The process of moving research discoveries from bench to bedside is far from straightforward, and researchers who undertake the challenge of bringing better treatments to market face two distinct “valleys of death” that all too frequently derail their efforts.
The first valley occurs when discoveries made in basic science research — in cells or animal models, for example — fall off a metaphorical cliff before reaching human subjects in clinical trials. Even if a discovery makes it into clinical trials as a potential treatment, another cliff looms during the commercialization process: Untold numbers of promising treatments fail to become available to a wider public because they can’t be successfully scaled up.
In the decade since the Robert H. and Clarice Smith Building opened in 2009, the Wilmer Eye Institute has actively worked to overcome the first valley of death by encouraging collaborations between clinical and basic science researchers. Today, the Smith Building brings together more than 278 researchers and clinicians — from materials engineers to stem cell biologists to chemists — who work in open or glass-enclosed lab spaces, ensuring they are aware of their neighbors’ work. In addition, shared equipment maximizes resources, and proximity throughout the day breeds team building and creative group problem-solving.
“For us, problem identification is a lot of where this interface is really important with the clinicians,” says Laura Ensign, Ph.D., the Marcella E. Woll Professor of Ophthalmology and a chemical engineer in Wilmer’s Center for Nanomedicine, which occupies the sixth floor of the building. “Engineers can come up with tons of problems to solve, but they may not be important problems. The clinicians are the only ones who can identify clinical need.”
Addressing the second valley, though, where discoveries that yield excellent results in clinical trials fall off the cliff before they can be commercialized, has required a Johns Hopkins-wide approach, which Wilmer Director Peter J. McDonnell, M.D., enthusiastically supports. Today, the primary engine for this activity is Johns Hopkins Technology Ventures (JHTV). JHTV helps faculty members license their discoveries to larger companies and has created an infrastructure in the form of incubators to encourage faculty members to create their own companies. The two incubator spaces — one on the East Baltimore campus and one near the Homewood campus — provide a combined
32,000 square feet of coworking, office, conference and lab space.
“One of the challenges, if you wish to start a company and you've never done it before, and you don't have tens or hundreds of millions of dollars, is how do you get started with the company and get it to the point where people wish to invest in it?” says McDonnell. “Now there’s this incubator space that faculty members can use to launch their startup companies away from their scientific research — in a different laboratory, where the company is doing the work needed to try to turn the discovery into a product that addresses an important, unmet medical need.”
Johns Hopkins faculty members who pursue such work are today known as faculty entrepreneurs. While employed full time at Johns Hopkins as researchers and/or clinicians, they work with the university and the appropriate oversight committees to get approval to create a company dedicated to achieving their dream of addressing a medical problem for which current therapies are inadequate and to bringing their treatments to market. Teams of Wilmer faculty entrepreneurs have created 13 such companies, with more companies in the early stages of formation — by far more than in other ophthalmology departments, according to McDonnell.
“Our founder, Dr. Wilmer, felt that the reason we exist and the reason why we do our research and our teaching and take care of patients is so that we can do the best possible job preventing patients from losing their vision or helping them to restore their vision. And so to me, the fundamental value of this activity is allowing us to help patients.
It all comes down to the patients: serving patients and serving mankind by translating scientific discoveries into better treatments,” says McDonnell.
The following faculty entrepreneurs at Wilmer are putting their time and energy into smoothing the course of scientific progress so that discoveries can travel across the continuum — from idea, to invention, to innovation, to patient treatment — without ever meeting a cliff.
What is an insight you have gleaned from starting companies?
“As faculty members, when we create something we think has value and could potentially be helpful to people and transformative to medicine, we want to make sure that it doesn’t get wasted. If there’s no patent protection or if a patent is abandoned, then you can be sure that its impact would be greatly diminished or lost.
“A patent is a way of sharing new knowledge. You’re supposed to share the best way you know at the time to create your product in order for the patent to be valid. You could just publish a discovery in a scientific journal. This was most common at Johns Hopkins for a long time. The problem was there were many tremendous innovations that were not sufficiently patented, and then nobody created either the device or the drug that could have helped people because there was no way for a company to recoup their costs.”
Companies Founded Include:
Kala Pharmaceuticals: The products use nanoparticles with proprietary coatings to help drug molecules penetrate mucus more effectively to deliver more of the drug to the targeted area in the body. Disease targets include ocular pain, ocular inflammation and dry eye disease. The current formulation is in eye drops.
Graybug Vision (with Peter J. McDonnell, M.D.; Peter Campochiaro, M.D., Jie Fu, Ph.D., and Christy Wyskiel): The lead product is a sustained-release intravitreal drug for the treatment of age-related macular degeneration, diabetic macular edema and macular edema resulting from retinal vein occlusion. The drug is paired with microparticles that provide effective drug levels for six months or longer, thereby greatly reducing the need for frequent ocular injections.
Spiral Therapeutics (with Hugo Peris and Eugene de Juan, M.D.): The company is developing products to prevent hearing loss.
Five additional companies with Wilmer and Johns Hopkins colleagues: Blue Jay Biomedical, Theraly Fibrosis, Neuraly, Ashvattha Therapeutics and Orpheris.
Why did you start Blue Jay Biomedical?
“If you license the technology to an existing company, there’s no guarantee that it will be developed into a product that reaches patients. Big companies, they could license something and then in a couple of months decide, ‘This isn’t a priority anymore.’ Our ultimate goal is wanting these treatments that we’re working on in the lab to get to the clinic in the fastest way possible. A lot of times, that’s done if the people who believe in it and are the most passionate about it are the ones who are driving it.”
Company Founded: Blue Jay Biomedical (with Justin Hanes, Ph.D.): The technology in development creates drug-loaded polymer films that greatly improve drug efficacy and duration at mucosal tissues in the body. Depending on the drug used, the treatment could become eye drops for retinal degenerative diseases or vaginal gels for prevention of preterm birth.
As a basic scientist, what do you see as the primary difference between what happens in the lab and what happens in the company?
“In basic science, we need to figure out the [biological] mechanism of action, how these drugs actually work. Our role is to demonstrate a proof of concept in animal models. And then we can provide our findings and molecules to industry teams. They do product development, which is a very different story. They focus on the scale-up and the very extensive safety study in animals, which will take one to two years. And then they need to design and prepare for the human clinical trials, which is out of our expertise.”
Theraly Fibrosis (with Justin Hanes, Ph.D.): The lead drug is a bioengineered human protein molecule used in tissue remodeling that can selectively target myofibroblasts, one of the significant originators of fibrosis, to treat various fibrosis—a debilitating condition that can affect any tissue type.
Neuraly (with Justin Hanes, Ph.D.): The lead product is a peptide drug engineered for sustained delivery that targets neuroinflammation in the brain, which could treat different neurodegenerative diseases, including Parkinson’s, Alzheimer’s, amyotropic lateral sclerosis (ALS) and multiple sclerosis.
When did you know you wanted to start a company?
“Before coming to Wilmer, I was on the faculty in an engineering department where if you develop a drug delivery product and you are evaluating it in animals, people thought you were doing significant work. In contrast, the first day I walked into Wilmer — the Smith Building — I ran into a Wilmer faculty member who is extremely well-known across the world. He saw what I was doing and the first thing he asked was, ‘Have you cured or have you given this to humans yet? That’s the only thing that counts.’ This was actually a stunning thing because basically what he’s saying is that the impact of your work is measured by whether you have cured the human disease. That is a very big bar! But I also realized that is the ultimate goal, and that should be what I strive for.”
Ashvattha Therapeutics (with Sujatha Kannan, M.B.B.S.; Justin Hanes, Ph.D.; and Jeff Cleland, Ph.D.): The technology under clinical development relies on treelike polymers known as dendrimers that can precisely deliver drugs to specific affected cells in the brain, eye and other organs, increasing effectiveness of treatment and reducing side effects.
Orpheris (with Sujatha Kannan, M.B.B.S.; Justin Hanes, Ph.D.; and Jeff Cleland, Ph.D.): The product pairs the dendrimer technology with a drug to treat neuroinflammation associated with brain disorders, including cerebral palsy, Alzheimer’s and ALS.
RiniSight (with Elia Duh, M.D., and Jeff Cleland, Ph.D.): The company is developing therapies in the field of ophthalmology for systemic treatment of age-related macular degeneration (AMD), diabetic retinopathy, dry eye, and corneal and battlefield injuries.
What part does the small startup company play in the development of treatments?
“To develop a drug that a company would be interested in taking past a phase I/II trial and into a phase III trial, you need investors. The cost for drug development is daunting. There are some estimates that taking a drug through a phase III to phase IV clinical trial may cost hundreds of millions of dollars. Unfortunately, that is not something the federal government is able to fund. To make that transition, from identifying a therapeutic target to developing and marketing a drug, there needs to be a mechanism. One mechanism has been the development of ‘NewCos’ — new companies that scientists can start in order to generate data to demonstrate the feasibility of a candidate drug and attract a larger pharmaceutical company to say, ‘OK, this looks like something we would be interested in pursuing.’”
HIF Therapeutics (with Gregg Semenza, M.D., Ph.D.): The research of both founders focuses on a transcription factor called hypoxia-inducible factor (HIF-1a) — discovered by Semenza, who won the 2019 Nobel Prize for his efforts — to determine HIF’s role in ocular diseases and cancer. The company is looking to improve upon the current standard of treatment for diseases related to abnormal blood vessel growth (angiogenesis) by developing HIF inhibitors to complement or even replace anti-vascular endothelial growth factor (VEGF) therapy.
What have you learned about the process of starting a company that surprised you?
“As an engineer who’s developing technology, [I’ve found] the technology that sounds the most ‘out there’ and novel is often the one that gets published in the top journals. But in terms of what gets made into a product, what partners and investors want to know are things like, ‘How can this be manufactured? Is it scalable? Is it stable? What does the regulatory process look like? Have there been other products that have gone down this path so that we know that this is very safe?’ A large company would much rather pay 10 times or 100 times more money for something that they feel has been de-risked and is a sure thing.”
AsclepiX Therapeutics (with Aleksander Popel, Ph.D.): The lead product is a sustained-release peptide drug injected intravitreally to treat diseases such as neovascular AMD and diabetic macular edema.
How has collaboration helped you?
“Working together with engineers, we’ve been able to develop processes by drawing on everyone’s talents in the team. There are clinical insights, which guide the process of innovation, but at the same time, it’s been really helpful to have engineers who can guide the process from a technical perspective. And by collaborating with colleagues who have experience bringing other technologies to market, it helps us develop a vision for the path forward.”
Treyetech: The products include medical devices to help with corneal transplantation. The initial device helps in storing and transferring tissue from the eye bank to the surgeon.
How would you describe the evolution of the relationship between academia and entrepreneurship?
“Right after the millennial clock ticked over, the Internet-fueled tech bubble burst, and then we had the housing market collapse. After a decades long trend of steady increases, funding for the National Institutes of Health essentially flatlined after 2003. Universities needed to explore other models to support their large investments in research infrastructure. You walked over to the patent offices, and you talked to upper administration people, and they were looking at Florida and Gatorade, saying, ‘We want some of this action, where we can pay for our research, independent of the federal government, simply by our own entrepreneurship skills.’
“And universities are such a natural fit for that. Young people who are thinking about the world's problems deeply for the first time in their lives are a hotbed of innovative concepts. Entrepreneurship fits us as a culture, as long as we find a way to thread that needle between [being] an institute of sharing knowledge and protecting intellectual property.
How do you get those two things married? You educate people that just because we're protecting [a technology] with respect to commercialization doesn't mean we're not allowing use of it for basic science research.”
Luminomics: The product is a robotics-automated screening platform for large-scale drug discovery in whole-tissue and whole-organism disease models.