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It’s been awhile since I’ve made the time to include an interview, but I’m glad to be back with Cordance, a company building technology that could have major implications for retrieving diagnostics from and delivering therapeutics to the brain.
Enjoy, and have a restful holiday break! Catch you in 2023.
Here’s what’s included in issue No. 20:
Using ultrasound to permeate the blood brain barrier
What is the blood brain barrier?
Improving focus with the two-list approach
Conversations with founders, investors, and thought leaders in mental health and wellness.
This week I connected with Ryan Dittamore, the CEO of Cordance, maker of a medical device using ultrasound for targeted access across the Blood Brain Barrier (more on that below). When Ryan was in middle school, all four of his grandparents died of cancer within a short period, setting him down a path of developing solutions for cancer patients. He didn’t want to be a doctor, and found that he had a skill for speaking the language of different disciplines: research, medicine, and business.
Ryan worked in a variety of commercial biotech roles before transitioning into an early research and development role at Ventana Medical Systems, working under the mentorship of Dr. Tom Grogan. There, he learned all about developing medical evidence and designing tests to bring devices through the FDA approval process. He then moved into the world of precision medicine and liquid biopsies under the mentorship of Dr. Howard Scher, developing the first predictive tests for metastatic prostate cancer to help patients determine if they should get chemotherapy. He went on to do similar work for Decipher, which had a successful exit to Veracyte for $600M.
Serendipitously, the day they announced the sale of Decipher, a mutual connection introduced Ryan to Bhaskar Ramamurthy, the founder of Cordance. Bhaskar was looking for a CEO and Ryan was a match. After consulting for a couple of months, he joined the company's leadership.
Let’s start off easy. What does Cordance do?
One of the great challenges we have with brain diseases is the Blood Brain Barrier (BBB). This is a barrier that blocks molecules from going in and out of circulation into the brain. It’s a two-way street. We mammals have evolved this BBB to block things from getting into our precious brain tissue, but a consequence is that it also blocks therapeutics, so we can’t easily get drugs into the brain or diagnostic biomarkers out of the brain.
Cordance is developing a focused ultrasound device to solve this. Think of it like a cap, a thin version of a bicycle helmet that fits nicely on a patient’s head, with a water jacket that supports it. With focused ultrasound, we can put sound energy on a target area (say, for example, where there’s a build-up of Alzheimer’s plaque) and inject micro bubbles of pressurized gas. When the bubbles hit the ultrasound, they start to vibrate in size and shape, pulling apart the BBB and allowing us to safely open up a particular region for about 4-6 hours. This creates a magic window for us to both get diagnostic biomarkers out so that we can understand the disease and how the different subtypes of disease look within patients, and then get therapeutics like large molecules or antibodies delivered. There is a very small subset of all therapeutics ever developed, maybe 2%, that can actually get through the BBB on their own, so this opens up a new opportunity to therapeutically target brain diseases.
How much of Cordance’s technology has been proven out already?
We’re fortunate in the fact that we're not alone. To change medicine, if you're alone, you're more likely to be in trouble. There are many other academics and a few other industry groups that are using focused ultrasound to permeate the BBB.
There have been a number of first-generation devices that use this technology, they’re just not very patient-friendly and require tertiary centers. But this technology has been demonstrated successfully in humans, increasing drug concentrations by 3-6 fold over the non-use of a device.
We’re not inventing the technology here, just making it more practical and usable. Think of it like turning the brick phone into an iPhone. Cordance is currently in preclinical studies testing on large animals, and we’ll start our first human clinical trial next year. Initially we’ll prove out the diagnostic application, and then we’ll work into a therapeutic application.
What use cases do you expect to apply the Cordance helmet to?
It’s all about precision medicine. The important part of this is to molecularly characterize the patient, understand what’s driving their disease, and then use a therapeutic that’s designed for that particular biology to extend life.
As we think about brain diseases as a whole, there’s a lot we still don’t understand. We don’t really understand the mechanisms driving different diseases, and when we think about the trial setting, there’s also a lot of guesswork. We take a picture of a patient’s brain, include them in a trial, hope the drug gets to where it needs to go, and then take another picture. We think Cordance can evolve the way we run trials with more precise diagnostics.
Ultimately we need to prove that the device has clinical utility, where the use of the technology improves outcomes over the non-use.
One of the first applications we’re going after are very lethal brain tumors, which allows us to measure one of the strongest endpoints of all: survival. Once we can demonstrate this, the device could be applicable to any brain disease, from neurodegenerative diseases, to mental health diseases, to autism, you name it.
Though you’re still far from commercializing this - how do you plan to make money?
We’re going down the regulated path to do this. With the FDA, we’re going after very difficult diseases that have short life expectancy. Given that, we’ll work to get reimbursement through Medicare and through different private insurers.
The end customer is really the physician who would write a prescription to use the Cordance device. Our target is the community physician or group of physicians who own a practice, and there are a lot of practices, so we need to make the capital equipment expenditure very low to get adoption.
The way physicians typically make money is by using the devices with patients. So, our model is the razor-razor blade model, where we provide the foundational device at a very low price, and then have a higher margin on the actual consumables (in our case, the personalized water jacket that fits under the cap and the micro bubbles being used).
What does the competitive landscape look like, and what differentiates Cordance?
One thing I’d say on how I view competition is that in this space, the need is so high, there’s really going to be room for multiple companies targeting different indications to compete successfully. So I’m not overly fixated on the competition with the lens that there’s only going to be one winner.
I am very fixated on what is the right path to get a device like this to market. How do we position our product to make sure that we can meet the market demand and achieve that product-market fit? It’s more likely that nobody wins here than that everybody wins - this is a tough problem to solve.
We do, however, learn a lot from our competitors by paying attention to what physicians do and do not like about them. The core companies we watch that are in human trials now with first-generation devices include CarThera, Insightec, and NaviFUS. All the technologies in the space use the same underlying focused ultrasound technology, so the differentiation comes to how you guide the ultrasound and how the therapy is delivered.
For example, one competitor actually does a craniotomy to place their device, which may work for a glioblastoma patient but isn’t likely to be something a patient would want to go through if they don’t have a lethal disease. Another group uses MRI, where the patient has to go into an MRI tube for 3-4 hours with a fixation point screwed to their skulls so that they can’t move while the beams are guided. Some newer companies are using optical navigation, but that still requires a lot of hardware using cameras across a room and requiring that patients sit in place.
Our approach is completely mobile for the patient, and on top of that, doesn’t require expensive machinery that limits where delivery of the therapy can occur to specialized tertiary centers. We think this will unlock much broader access - 85% of patients are treated in the community. We also think this approach opens up the ability to perform precision medicine, allowing us to easily capture diagnostics from the brain - a patient might be willing to sit for multiple hours in an MRI tube for a one-time therapeutic delivery, but becomes less willing to do so just to run a diagnostic. And that diagnostic has so much value.
What’s been the most difficult and most exciting part of building the business?
The most challenging part I think is always keeping focused - this is a device that can go into 100 different applications. We’re lasered-in on getting the product through the FDA and demonstrating that it can be useful, and after we do that we can start chasing all of these use cases. It’s difficult to keep that.
Another challenge is, we’ve gone from a lot of whiteboard and sketches to actually creating a product under real design controls. But that’s also what I’m most excited about - in my career, I’ve always enjoyed watching technologies transition from the benchtop into humans. This next year is going to be very exciting as we start that first journey into humans and see the potential of all the things w'e’ve been working on.
How have your plans changed to weather the current market environment?
Fortunately, we’ve always had a kind of batten-down-the-hatches approach, even when the economy was good. I’ve learned through my career that you need focus, need to execute, and you have to be gritty with really no frills. The current environment just emphasizes the importance of that mindset.
We keep our heads on demonstrating progress on meaningful work, which motivates investors to get behind us and motivates our staff to to the finish line and hit our most important inflection points.
As a small company, I find that we can’t make as many mistakes, and when we do, we need to adjust quickly. I have a kind of motto which is, measure twice and cut once, but do it really fast.
Any advice for other founders in this space?
I can’t stress enough that endpoints matter. Whatever your device or therapeutic, really think about how you measure those endpoints, and how they’re measured by physicians.
CMS insurers are worries about two things: is it reasonable, and is it necessary. So think not just about whether it’s safe and efficacious but if it is better than existing treatments and a reasonable treatment for the target indication. Drugs also get a lot more of a free pass on reimbursement than devices, so keep that in mind.
More generally, start with something you can make a difference in and expand from there. Disrupt the small market and show a path to the larger market.
Finally, don’t focus on the competition. Focus on what your product will do for the patient - human health is a wide opportunity.
Discussion of clinical concepts, studies, or perspectives on mental health and wellbeing.
According to BrainFacts.Org (great website name), the first evidence of the blood brain barrier was discovered by accident when German scientist Paul Erlich was trying to find new compounds that could attack disease-causing microbes. “In 1885, Ehrlich injected blue dye into the bloodstream of mice. The dye stained all of the animals' organs blue — except their brains. In a follow-up experiment in 1913, one of Ehrlich's students injected the same dye directly into the brains of mice. This time, the brains turned blue, whereas the other organs did not.”
So how does it work? If you’re more of a visual learner, check out this short (1 minute) video showing how the blood vessels in the brain have endothelial cells that are much closer together than other blood vessels, preventing most drugs from making their way into the brain:
Rundown of recent investment news in mental health and wellness companies.
Amwell, a telemedicine company, is in talks to acquire Talkspace, a virtual tele-therapy company, for $200M (Link)
BehaVR, a VR mental health company, and OxfordVR, another VR mental health company, merged and announced a $13M Series B led by Optum Ventures and Oxford Science Enterprises (Link)
Bionaut Labs, developer of magnetically driven robots designed to deliver treatments to the midbrain, raised $43.2M in a Series B led by Khosla Ventures (Link)
Bloom, a mental wellbeing app applying CBT to self-guided therapy, raised an $8M Seed round led by Target Global (Link)
Breathonics, a breathwork and mindfulness app that claims to be building “products across both Web2 & Web3,” raised an undisclosed sum in its Pre-Series A round led by OliveX (Link)
Cajal Neuroscience, a company integrating human genetics, functional genomics and advanced microscopy for neurodegenerative drug discovery, launched with $96M in Series A funding led by The Column Group and Lux Capital (Link)
Dawn Health, a digital health app targeting insomnia, raised a strategic funding round led by Kindred Ventures (Link)
Empyrean Neuroscience, a genetic engineering company developing neuroactive compounds to treat neuropsychiatric and neurologic disorders, launched with a $22M Series A (Link)
Floreo, a VR behavioral therapy platform, raised $10M in a Series A led by Tenfore Holdings (Link)
Gilgamesh, a biotechnology startup developing short-acting psychedelics to treat depression, raised $39M in its Series B led by previous investor Prime Movers Lab (Link)
Hazel Health, a pediatric mental and physical health provider, raised a $51.5M in a Series C1 round (Link)
Healios, a London-based company providing digital mental health support to families, raised over $16M in funding (Link)
HeyRitual, a couples therapy app, raised a $2M Pre-Seed round led by GroundUp Ventures (Link)
Inflow, a CBT-based self-help app, is acquiring Lina, a tele-mental health clinic (Link)
In-Med Prognostics, an AI brain imaging startup, raised $2M from Exxora (Link)
InStride Health, a virtual care provider for pediatric patients with moderate to severe anxiety and OCD, launched with $26M in funding (Link)
Kyros, a platform that connects patients with substance use disorder with providers, raised $2.4M in Seed funding led by Rally Ventures (Link)
Luminopia, a prescription digital therapeutic for neuro visual disorders, raised a $5.7M Seed extension round led by ShangBay Capital (Link)
Mindful Care, an in-person and virtual behavioral health provider, raised a $7M Series B led by Sopris Capital (Link)
Neurotrack, a company developing digital cognitive health tools, raised $10M in new funding (Link)
Options MD, a telehealth startup focused on severe depression, raised $2.4M in Pre-Seed funding led by Bread & Butter Ventures (Link)
Resilience Lab, a company aiming to boost the number and diversity of mental health providers in the sector, raised a $15M Series A led by Morningside and Viewside Capital Partners (Link)
Sensorium Therapeutics, a company developing novel psychoactive therapeutics as mental health treatments, raised a $30M Series A (Link)
Sonde Health, an AI-enabled voice technology platform that can detect depression, raised a $19.3M Series B led by Partners Investment (Link)
SonderMind, a mental health provider, acquired Total Brain, maker of a mental health monitoring and support platform (Link)
Synchron, maker of a brain-computer interface implanted in via blood vessels that aims to give paralyzed patients control of digital devices with their thoughts, raised a $75M Series C led by ARCH Venture Partners with participation from Bezos Expeditions and Gates Frontier, among others (Link)
Upheal, a platform that helps mental health professionals with note-taking and documentation, raised $1M in Pre-Seed funding led by Kaya VC (Link)
Valera Health, a virtual mental health platform for high-acuity patients with serious mental illness and severe depression, raised $44.5M in growth equity led by Heritage Group (Link)
Wellin5, a creator of virtual counseling and therapist tools, raised a $2M Seed round (Link)
Wesper, a sleep therapy platform, raised a $7.5M Series A (Link)
Wispr AI, a neurotechnology company building ways to interact with technology more naturally, raised $10M (Link)
Sometimes mental health-related. Sometimes just things I find interesting.
101 rules for life, disguised as design rules. Brian Collins
A virtual machine inside of ChatGPT. Engraved
10 people who shaped science this year. Nature
52 things learned in 2022. Tom Whitwell
Don’t agree with this take on the brain, but it’s a take nonetheless. Aeon
A brief history of the world in 13 maps and infographics. The Cultural Tutor
Memories vs. perceptions. Quanta Magazine
Every dating profile ever. Twitter
Tips to improve your mental health and wellbeing.
This week’s tip comes from a recent Sahil Bloom newsletter, and apparently the idea originates with Warren Buffett. I’m trying it out because it’s simple and resonated with my growing to-do list.
It’s called the two-list approach, and it’s all about ruthless prioritization.
Create a list of all of the different projects you’re working on right now (you could also do this on a smaller scale, creating a list for all of the things you’re working on within one project).
Circle the top 3-5 items - the most important, need-to-accomplish must-haves. These should have the greatest impact on your success out of all of the items.
Focus on those 3-5 priorities - this is your new list - and treat the rest of the items as “avoid-at-all-cost.”
I’m personally going to give it a go - I have a tendency to “productively” procrastinate by getting little things done instead of the bigger important items. Sometimes it just takes a mindset shift…always willing to experiment with new ways to trick my brain into getting shit done.
Email me at dt@vine.vc with any reactions to the newsletter.
If you’re working on something in mental health and wellness, let’s talk. You can book some time with me here.
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Written by Daniel Tarockoff, a partner at Vine Ventures exploring the future of mental health. Born in Detroit, MI. Based in San Francisco, CA.
