A Passion for Precision Medicines: How Three Start-ups Are Changing the Paradigm

Innovation That Matters

By Hui Cai, Vice President of Corporate Alliances and Head of Corporate Communications, WuXi AppTec

Troy Wilson jokes about time travel being the basis of his next company, and it’s with good reason. A serial entrepreneur, he has been remarkably productive over the last several years, creating three different start-up companies – Kura Oncology, Avidity Biosciences, and Wellspring Biosciences – each blazing new paths in the field of precision medicines.

Kura is a clinical-stage company focused on the development of new precision medicines for the treatment of cancer. Kura’s lead drug candidate is tipifarnib, which has shown encouraging results in a Phase 2 clinical trial in patients with HRAS mutant squamous cell head and neck cancer. In addition, Kura is evaluating tipifarnib in three other Phase 2 trials with a goal to initiate a first pivotal trial in 2018. Kura recently started a Phase 1 clinical trial for KO-947, an ERK1/2 inhibitor, and presented exciting preclinical data in KRAS- and BRAF-mutant adenocarcinomas as well as squamous cell carcinomas. It is also advancing KO-539, an inhibitor of the menin-MLL protein-protein interactions for the treatment of certain acute leukemias.

Avidity is pioneering antibody-siRNA conjugates (ASC) to overcome barriers to oligonucleotide delivery. Avidity has shown that ASCs can knock down mRNA levels potently and selectively in multiple important tissues, including muscle, heart, liver, immune cells and tumors. Through collaborations with strategic partners, Avidity is working to apply the technology to discover novel drug candidates and advance a pipeline of ASCs in multiple therapeutic indications.

Wellspring Biosciences is focused on drugging KRAS, one of the most important therapeutic targets in cancer. Ras genes are mutated in up to 30% of human cancers; yet, KRAS has resisted all drug discovery efforts for more than 30 years. Wellspring has pioneered a groundbreaking scientific approach to pursue small molecule drug candidates that bind irreversibly to a common oncogenic mutant, K-Ras G12C, and engineered a unique partnership with Janssen to support the R&D effort.

Wilson, who has a Ph.D. in bioorganic chemistry as well as a law degree, talks about the strategies behind each company, the promise and challenges of developing precision medicines, the R&D pain points of the industry, and his personal drive to develop better treatments for cancer.

Hui Cai: What are the perks and challenges of simultaneously running three biotech startups?

Troy Wilson:  The perks are simple – the data, the people and, most importantly, the patients. I’m a data junkie – whether it’s the laboratory or the clinic, I love a steady stream of data. And, I think it’s important to stay close to the data. George Rathmann, the former CEO of Amgen, once said, ‘If I stay close to the science, everyone will stay close to the science.’ I agree. If you look across my companies, each is tackling a fundamental scientific problem. Ours is a science-driven business, and you need to stay close. The second perk is the people. I’m blessed to work with a lot of terrifically creative and talented people, many of whom I’ve known for years. They really make the magic. The last perk is my favorite – the potential to make an impact on the lives of patients. The challenges are similarly straightforward – to set ambitious and achievable goals, to recruit great people, to create a passionate, creative, hard-working culture where your people can thrive.

Hui Cai: Let’s first talk about Kura. You have been quoted as saying that tipifarnib was “a drug developed ahead of its time” before it was shelved in 2006. Why is now the right time?

Troy Wilson: Tipifarnib is a potent and selective inhibitor of farnesyl transferase, or FT. FT was one of the first molecular targets in cancer in the 1990s, and a big part of the excitement was that, by targeting FT, people thought they could inhibit RAS-driven tumors. Unfortunately, this was a time when people were still unraveling the biology of cell signaling in cancer and, perhaps more importantly, the availability of technologies such as next-generation sequencing (NGS) were not widespread. Essentially, at that time people were trying to develop a precision medicine before they had the tools and technologies and understanding to do so. For these reasons, although several major companies were pursuing FT inhibitor programs, those programs had largely been abandoned by 2006.

We in-licensed tipifarnib because we saw several features that made it a compelling drug candidate: durable anti-cancer activity in certain patients, a manageable side effect profile and a safety database of more than 5,000 patients. The challenge was that tipifarnib needed a molecular hypothesis and the right patient population. We thought we could bring both insights into the biology of farnesyl transferase, capitalize on the observations of encouraging clinical activity and use NGS and other technologies to select the right patients. We’re now developing tipifarnib using a precision medicine-based approach – one that’s worked for several other cancer targets, including EGFR, ALK, BRAF and TRK. Although tipifarnib may initially have been developed ahead of its time, I’m optimistic that time may now be coming.

Hui Cai: What are the indications you’re focusing on right now for tipifarnib?

Troy Wilson: We’re currently evaluating tipifarnib in Phase 2 trials in four different indications. Tipifarnib has shown an encouraging level of activity in patients with HRAS mutant squamous head and neck cancers. The data is in a small number of patients, but we’re seeing very encouraging signals of clinical activity. The fact that we’ve rapidly identified HRAS mutant squamous cell head and neck carcinomas as an indication of interest illustrates the power of a precision medicine-based approach. We’re now working hard to enroll additional patients and build on those initial findings, as well as conduct three more phase 2 trials with data readouts over the next year or so, so it’s an exciting time.

Hui Cai: Is this above or below your expectations?

Troy Wilson: We are really pleased with our progress. All the preclinical data suggested HRAS was a druggable oncogene, but you can never be sure that preclinical data will translate to clinical data. So we were very pleased to observe the promising clinical activity of tipifarnib in patients with HRAS mutant squamous cell head and neck cancer. What has impressed us, however, is the durability of the responses we have observed. We’ve only presented data on three patients, so it’s early. But, of these first three patients, two have been on study for 16 months and 10 months, respectively. That’s very unusual. It’s an exciting time, and we’re working very hard to enroll additional patients and keep the program moving forward.

Hui Cai: Let’s move to Avidity, which raised a $16 Million Series B in January. What gap is Avidity trying to bridge?

Troy Wilson: The opportunity with Avidity is the potential to overcome traditional barriers to the delivery of siRNA and other oligonucleotides. Although siRNA-based therapeutics have demonstrated significant clinical and commercial promise, conventional approaches are largely limited to targeting the liver. Avidity is doing something fundamentally different. Avidity’s antibody-siRNA conjugates, or ASCs, are showing unprecedented levels of gene knockdown in a range of tissues including muscle, immune cells and tumors, which provides the potential to impact a broader range of therapeutic areas, including inflammation, muscle disorders and oncology. Avidity is partnering with leading biotechnology and pharma companies to deliver a pipeline of ASCs targeting genetic drivers of disease. Two of those partnerships are underway, and I anticipate additional partnerships in the future.

Hui Cai: Can you now talk about Wellspring and what developments we might expect in 2017?

Troy Wilson:  I can’t say too much yet about Wellspring and its programs. What I can say is the team has published some impressive papers around this groundbreaking approach to drugging the KRAS G12C mutant oncoprotein. With each publication, you can see the compounds becoming more potent, more selective and more drug-like. For years, people said “RAS is undruggable,” but now at scientific conferences, you’re hearing whispers that KRAS G12C may be the first KRAS oncoprotein to be drugged successfully. The Wellspring team is working hard and is determined to be the first to target KRAS successfully.

Hui Cai: What drives your passion behind oncology and trying to drug the ‘undruggable?’

Troy Wilson: Shortly after I started my career, my mother passed away from metastatic non-small-cell lung cancer. I spent a lot of time caring for her in the last year or so of her life, and that experience really opened my eyes to the personal pain and the desperate need of better therapies. If you fast-forward 20 years, we’re now in a golden age of oncology, and I want to do everything in my power to help turn cancer into a long-term manageable condition in the way HIV, hepatitis or certain rare diseases have become. I think we’ll get there.

Hui Cai: From your perspective, how has cancer R&D evolved over the last 10 years?

Troy Wilson: The most significant evolution in cancer research and development is the accelerating trend toward precision medicine – how to select the right drug for the right patient at the right time. A precision medicine-based approach has the advantages of higher translatability from pre-clinical to clinical, potential for increased overall response rates, and the potential for expedited clinical development in areas with high unmet need. In oncology, we’re now reaping the benefit of a 50-year investment in understanding biology, which has yielded a more thorough understanding of tumor biology and molecular mechanisms of action. Personally, what I hope we’ll see is the same approach being applied to other areas like inflammation and neuroscience. It will take huge investments to better understand the biology as well as innovations such as better models and tools to support the translational research.

Hui Cai: Do you think precision medicine has reached an inflection point?

Troy Wilson: Definitely. We’ve seen drugs now like AstraZeneca’s Tagrisso that advanced very quickly from first patient dosed to FDA approval. That should be the standard to which we all aspire. The speed with which AZ moved through development was due to the high activity of their drug in EGFR T790M mutant lung cancer and the fact that they understood their target patient population. With immune therapies, we’re seeing the same themes – a focus on biomarkers and selection algorithms. Precision medicine is one of the most important themes we’ve seen in oncology drug development, and it’s here to stay.

Hui Cai: Any comments on the current precision medicine initiatives around the world?

Troy Wilson: Success in precision medicines requires a commitment to three things. First, the availability of patient samples. You need to screen enough patients to find the ones who will benefit. Second, you need a robust diagnostic assay, one that can be used as easily in Shanghai or Warsaw as in San Diego or Boston. Third, you need effective therapies. The increase in FDA approvals for cancer drugs over the past 10 years is due, in part, to the fact that, as an industry, we’ve learned how to make potent and selective small molecules, particularly kinase inhibitors, as well as monoclonal antibodies that inhibit key pathways and processes critical to cancer.

Hui Cai: Now looking into 2017, what has you most excited in terms of industry developments?

Troy Wilson: I really think that the progress we’ve made as an industry developing small molecule precision medicines is extraordinary – just look at the last 10 years of FDA approvals in oncology. But, there’s also a whole set of so-called “undruggable” targets, and there, I would have to say gene therapies, antisense and RNA interference are very exciting. With gene therapies, we’re seeing some extraordinary new therapies being brought forward, primarily for local delivery, and that trend is accelerating. With antisense and RNA interference, we’ve seen the approval of a drug for spinal muscular atrophy, and there are a number of additional drug candidates in late-stage trials. I am hopeful that we’ll soon see oligonucleotides take their place alongside small molecules, proteins/antibodies and peptides as a major therapeutic class.

Hui Cai: What concerns you the most then?

Troy Wilson: What concerns me most is our need to create a sustainable system that rewards innovation. We need to continue to provide incentives to the entrepreneurs, the companies and the investors to develop breakthrough therapies, and we need to reward them when they’re successful. And we need to make it less attractive for people to take shortcuts and come up with ‘me too’ type of things that really aren’t innovative or adding to the quality of life of patients. I have ideas, as I know others do, and we need to come up with a sustainable system that rewards innovation on a global basis.

Hui Cai: The 22 drug approvals in 2016 remind us that that there is still room for improvements in R&D productivity. In your view, what are the pain points in the industry and what could be creative solutions? How may Kura, Wellspring and Avidity fit into the solution?

Troy Wilson: One obvious pain point is that we have too few companies pursuing real innovation. Not long ago, Richard Pazdur chided the industry about the tsunami of PD-1 and PDL-1 therapies. He said, “People should ask themselves … would we be better off spending those resources into looking at more novel drugs?” and his advice to drugmakers was to stay focused on the cutting edge and lose the me-too drugs in the cancer pipeline. He’s right. Our industry suffers from a lack of innovation as well as a lack of incentives to innovate. Innovation is hard and it’s risky, but it’s vital to the long-term health of our industry.

I may sound like a broken record, but a precision-medicine based approach has a lot to offer the industry in terms of innovation and productivity and R&D. We should set a high bar for success and challenge ourselves to create value and de-risk programs as quickly and inexpensively as possible. We need to invest in biology. We have great tools and technologies, but our ability to use them is only as good as our understanding of the basic biology we seek to modulate. That’s how I hope all of my companies can contribute. Whether it’s small molecule drug candidates at Kura and Wellspring or antibody-siRNA conjugates at Avidity, they are pursuing a precision medicine-based approach to drug discovery and development. That’s the future, and I hope we’ll continue to lead the way.

Hui Cai: As a well-known serial entrepreneur, how would you compare the startup environment today versus when you started Intellikine a decade ago? What are some of the important lessons you’ve learned along the way?

Troy Wilson: There’s no question that, even in the last five years, it has become much more expensive to start a biotech company. The good news is there are many more sources of funding, including VCs, crossover and public investors, strategic investors, foundations and, in rare cases, even crowdsourcing. The key is innovation – as an entrepreneur, you must innovate as much on the business side as you do on the scientific side.

In terms of lessons learned, I follow a simple formula and one that I’ve developed and refined over time. You need to have a bold vision, work on hard and important problems, recruit the best people and give them resources to be successful, recruit investors and partners who share your vision and who have the resources to stay with you, and most importantly, you have to challenge yourself and your people to do amazing things. When I started Wellspring to drug KRAS and Avidity to solve the problem of RNA delivery, people thought I was crazy. Then, I started Kura to bring tipifarnib back from the dead, and some people shook their heads. But, we did it – we pushed ourselves and the frontier and built three, thriving companies.

Hui Cai: How did you successfully move from being a scientist to being an entrepreneur?

Troy Wilson: As a scientist, I was able to focus on advancing our understanding of the science. When I became an entrepreneur, I realized that, although the science remains important, as soon as you take money from investors, everything changes. Investors are interested in the science, but they measure success in terms of return-on-investment. Taking money from investors is a big responsibility and people who make the leap successfully understand that responsibility.

Hui Cai: Is there anything that keeps you up at night?

Troy Wilson: Sure, I worry about everything. I’m the CEO and, in the end, the buck stops with me. But, I’m blessed to have great people – I trust them and they trust me. And I’m thankful for our investors and partners, who invest so that we can crack some of the most important scientific problems of our time. We work with super smart people, do great science, and hopefully, create medicines that make a positive impact on the lives of patients. So, while I have some sleepless nights, there’s nowhere else I’d rather be.




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