Drug Hunter: Discovering New Frontiers in Cancer Treatments & Beyond
INNOVATION THAT MATTERS
By Rich Soll, Senior Advisor, Strategic Initiatives at WuXi AppTec (@richsollwx)
As a self-proclaimed drug hunter, Phil Jones is on a mission to identify the next generation of cancer medicines that improve the lives of patients with cancer. He leads a multi-disciplinary team of scientists at The University of Texas MD Anderson Cancer Center’s Institute for Applied Cancer Science (IACS) that are developing impactful small-molecule cancer therapies. IACS is part of MD Anderson’s Therapeutics Discovery division, a group of clinicians, researchers and drug development experts working collaboratively to develop small molecule, biologic, and cell-based therapies. The division, where Jones also serves as VP of Therapeutics, was created to eliminate the bottlenecks in traditional drug development. The platforms of Therapeutics Discovery are supported by MD Anderson’s Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
Under Jones’ leadership, IACS and has several success stories, including the development of IACS-10759, the first small-molecule drug to be developed from concept to clinical trial by the Therapeutics Discovery team; several Pharma licensing partnerships; and the launch of three startups, the most recent being Magnolia Neurosciences, to speed development of neuroprotective therapies.
I recently spoke with Jones, who shared his insights on changing the drug development paradigm, the Institute’s expanding platform, as well as Houston’s growing biotech and medical ecosystem.
Rich Soll: Can you give me some background on the Institute for Applied Cancer Science and how it has evolved?
Phil Jones: We kicked off the Institute for Applied Cancer Science in the fall of 2011. With new leadership at the institution, we had an opportunity to really change the way we do drug discovery. We felt we could really leverage the whole institution to redefine the drug discovery process and break down the various silos to make it more efficient. We brought together our clinical faculty, with their insights into the pathways driving clinical resistance or relapses, along with our talented research scientists, with their new insights into fundamental cancer and immune biology, and then incorporated a professional drug discovery group. We assembled a group that understands what it means to develop the right molecule with all the key attributes to be able to modulate a protein target in a human with a meaningful impact. We felt this would change the drug discovery paradigm and bring impactful cancer therapeutics to our patients quickly.
Rich Soll: What is the vision of your Therapeutics Discovery division?
Phil Jones: Ultimately, we’re working to eradicate cancer. We develop small molecule drugs, biologics and cellular therapies, inspired by the needs of our patients and guided by the expertise of our clinical scientists. Things have been so successful at IACS over the last six years developing small molecule therapeutics that we’ve really broadened our vision into other modalities. We’ve expanded into the area of biologics and created the ORBIT platform, which stands for Oncology Research in Biologics and ImmunoTherapy. We now have a portfolio of antibody assets, one of which already is in the clinic through a partnership with GlaxoSmithKline; a second is going into the clinic in collaboration with Astellas Pharma.
Beyond that, we’ve launched the Neurodegeneration Consortium in 2012 thanks to a generous gift from the Robert A. and Renee E. Belfer Family Foundation. We recognize that many of our cancer survivors here at MD Anderson experience a lot of chemotherapy-induced neurodegenerative side effects, whether it be peripheral neuropathy or general cognitive defects known as chemo-brain. As an institution, we’re thinking more about survivorship and are very much interested in expanding our efforts in this area. More recently, clearly with the advent of CAR-Ts, we now also have activities in the area of cellular therapies.
All of these platforms are part of Therapeutics Discovery at MD Anderson, and we share a common approach for operating our programs. These are not typical academic departments, but rather very much driven as a standalone business unit, each with their own profit and loss. All of our team members work from a foundation of team science, coming together to work on projects with defined objectives and go/no-go decision points. This is somewhat different from traditional academic research labs.
Rich Soll: Could you give me some examples of how IACS has been successful?
Phil Jones: We now have two molecules in the clinic. IACS-10759 is our first small molecule to advance into the clinic and is currently in two trials for patients with leukemia and solid tumors. It is an oxidative phosphorylation inhibitor. A second example is our antibody program that is now in several trials through a partnership with GSK. There is a second biologic going first-in-human before the end of the year, and we have two small molecules destined for first-in-human trials in early 2019.
In terms of business development, we’ve established multiple collaborations with large pharmaceutical companies to accelerate our medicines to the clinic. Those include relationships with GSK, Astellas, and with Ipsen. We’ve also established a number of new companies, such as Magnolia Neurosciences through partnership with Accelerator Life Science Partners. A second is Navire Pharma, focused on allosteric SHP-2 inhibition, for which we partnered with BridgeBio Pharma. We also launched Vescor, together with by Deerfield, to focus on autophagy. And there are a couple of others that are still under the radar.
Rich Soll: Can you describe the collaborative environment at MD Anderson and how it’s unique? Is discovery going faster or are you more informed before you start your programs?
Phil Jones: As we’ve become more established over the past several years, we are regularly approached by people from all disciplines. Our clinicians bring forward ideas for new programs based on subsets of their patients not responding to available therapies. They have ideas for treating those patients or about mechanisms of resistance emerging in the clinic – they want to shut them down. They also seek us out for running clinical trials in their discipline with our current compounds.
On the other hand, basic science researchers are approaching us with ideas around entirely new concepts, and so we are seeing prepublication data, which is a big plus. We collaborate with those researchers and point out where we need to get a bit more translational data. Quite often, they will work on the programs for another six months and bring back those missing pieces, at which point we join forces to pick up the concept and insert into our portfolio. We create a joint project team and start moving the project ahead.
Obviously, we have unique access to whatever translational reagent is out there, such as PDX models, ex-vivo organotypic cultures and all the –omics data coming from our institutional genomics and immune-profiling efforts. We’re able to tap into our clinical data to really substantiate that this clinical population exists out there. We can also tap into our Phase 1 physicians, who will be driving Phase 1 clinical trials, and design those Phase 1B proof-of-concept trials in small subsets of patients. So, it is that value add for programs that you would be lacking in pharma. We’re inside the firewall; being part of the institution, we have that unique access.
Rich Soll: Why was the oxidative phosphorylation inhibitor IACS-10759 chosen as the program to go forward first?
Phil Jones: When we came here to MD Anderson, there was an explosion of interest in alternative cancer metabolism programs. At that time there was a lot of dogma that all tumors are glycolytic and depend on the Warburg hypothesis. Data from our own lab, and a number of other investigators, suggested that oxidative phosphorylation gets turned up in tumors as they develop resistance. Through extensive collaborations, we were able to demonstrate that there are some solid tumors and cell types, including AML blasts, which depend on oxidative phosphorylation.
We saw this as a unique opportunity and a differential program. As soon as we had a cell-active compound, a huge opportunity here at MD Anderson exploded. With that in vivo tool molecule, we were able to start collaborating broadly across the institution. We must have been collaborating with more than 15 different investigators, each exploring unique aspects of oxidative phosphorylation biology. That helped us to refine our clinical program as we moved forward.
Rich Soll: One of the areas you are working in is neurodegeneration. Can you describe the connection between cancer and neurodegeneration?
Phil Jones: We were able to point out that chemotherapy gives rise to neurodegeneration. It’s a pretty significant consequence of chemotherapy. More than half of patients in certain regimes will experience some aspects of peripheral neuropathy. That’s actually very bad for two reasons. First, it typically leads patients to reducing their chemotherapy dose or even stopping treatment, which obviously has a significant impact on their overall survival and quality of life.
Secondly, the cognitive deficits are pretty severe as well. Sometimes it can be so severe that they’re not able to perform certain tasks of daily living. You will hear people talk about “chemo-brain” or “chemo-fog”, these are very similar to age-related neurodegeneration. When you start looking at the biological mechanisms, they are very similar between age and chemotherapy-induced neurodegeneration.
We believed this was a good opportunity to not only develop a therapy for an unmet medical need, but also to create a new paradigm for testing and developing neuroprotective agents — you know when you give chemo, so you know when neurodegeneration starts. We know from all of our medical records what the latency is and when you’re going to see a signal, which makes it an opportune area for study.
Thanks to the generosity of the Belfer family, we were able to launch the Neurodegeneration Consortium in collaboration with several other institutions. Our investigators are focusing drug discovery programs in this area and have collaborative relationships across MD Andersons with physicians familiar with these neuropathies and cognitive deficits. We have a lead drug discovery program in this area where we’ve created intellectual property and development molecules that form the basis of Magnolia Neurosciences.
Rich Soll: How do you balance your internal resources and capabilities versus external relationships?
Phil Jones: We deploy a blend of internal and external resources on each program. Anything that is mission critical, a critical part for our programs, happens internally or we have very strong consultants that take ownership of execution. We then decide if the work happens internally or is conducted externally. Whether it’s WuXi or another contract company, we recognize that there is a wealth of services on the outside and that’s what we tap into. In the last six years, we’ve established a pretty significant network of business interactions to go beyond the staff that exists within our Therapeutics Discovery team. A large portion of our programs are undertaken at WuXi.
Rich Soll: How has WuXi enabled the work that you’re doing?
Phil Jones: WuXi has really enabled a lot of aspects of many of our programs, everything from protein production, crystallography, making Medchem SAR compounds, compound scale-up, pharmacology studies, and ADME/PK. With respect to IND-enabling studies, drug substance and drug product work, including the clinical material for the 10759 trial has been done at WuXi, as well as a significant portion of the safety/toxicology work.
Rich Soll: IACS itself is actually part of MD Anderson’s Moon Shots Program. Can you explain how that works and what you have contributed to that effort?
Phil Jones: MD Anderson’s Moon Shots Program was launched in 2012 to bring together focused, multi-disciplinary teams to more quickly bring forward discoveries from the lab into the clinic. The goal of the program is to accelerate progress and reduce mortality from cancers by focusing on the entire spectrum of care – including prevention, early detection and treatment.
In 2012, the time was right – with emerging therapies coming forward, a real understanding of cancer genetics informed by advances in sequencing technologies, breakthroughs in cancer immunology, and advances in early detection. All of the tools started to be in place here to really have a paradigm shift in the way we tackle the cancer problem. Our Moon Shots Program was a call to action for people to work collaboratively to tackle big issues – harnessing innovation, collaboration and scale to get us there faster. The Moon Shots focus on several different cancer types with clear unmet need and set up invaluable infrastructure, including our Therapeutics Discovery platforms, to enable clinicians and researchers to work more efficiently.
That has been really successful here within the institution. We’re seeing cohesive teams working together and tackling key issues, and we are having a direct impact on our patients’ lives.
Rich Soll: So, when you look at IACS or Therapeutics Discovery, what do you see five years from now?
Phil Jones: We truly have a dream. We would love to see a least one, if not more, of our programs in pivotal registration trials or very close to NDA filings, as well as a sizable pipeline of early-stage programs showing proof of concept in the clinic. Ultimately, we’re here for improving the lives of patients. We see Therapeutics Discovery as starting with “the bench at the bedside” – and with each patient and their cancer. We’d also like to see our programs spinning out a biotech-like ecosystem here in Houston and Texas more broadly.
Rich Soll: Do you see that as a catalyst for the local ecosystem in addition to having more compounds in the clinic?
Phil Jones: Yes. If you come to the Texas Medical Center, there’s 1.5 square miles of hospitals nearby – Baylor, Methodist, UTHealth, Texas A&M, and many others. All of those institutions have committed to building something a little bit like Kendall Square, called TMC3.
We would love to be part of expanding the ecosystem going forward. There are 60,000 people who come on to work at the Texas Medical Center every day. It’s surprising that it’s a very much untapped ecosystem.
Rich Soll: How has drug discovery evolved over the time that you started in industry more than 20 years ago?
Phil Jones: It’s been a transformation. If you think where we are today in terms of data, we’re clearly now in a genomic world, and we’re not just looking at phenotypes anymore, we’re looking at pathways. We’re also looking at the whole interplay of multiple different cell types that all have a role in disease progression. We also recognize that not every patient with the same disease is identical. Traditionally we have tended to bundle patients together based on disease location, but the disease mechanisms and treatments required are very different.
But I think the biggest change has been in the modalities – we’ve progressed from classical small molecules to molecules that are outside of “Rule of 5” space, including peptide therapeutics, antibodies and other protein therapeutics, and cellular therapies and modified cellular therapies. You also have antibody drug conjugates and antibody immune conjugates. I don’t think anybody would have dreamt that 20 years ago.
Science is much more exciting and cancer therapy is not the same set of blunt tools it used to be. I’ve seen significant headway in terms of transforming cancer from a death sentence to a chronic disease or chronic management.
Rich Soll: What has been your motivation and inspiration for being a drug hunter?
Phil Jones: When I was working toward a bachelor’s degree, I had this unique opportunity to spend 12 weeks working in Merck’s UK lab. And I just got the bug; I really saw the opportunity to use chemistry to have an impact on biology and human health. I had a fantastic mentor at that time and that individual encouraged me to go off and get my academic qualifications. After PhD and post-doc, I actually went back to work at Merck. I had the fortune of working on some pretty impactful programs across multiple indications. And it stuck with me ever since. Now being at MD Anderson, I get to see the patients and their families walk around the cancer center every day and it gives me the kick to get back into the lab and work with my teams to deliver.