Levels of Activin A are elevated in certain patients with ovarian cancer, making Activin an attractive target for novel therapeutic approaches. There are also genetic mutations associated with some cancers that may perturb normal Activin A signaling. We are investigating whether STM 434 can change the course of ovarian tumor growth by blocking the action of Activin A.

Why did you select ovarian cancer as a target for STM 434?

Amgen published a preclinical study in the journal CELL about a molecule acting as a surrogate for STM 434. Plus, I was also aware of other interesting data around the time my mother was diagnosed with her ovarian cancer. I reached out to Amgen about the status of STM 434. It just so happened that this agent, along with the others that Atara eventually licensed, didn’t fit in with Amgen’s late-stage pipeline at the time. We were able to construct a creative licensing offer that served as the basis for the formation of Atara. We were at the right place at the right time.

Are ovarian cancer treatments still poor?

Ovarian cancer is the fifth leading cause of cancer death in women in the U.S. While surgery and cytotoxic chemotherapies are widely used to treat ovarian cancer, outcomes have changed very little in 40 years. The proportion of all ovarian cancer patients surviving five years after diagnosis was only 44%, based on the National Cancer Institute SEER database for women diagnosed from 2003 to 2009. We believe that new therapies are needed to address this important issue in women’s health.

What have you seen in your research with STM 434?

Published pre-clinical data with the surrogate of STM 434 showed potential antitumor activity as well as a survival benefit in an animal model of certain ovarian cancers. The surrogate of STM 434 also showed the ability to increase body weight in preclinical studies. This is of particular importance as it has been estimated that one-in-five cancer deaths in solid tumors is associated with cachexia, or progressive loss of body weight.

What about treating other solid tumors with STM 434?

STM 434 is in a Phase 1 study that is open to patients with a number of different advanced solid tumors. Published studies by other researchers have shown associations of high levels of Activin A in pancreatic, head and neck, and lung cancer, among others.

What’s the clinical status of STM 434?

We began a Phase 1 open label study late last year at four cancer institutions in the U.S., which plans to enroll up to 66 solid tumor patients who have previously received at least one therapy. We have guided to an initial data release in the first half of 2016, but because this is an open label study, depending on what we see, we may have data during 2015.

Can you provide a brief overview of the MSK collaboration?

MSK is a leader in the development of T-cell therapies for cancer and other infectious diseases. Our collaboration with MSK centers on three clinical stage product candidates, the EBV-, CMV- and WT1-targeted CTLs, which share a common technology in which T-cells, part of our innate immune system, are collected from the blood of third-party donors. The T-cells are educated to certain antigens, thereby activating them towards a particular target. The resulting activated T-cells are then expanded, characterized, and stored for future therapeutic use in a partially human leukocyte antigen (HLA) matched patient. MSK has developed banks of these “off-the-shelf” target-specific T-cells for investigational use in patients with a wide range of HLA types. When needed, these cells can be used in a clinical trial within days.

MSK Platform Attributes

MSK Platform Attributes

The FDA recently granted breakthrough therapy designation to your optioned CTL against Epstein-Barr Virus (EBV-CTL). What’s the significance of that?

The FDA’s breakthrough therapy designation is designed to expedite the development and review of new drugs for the treatment of serious or life-threatening conditions. To qualify for this designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus standard of care to the standard of care alone. The designation confers several benefits, including intensive FDA guidance and discussion and eligibility for submission of a rolling biologic license application.

Can you describe the results with EBV-CTL that led to breakthrough designation?

Breakthrough therapy designation for EBV-CTL was based on data from two separate clinical trials of EBV-CTL conducted by MSK. Data from these studies have been submitted by MSK for presentation at an upcoming medical conference in 2015.

How does efficacy with CMV-CTL compare?

MSK presented data at ASH last December from a Phase 2 clinical study of CMV-CTL demonstrating preliminary evidence of safety and efficacy in immuno-compromised patients with either high CMV viral load or overt symptomatic CMV disease, including retinitis, who had failed a median of four prior anti-viral therapies.

Are there more data coming?

Even though we have an option to license these compounds, MSK still runs these clinical studies and handles the submission of data for publication. MSK has submitted data to a number of scientific meetings this year. And based on the data generated to date, MSK is expanding its clinical programs to evaluate the safety and efficacy of these targeted T-cells in other clinical trial settings.

What’s your current cash position?

It was about $104.1-million as of Dec. 31, 2014, excluding $69.4-million in net proceeds from our follow-on offering in February 2015, and our goal is to expand spending on all of our programs.

What should we expect moving forward for the company?

Outside of the rights to PINTA 745 in Japan, we own, or have an exclusive option to license under our agreement with MSK, worldwide rights to all of our programs, which is very valuable for Atara and allows us to define our destiny. In addition, over the next 12-to-18 months, we expect to release results from our various licensed and optioned clinical programs, which we hope will provide multiple opportunities for value creation.