The 12th annual Business of Regenerative Medicine conference, hosted by the Harvard Stem Cell Institute on 15-16 July 2019, examined how to define and create “value” in a field set to transform human health.
At the 12th annual Business of Regenerative Medicine conference, hosted by the Harvard Stem Cell Institute, over 150 people gathered to discuss social, economic, and operational challenges in this game-changing field. Scientists, CEOs, biotech pioneers, venture capitalists, and patient advocates all shared their perspectives on this emerging field, which is closer than ever to producing cures that disrupt conventional paradigms in business and health care.
The theme of the conference was “Defining and Creating Value,” addressing the tension between curing people on one hand, and an unprepared health care market on the other. Featured speakers and panelists grappled with challenges presented by an intensely competitive discovery and clinical environment, shared experiences and lessons learned, and discussed recent developments in the field.
Regenerative medicine heads into the clinic
Janet Lambert, Chief Executive Officer of the Alliance for Regenerative Medicine (ARM), gave an overview of recent therapeutic approvals, adding that close to 60,000 people are in (or plan to be in) clinical trials. There are near-term approvals for many gene, cell-based immuno-oncology, cell, and tissue-based therapies.
“We are not talking about incremental change for a small number of patients,” she said. “We are talking about an impact for many, many patients and that’s what makes this sector so exciting.”
Lambert explained that there are currently over 1,000 clinical trials in progress (93 in stage 3), well over half of which are in oncology. Trials are also active for cardiovascular, central nervous system (CNS), musculoskeletal, eye, skin, and immunology indications.
“This is a heady investment climate – close to $5 bn, with $2.5 bn invested in this quarter alone, and corporate partnerships on the upswing,” said Lambert. “There are eight recently approved therapeutics, but much work to be done on access and reimbursement.”
Leadership, talent, and management
The best of all worlds
HSCI faculty member Mark Fishman presented his vision of a unified research ecosystem, in which scientists incorporate best practices from both business and curiosity-driven, academic science.
“There is no field that promises more to help people than regenerative medicine, but we should use a different structure from the one we're using,” he said. “I believe the way to drive it forward is to put biotechnology companies, translational medicine, and discovery biologists under one roof. Cultivating strong links between academic laboratories, hospitals, and biotech companies is crucial, because together they can drive enterprise and innovation.”
“There is no field that promises more to help people than regenerative medicine, but we should use a different structure from the one we're using.” - HSCI Faculty Member Mark Fishman
Fishman articulated a sticking point for many biotechnology companies: “The standard structure of a biotech company makes it very difficult to give up on projects, because everyone has an interest in keeping it going,” he said. “Great scientists are risk takers but you need to have a clear idea of what success looks like. You should have a sense of whether a project will work, and whether it is not working. And be able to deploy people and money accordingly, which is hard in the typical academic and corporate structures.”
Hire for talent, train for skills
Sarah Larson, Partner and Chief Human Resources Officer at Third Rock Ventures, talked about how to live up to the adage that people are a company’s most important asset. Referencing a recent study of startup companies that showed failures were mostly not due to technical but to organizational and managerial issues, she urged startups to focus on building capacity, strengthening their business plans, and reducing organizational complexity.
Larson advised companies to replace hierarchy with teams, consider the realities of today’s family unit, and reframe the benefits of bringing in people who are different from one another. She also explained the importance of having a person with a strategic mindset leading HR and including them in top-level decision making. She also pointed out that many HR leaders go on to become CEOs.
Courage and commitment
Nancy Koehn of Harvard Business School captivated the audience with stories of Abraham Lincoln, Frederick Douglass, and Ernest Shackleton’s courageous leadership during times of crisis. Focusing on Shackleton in particular, she demonstrated how small, critical steps make it possible to steer a group of people through difficult times.
“A moment arises when a person recognizes the demands of their leadership, and makes a covenant to sign up for the mission. That commitment can be the glue that helps the organization stick together in its hardest moments,” she said.
Clear articulation of the mission from the leader and investors is the best way to demonstrate commitment, Koehn said, adding that this means actually talking with people: “If you’re not repeating yourself about what we’re doing, why, and how we’re going to do it … you’re not talking to people enough.”
“The higher the stakes, the more you have to hire for attitude and train for skill.” - Nancy Koehn
Koehn advised leaders to delegate while thinking ahead, warning that splitting attention between too many things makes it difficult to think creatively about the future: “The higher the volatility, the greater the turbulence, the greater the need for a leader to find time to him or herself to think. To find a moment to reflect, detach, and calculate.”
One of the lessons Koehn shared from Shackleton’s leadership of sailors stranded on ice for months at a time was, “The higher the stakes, the more you have to hire for attitude and train for skill.”
Geoffrey Mackay, President and CEO of the publicly traded company AvroBio, described the course his company piloted through the choppy waters of biotech investment. Like Koehn, he emphasized the need to communicate clearly about the mission.
“Until we had a roadmap, the rest of the organization was paralyzed,” he said. “Once we were firm that this was the way we were going, that made everything else clear: who we would recruit and who we would partner with.”
“Until we had a roadmap, the rest of the organization was paralyzed.” - Geoffrey Mackay
AvroBio sought accelerated clinical pathways, initiating studies in Canada and Australia, which Mackay said have highly efficient trial systems for regenerative medicines. Before going for venture capital at an early stage, the company made sure they ticked all the boxes for their investors: great science, big innovation, experienced team, capital efficiency, defensible IP, and a realistic exit path.
One of his key lessons was that a group of individual stars in their field may not always make up the best team. “There is nothing more important in this industry than figuring out who you want to and can work with,” MacKay said. “As a CEO, you need to be recruiting 24/7. But first you need to define your values and benchmark the best in the world.”
From science to early-stage business
Amritha Jaishankar, associate director of the Maryland Stem Cell Research Fund (MSCRF), described how the fund works with scientists to develop product profiles as early as possible – whether they’re going down a clinical path or starting a company.
Keith Thompson, chief executive officer of the UK’s Cell and Gene Therapy Catapult, described how the cost of production has been divorced from the price of the potential treatment. By investing in production infrastructure through the Catapult, the UK government is helping to accelerate the process of getting new treatments to the market and enabling industry to benefit from that shared expense.
“Since the majority of startups fail, how to we make sure lessons are learned?” asked Roger Kitterman, vice president of venture and managing partner at the Partners Innovation Fund. He described how PIF includes knowledge exchange in the management of their portfolio of startups, actively encouraging their portfolio companies to talk to each other. Jaishankar added that MSCRF does the same, aiming to share new knowledge across the sector as early as possible to keep new companies from failing.
“Since the majority of startups fail, how to we make sure lessons are learned?” - Roger Kitterman
In her presentation, Geraldine Hamilton, president and chief scientific officer of Emulate, said that to create a company that can scale up from startup to global distribution, it is essential to think about manufacturing very early in development. “The longer you wait, the more complex the issues will become,” she said. “Are you really designing something scalable and reproducible? You will have to bring in the expertise, because you can’t answer this question on your own.”
Look for more than money
“If you ask for money, you’re going to get advice. And if you ask for advice, you’re going to get money,” said Jason Hafler, senior director of investments at Sanofi Ventures. This sentiment was echoed by several of his fellow venture capitalists.
“If you ask for money, you’re going to get advice. And if you ask for advice, you’re going to get money.” - Jason Hafler
Thomas Needham, director of Broadview Ventures, cautioned audience members to pay attention to the quality, strength, and composition of the investment syndicate. “It takes an incredible skill set to succeed,” he said. “You have to want to find a partner, be open to their help, and appreciate they’re bringing you more than capital. We have a lot of relationships and expertise we can bring at the earliest stage.”
Larson advised paying close attention to who is on the board of a syndicate. “Don’t just look at the firm – be clear about who they are going to assign to you. You could easily get the wrong profile team on your board.”
Amir Nashat, managing partner at Polaris Partners, added that it is no small feat to get the match right between investment firm experts and biotech entrepreneurs, who are very different from one another in terms of experience and goals.
How much, and who pays?
How much regenerative medicine will cost, and who is going to pay for it (and how) are as-yet unanswered questions.
“From a payer perspective, and even investors, everyone agrees that one-time up-front payment doesn’t make sense – we need more creativity in the reimbursement model,” said Whitney Ijem, director and senior biotechnology analyst at Guggenheim Securities.
“We’ve seen the first few ice cubes of the regenerative medicine iceberg,” added Eric Faulkner, vice president at Evidera. “Our reimbursement systems were not built with these curative therapies in mind.”
Faulkner described a macroeconomics-based scorecard his group is developing, with input from patients, advocates and others, to address evidentiary and reimbursement issues. The model gives an impact profile for different treatments. “If you pay for this technology at once, no health system in the world is set up to absorb the cash flow for a one-time treatment,” he said. “How we address these issues is critical to the welfare of the industry.”
“If you pay for this technology at once, no health system in the world is set up to absorb the cash flow for a one-time treatment. How we address these issues is critical to the welfare of the industry.” - Eric Faulkner
“When you see a one-million-dollar therapy, it’s not the patient paying for it, it’s everyone – it’s going into the insurance pool so you’re going to see increases in premiums,” added Michael Sherman, chief medical officer and senior vice president of Harvard Pilgrim Health Care. “The first gene therapy that was available was for blindness, and none of the benefit was returned to the insurer. It was valuable because of what’s important, even though it didn’t play into our business model.” He went on to point out, “We do not have any sustainable mechanism for this.”
“We don’t have a single payer system and it’s not clear who will pay for any of these treatments,” said Amitabh Chandra of Harvard Business School. “When the payer struggles to pay for a treatment, future manufacturers get the message that even if they build it, no one will be able to pay for it. This will lead to under-investment. The stakeholder who is not fully represented here is the future patient who has some unmet medical need who would beg us to pay more now.”
"The stakeholder who is not fully represented here is the future patient who has some unmet medical need who would beg us to pay more now.” - Amitabh Chandra
For John Doyle, vice president and global healthcare innovation lead at Pfizer, the industry needs to agree on definitions of success and value for each therapy: “Is it that the patient is alive? Can they walk up the stairs? That’s the negotiation that’s going on,” he explained.
Measuring value for patients is not straightforward, either. Ijem described how hemophilia patients see a number of approved therapies, but are faced with a dilemma: “How eager is this population going to be to try the first gene therapy when with today’s science, you only get one chance to be in a clinical trial?” she said. “Is it going to last one year, or two years? The longer you know you’re going to benefit, the more likely you are to try it. It’s an exciting time for patients, but there are a lot of questions for us.”
Stories from biotech
The 2019 Business of Regenerative Medicine meeting featured several presentations by entrepreneurs and scientists who are moving the field forward.
Working with regulators
Marcie Glicksman, chief scientific officer at Orig3n, gave a birds-eye view of the cell-therapy regulatory environment. Japan is leading the way, she said, and Congress passed an act recently to clear the regulatory path (following a series of discussions facilitated by ARM). Glicksman shared Orig3n’s strategy for making the most of the new environment.
“The cost of cell therapy is just way too high, so we decided to focus on allogeneic therapy,” she said. “Cells need to be ready for an acute need, so it is critical to develop off-the-shelf technology. Having highly characterized, readily available cells is important, rather than trying to do this on a per-patient basis.”
"Cells need to be ready for an acute need, so it is critical to develop off-the-shelf technology." - Marcie Glicksman
Orig3n started by building a cell bank, and quickly discovered that consent was the biggest roadblock. To build their own, they went to triathlons and music festivals in many cities, set up tables with phlebotomists, and asked people to give blood. Disease foundations also contributed. They created one of the largest collections of cells, achieving an HLA match to 90% of the US population. The cell bank has become a useful resource with many potential applications.
Organs on chips
Many clinical studies fail because animal models do not translate well to human disease. Hamilton talked about the urgent need for more predictive models and human-relevant approaches. She presented organ-on-a-chip technology from Emulate that reproduces human biological complexity in an in vitro system – technology that led to the formation of the company by Wyss Institute researchers in 2015.
Hamilton’s intestine-on-a-chip allows researchers to expose human gut cells to complex biological forces: “When we populate them with patient-derived organoids, these devices become a magnificent cell source for patient-derived tissue,” she said. “You can see beautiful 3D structures and the functionality that comes along with it. We can use it to identify disease mechanisms and identify potential targets.”
Mark Skylar-Scott from the Jennifer Lewis lab at Harvard University talked about the impact of 3D bioprinting and the aspiration for ‘printing at the bedside’: “The idea is to have a printer with your licensed ink residing in a hospital ward,” he said, describing existing technologies that can be combined to make this a possibility in the foreseeable future. “With bioprinting, we could make things to scale in vitro and, one day, alleviate the supply and demand gap in donor organs.”
“With bioprinting, we could make things to scale in vitro and, one day, alleviate the supply and demand gap in donor organs.” - Mark Skylar-Scott
Jennifer Elisseeff, director of the Translational Tissue Engineering Center at Johns Hopkins, presented synthetic implants as an alternative for organ transplantation. Studying rejected implants from patients, she gained insights that inspired her team to examine how the immune response itself might direct repair.
“What is the profile of a healing wound, versus a non-healing wound like fibrosis or chronic inflammation? Can we shift the one to the other?” she asked. “All synthetic materials will evoke some immune response. It’s not necessarily about regeneration – you don’t always have to promote tissue repair, sometimes you just have to take away inhibitors that are keeping healing from happening.”
"You don’t always have to promote tissue repair, sometimes you just have to take away inhibitors that are keeping healing from happening.” - Jennifer Elisseeff
Paula Hammond, founding member of the MIT Institute of Nanotechnology, described her work on multi-layered biomaterials: “We can use charged materials to create different layers of a thin film and release drugs at different times, at different rates, within the same complex,” she said. Using orthopedic implant coatings as an example, she explained how a single material could deliver antibiotics, nucleic acids, and small molecules as needed.
This is one area of regenerative medicine where the technology has moved faster than regulators can keep up.
“For tissue products, people have abused loopholes and it’s hurt the field. Educating the FDA is going to be a long process and that’s where industry–academic collaborations could be useful,” said Hammond. “We have to accept that personalization means more complexity… in time, I hope to see some reform from the FDA in how they approach these technologies.”
Bone marrow transplants
“We are bringing about a long-overdue revolution in patient preparation, and changing the conversation patients and donors have with clinicians about bone marrow transplants,” said Jason Gardner, co-founder of Magenta Therapeutics. Patients currently go through several days of painful treatments in which they are exposed to toxic agents that come with severe side effects. Magenta’s new approach to the targeted removal of stem cells would be a single dose, with no side effects. It is slated to move into the clinic in 2020.
“We are bringing about a long-overdue revolution in patient preparation, and changing the conversation patients and donors have with clinicians about bone marrow transplants.” - Jason Gardner
“We spent a lot of time talking with clinical centers, because we see the company in partnership with them as we launch this first product. We also partnered with Be the Match, which coordinates the registry and all transplants in the US,” explained Gardner. “In the long term, our vision is to make stem cell transplants an outpatient procedure.”
HSCI faculty member Albert Edge, director of the Tillotson Cell Biology Unit at Massachusetts Eye and Ear, described how his lab is using newly identified progenitor cells to make hair cells in the adult mammalian ear for the first time. This type of work is being taken forward in different ways by three companies: Audion, Decibel, and Frequency Therapeutics.
HSCI faculty member Vikram Khurana, scientific co-founder of Yumanity Therapeutics, talked about protein-folding diseases, which represent a huge area of unmet need: “We can relate the consequences of protein folding in yeast to disease-relevant cells from patients that we built into a platform,” he explained. “We can screen millions of compounds, find ones that correct the complex cell, revert to the simple cell, and use molecular tools to identify the phenotypic target.”The platform sparked the launch of Yumanity, which attracted substantial investment.
George Church, geneticist at Harvard Medical School, challenged the audience to think in a different way about technologies and treatments and how they could apply across disease areas.
“For example, we have one combination therapy that tackles five diseases,” he said. “If you try to get to the core of conditions like aging, that should let you get to a much bigger range of diseases. Rather than having one shot on goal, you’d have millions.”
The patient perspective
Cystic fibrosis activist and patient Joan Finnegan Brooks spoke to the meeting about how she manages this genetic lung disease by doing more than six different breathing treatments and taking over 50 pills a day.
“When my brother and I were children, there were very few treatments available to us,” she said. “We struggled to breathe and my parents pounded our backs to help us get the thick, sticky mucus out of our lungs. They always encouraged us lead ‘normal’ lives and not dwell on our health challenges. Sadly, we lost my brother when he was just 15 in 1969. Medicine has come so far since then. Improved treatments and my involvement in sports have helped me maintain my lung function, but at age 59, managing my disease has gotten more difficult. I experience recurring lung infections requiring treatment with multiple antibiotics more frequently and I worry about how long those drugs will keep working. There are many young people whose lives will be cut short by this disease, and I want to do everything I can to help them.”
"I experience recurring lung infections requiring treatment with multiple antibiotics more frequently and I worry about how long those drugs will keep working." - Joan Finnegan Brooks
Brooks champions research through the Cystic Fibrosis Foundation. HSCI faculty member Jayaraj Rajagopal, who shared the stage with Brooks, talked about his research into the disease. “We’ve known for a long time which specific gene causes cystic fibrosis when it gets mutated,” he said. “But it wasn’t until last year that my colleagues and I were able to identify where in the lungs this gene gets expressed. That was possible because of advances in sequencing technology and cell biology, and because we had the support of the Cystic Fibrosis Foundation.”
George Q. Daley, dean of Harvard Medical School and HSCI faculty member, gave his perspective on the state of regenerative medicine.
“We are at an inflection point in regenerative medicine, when CAR-T cells, dopaminergic neurons for Parkinson’s disease, beta cells for type 1 diabetes, and treatments for the retinal epithelium are making history,” he said. “But we have to remember that transformative therapies typically take between 30 to 40 years to mature, and we are one decade into our investments in regenerative medicine products.”
“We are at an inflection point in regenerative medicine, when CAR-T cells, dopaminergic neurons for Parkinson’s disease, beta cells for type 1 diabetes, and treatments for the retinal epithelium are making history." - George Q. Daley
Daley addressed the threat posed to legitimate therapies by “stem cell charlatans,” and said that the current U.S. administration is beginning to clamp down. He also spoke of the astronomical cost of R&D, and the need for stronger, more validated hypotheses moving into the clinic to reduce the failure rate, patient risk, and business risk. Otherwise, there is increased incentive to bring products to market that are not yet ready. Daley also cautioned that countries should uphold robust regulation on regenerative medicine products.
“It’s going to take the better part of this century to figure out how to make cells into medicine,” he concluded. “It’s going to be worth it.”