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SPIE Professional April 2013

Birth of a startup

Building a machine to fight cancer: A perspective from the founders of RefleXion Medical.

Sam Mazin and Akshay Nanduri, both 34, are cofounders of RefleXion Medical, a seed-stage medical technology company based in Silicon Valley. RefleXion is developing an innovative radiation-therapy system with the potential to revolutionize cancer care by treating metastatic disease with highly precise and focused radiation.

In this article, they offer their views as founders of a life-sciences startup and detail the opportunities and challenges encountered in the pre-revenue stage of commercializing a photonics technology for medicine.

Editor's Note: In early 2014, RefleXion raised $11.6 million in Series A financing from Sofinnova Partners, Pfizer and Venrock.

The problem: breath and tumor motion

After completing his PhD in electrical engineering at Stanford University (USA), Mazin started a postdoc position focused on medical imaging in the Radiological Sciences Lab, also at Stanford. While attending a 2007 talk on campus by a professor from the Radiation Oncology department, Mazin was introduced to radiotherapy — the modality of treating cancer with radiation.

Mazin learned that the biggest challenge in the field was determining the exact location of cancer in the body during treatment and that this problem was exacerbated by tumor motion caused by patient breathing.

With his strong training in medical imaging (and an issued patent for a novel X-ray CT system developed as part of his PhD work), Mazin quickly understood the limitations of current radiotherapy systems, which rely on anatomic imaging like X-ray, computed tomography (CT), ultrasound, or magnetic resonance imaging (MRI) to visualize a tumor and infer its motion. Mazin also thought about positron emission tomography (PET), a form of biological imaging and the gold standard in noninvasive cancer detection and staging.

“Why couldn’t PET, the most powerful imaging modality for cancer visualization, be used at the time of treatment?” he wondered. “If cancer signaled its location back to the therapy machine, the motion problem would be solved.”

Mazin realized that the key challenge was to overcome PET’s fundamentally slow image-acquisition time. After some more thinking, a light bulb flicked on.

In PET, a radiotracer administered to the patient causes cancer to emit a pair of photons forming a so-called ‘line of response.’

“Instead of waiting for the thousands of lines that are detected and used to reconstruct an image, I imagined sitting at one of the endpoints of a ‘line of response’ with a baseball bat and smashing that photon right back to where it came from,” he thought. “In practice, a therapeutic radiation beamlet would be delivered right back to the source of the photon pair emission along the same linear path.

“If this process is repeated for most of the detected photon pairs, the therapeutic radiation dose would accumulate as the PET image is forming!”

Concept of RefleXion system.
Startup business plan takes shape

Becoming increasingly fixated on the idea, Mazin devised a practical design of a hardware system implementing this concept (RefleXion now has an issued patent for the innovation.). He also started developing a business plan, which was jumpstarted in the summer of 2008 by participating in Stanford Ignite, a four-week crash course in business for entrepreneurs without business backgrounds.

After completing the program, Mazin began looking for a cofounder. “I needed someone I could trust, who had succeeded at an early-stage startup, and whose skills would complement my training,” Mazin says. And Nanduri, one of his closest friends from high school and from his undergraduate engineering days at University of Waterloo (Canada), met all of these criteria.

Indeed, after Nanduri completed his undergraduate degree in computer engineering in 2001, he had joined a venture-backed startup in Canada as its first employee. Nanduri eventually became the director of software development at SlipStream Data, leading a software team of 10 engineers, and played a crucial role in the company’s acquisition in 2006 by Research in Motion, the pioneering smartphone giant and maker of the BlackBerry.

Moreover, Nanduri was rounding out his startup experience with formal business training at Massachusetts Institute of Technology (MIT). Mazin successfully recruited Nanduri, and RefleXion was incorporated in California on 17 March 2009.

Kauffman Foundation fellowship jumpstarts funding

In contrast to the workings of most biotechnologies and medical devices, the performance of image-guided radiotherapy technologies can be predicted by physics software simulations and imaging experiments. The next crucial milestone in RefleXion’s execution plan was proving that its core technology worked through these software simulations.

Startup capital was needed to begin this important work. In a stroke of good fortune, Mazin was accepted to the 2009 Ewing Marion Kauffman Foundation (USA) Postdoctoral Entrepreneurship program, designed to help scientists commercialize innovative technology. The program gave Mazin the freedom (and a year’s funding) to focus 100% of his postdoc time on the company.

With the Kauffman fellowship serving as RefleXion’s first funding and Nanduri completing his MBA at MIT’s Sloan School of Management, Nanduri moved to Palo Alto in 2009 and the two cofounders began weeks of all-night coding sessions.

Using a refurbished personal computer in Mazin’s living room and open-source software packages (for physics simulations and for an integrated development environment), Nanduri and Mazin created a complete physics software simulation framework that modeled key aspects of their proposed system.

Their efforts consisted of more than 30,000 lines of C++ code and played a crucial role in raising a seed-round of funding from former industry executives and clinicians in late 2010.

This work was also instrumental in obtaining a Small Business Innovation Research grant from the U.S. National Cancer Institute in 2011 to carry out the first PET imaging experiments in collaboration with the Stanford Cancer Institute.

Founders cultivate a low-key marketing approach

Generating ‘buzz’ for medical technology is a delicate process where overly aggressive claims can backfire by upsetting the U.S. Food and Drug Administration (FDA) and alienating clinicians. Mazin and Nanduri decided on a grassroots approach, where credibility with the medical-physics and radiation-oncology communities would be earned through concrete data and results.

In July 2010, the initial physics software simulations were submitted to the American Association of Physicists in Medicine (AAPM) annual meeting in Philadelphia, where they showed how radiation would track a moving PET-active target.

At a 2012 AAPM meeting, more than 100 physicists and R&D industry executives attended RefleXion’s oral presentation on a retrospective patient-feasibility study in collaboration with Stanford and the Georgia Institute of Technology (Georgia Tech).

To date, RefleXion has participated in nine scientific and medical conferences, and through these has cultivated key relationships with leading physicists, oncologists, and industry executives.

“We are a scrappy startup inspired by many of our innovative predecessors who have brought new technologies to market in a cost-effective manner,” Nanduri says of the company’s marketing strategy. “RefleXion’s ‘booth’ at these shows has historically been a small table commandeered outside the exhibit hall. Clinicians huddle around a laptop and get excited about our results and experiments, which is reassuring and fits our current budget.”

The gray hair factor comes into play

Unlike Internet startups, new companies in the life sciences can be penalized for having a young founding team. To address this, RefleXion decided to recruit a respected group of scientific and business advisers, not only to gain credibility but also to answer key clinical questions and solidify their business/execution plan.

This “gray hair” factor became increasingly important as RefleXion pursued institutional funding from venture capitalists. Through the Kauffman Foundation, they recruited Jay Watkins, a highly experienced med-tech entrepreneur, executive, and venture capitalist, to join their Board of Directors.

“Jay Watkins and our business advisers have made numerous introductions to leading venture capital firms, helped us hone our business plan and investors’ pitch, and continue to be a highly-valued strategic sounding board,” Mazin says. “They are also playing a key role in pulling together our first round of institutional financing.”

The company has also recruited key thought leaders from radiation oncology, radiology, and molecular imaging to join the Scientific Advisory Board. Through these relationships, RefleXion has formed important research collaborations with Stanford, the University of Chicago, the MD Anderson Cancer Center, and Georgia Tech.

Investors become advisers

A common financing path for startups is to raise seed capital from friends and family. These entrepreneurs, however, believed in a different approach and decided to exclusively target individuals and organizations who would add value on top of their money.

Former industry executives, leading clinicians, entrepreneurs in medical imaging, and even a free-standing cancer center were targeted and ultimately invested in RefleXion based on promising scientific simulation results and the potential of the core technology.

RefleXion is now reaping the rewards from that decision with its seed investors constituting a second set of advisers who actively contribute to the success of the company.

Moreover, the seed-round fundraising strategy sends a strong signal to the market as well as future/prospective investors that RefleXion’s biologically guided radiation-therapy system is a big opportunity in cancer care.

RefleXion gets a little help from friends

Throughout its four years of life, RefleXion has forged key partnerships with academic institutions, research entities, and companies that have been instrumental in solidifying the company’s position in intellectual property, R&D tool/efficiency, and clinician acceptance.

For example, the University of Chicago granted RefleXion an exclusive license on critical complementary IP in 2011, and the National Research Council of Canada provides a key Monte Carlo software package. CliQr, a venture-backed Silicon Valley startup that builds cloud-computing software and services, works closely with the young company on improving the execution time of simulations; and a leading diagnostic imaging-system player recently donated a radiotherapy treatment-planning workstation for research purposes.

RefleXion has also benefited significantly from connections with Stanford (Ignite, BASES business plan competition) and MIT (the MIT $100K business plan competition, MIT Venture Mentoring Service, and the Sloan alumni network).

“In a cash-constrained climate, it is critical to search relentlessly for organizations, institutions, and people that believe in your mission and are aligned with your company’s goals,” Nanduri says. “This can lead to partnerships and relationships that create significant value in a cost-effective manner.”

Next steps for RefleXion

With support from a business and scientific advisers, engaged seed investors, the National Cancer Institute, and key partnerships, RefleXion Medical is poised to execute its vision for dramatically improving cancer treatment with its biologically guided radiation-therapy system.

RefleXion’s patented technology uses signals emitted from the tumor itself to guide the treatment beam.

“Personalized radiotherapy has long been desired as a tool for clinicians to improve efficacy,” says John C. Ford, a seed investor in RefleXion and former senior vice president and senior scientist at Varian Medical Systems.

RefleXion anticipates closing a major round of institutional funding in 2013 that will result in an expansion of the R&D team to 12 engineers (mechanical, electrical, and software) and physicists.

When that is completed, the next step will be the development of the first hardware system that will bring biological information into the treatment room for the first time.

photo of RefleXion Medical founders

Sam Mazin is president and cofounder of RefleXion Medical and inventor of the company’s core technology. He has a BASc in computer engineering from University of Waterloo (Canada) and a PhD in electrical engineering from Stanford University (USA). He has presented several papers at SPIE Medical Imaging and received the cum laude poster award at Medical Imaging 2007 for “A Fast 3D Reconstruction Algorithm for Inverse-Geometry CT Based on an Exact PET Rebinning Algorithm.”

–Akshay Nanduri is RefleXion’s cofounder and vice president of business development. He has more than 10 years of experience in software engineering, product management, and technology commercialization and led RefleXion to the semifinals of the MIT Business Plan Competition in 2009. His MASc and BASc degrees in computer engineering are from University of Waterloo, and his MBA is from MIT.

From bench to marketplace

SPIE Professional has a special focus on entrepreneurs who are succeeding at transferring photonics technologies into commercial products and services.

This issue of the magazine offers perspectives on photonics commercialization from various places on the entrepreneurial spectrum — from those at entrepreneurship’s early stages to one entrepreneur with enough experience to write a primer on the subject.

In this article, two 34-year-old optics and photonics professionals who have yet to begin manufacturing their radiation-therapy system offer the story of their company’s beginnings and their hopes for the future.

See other articles in this issue about photonics entrepreneurship, including coverage of the SPIE Startup Challenge and David A. Krohn’s new book, Commercialization Basics for the Photonics Industry.

DOI: 10.1117/2.4201304.11

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