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“Viruses are such elegant machines. I fell in love with the idea that we could engineer them as therapeutics and never looked back.” David Kirn, MD
Could you summarize your career path and what led you to found 4D Molecular Therapeutics (4DMT)?
I’ve been in the biotech industry for about 30 years. I grew up in Silicon Valley, surrounded by entrepreneurship, but I always loved team sports. That combination of science, innovation, and teamwork, has always driven me.
By training, I’m a physician scientist. My journey started at Berkeley, then UCSF for medical school, Harvard for internal medicine, and back to UCSF for oncology and clinical trial design. I went into oncology, but I was really torn between that and infectious disease. I’ve always loved the elegance and beauty of viruses and spent much of my career focused on viral vector-based genetic medicines.
When I was at UCSF in the early 1990s, oncogenes, the genes that drive cancer, had just been discovered. Onyx Pharmaceuticals was being formed to target the molecular drivers of cancer, and I joined as employee number 12. It was an amazing time – the idea that we could be the first to target cancer at its molecular roots was invigorating.
Even while focused on oncology, I found myself drawn to the potential of viral therapies; the idea that you can engineer viruses as therapeutics fascinated me. I transitioned to the field and have been doing that for much of my career. 4DMT is startup number five for me in viral vector-based genetic medicines. After I sold my last company about 12 years ago, I became intrigued by the process called directed evolution. My 4DMT co-founder was at UC Berkeley, applying directed evolution to adeno-associated virus (AAV) vectors. I thought, “We can use this to invent new vectors and new biologics for a range of diseases.”
Combining the power of genetic medicines and directed evolution enables us to build a platform that can generate multiple products, not just one. This has the potential take us to a whole new level of therapeutics.
Most gene therapy companies start in ultra-rare diseases. Why did you aim for larger markets, and what gave you confidence to succeed there?
After doing this for a long time, you start to see patterns. Most gene therapy companies start with very small patient populations – a few thousand people treated once and then you’re done. There’s no recurring revenue, and that model isn’t sustainable.
To make gene therapy a lasting, scalable industry, we need to move into large markets and make treatments that are accessible.
From the start, I wanted 4DMT to go after large markets – in areas like wet age-related macular degeneration (wet AMD) or diabetic macular edema (DME), where there’s a high incidence, or areas like the lung, where you can potentially redose patients effectively and safely. That’s where the business model becomes sustainable.
Directed evolution is what makes that possible. It gives us vectors that are far more efficient, so we can use much lower doses. That means better safety, lower cost of goods, and more flexibility.
Redosing is a big challenge in gene therapy because of immune responses. How are you addressing that?
One of the reasons we started 4DMT was to solve that problem. With directed evolution, we’re able to create vectors that are naturally less immunogenic and much less inflammatory. They’re also more efficient, so we can use lower doses, which improves overall safety.
Redosing depends on the tissue. For example, antibodies don’t really matter for our intravitreal product for wet AMD and DME. Even if a patient has preexisting antibodies in the blood, intravitreal injection bypasses that. You get local delivery, and it doesn’t interfere with efficacy.
For the lung, it’s a little different. Based on animal studies, we think lung cells turn over roughly every one to two years, which means you can get gene expression for one to three years and then redose, if needed. In cystic fibrosis, we’re already seeing strong gene expression in patients treated in our AEROW Phase 1/2 clinical trial. The next step will be to test if we can safely and efficiently treat patients with additional doses to potentially provide sustained clinical benefit with long intervals in between treatments. That makes pulmonary gene therapy a very attractive long-term market.
You’ve worked with major pharma partners but kept key programs in-house. How do you decide when to partner?
In biotech, you have to think several moves ahead, as in chess. Ultimately, your long-term value as a company comes from the assets you own. Many investors assume the real upside comes when a company is acquired by a large pharma, usually around Phase 3 or commercialization. If you’ve already given away too much, you’ve limited that future value.
My philosophy has always been to get validation and funding through partnerships but not give up ownership of core programs. In the eye space, for example, we partnered with Roche early on. They said, “We want you to invent an intravitreal vector.” I said, “OK, you fund the discovery, but we own the vector.” So, they had rights to use it for a couple of rare diseases we weren’t targeting, and that was it. The partnership validated our platform, paid for the work, and we kept rights for the major indications.
Recently, we announced a strategic partnership with Otsuka in Japan to develop and commercialize 4D-150 for the treatment of wet AMD, DME and other future retina indications in Japan, China, Australia and other Asia-Pacific markets. Together, we aim to receive 4D-150 marketing approval and commercialization in major markets globally, bringing this important therapy to millions of patients. It’s a great partnership because both companies bring so much to the table; we will combine our expertise in AAV genetic medicine, development in retina and manufacturing with Otsuka’s strong development expertise, regulatory experience and commercial infrastructure across APAC markets.
What are some of the biggest pitfalls at the commercialization stage that founders should avoid?
The biggest one is manufacturing. With gene therapy, the FDA says, “The process is the product.” If you make significant changes, say, switching a manufacturing cell line or purification method, regulators can consider it a different product. Then you’re facing new comparability studies in humans, which causes huge delays.
In biotech, where speed is survival, that kind of delay can kill a company.
You really have to start with the end in mind and lock down your process and analytics early. Ideally this happens during Phase 1, so that when you reach Phase 3, you’re using the same material and process you’ll commercialize with.
In our 4D-150 program for retinal diseases, we manufactured internally up to Phase 3, then tech-transferred to a top-tier CMO so that commercial material would be included in our Phase 3. That helps with regulatory approval of both the product and the supply chain.
Can you tell us about your cystic fibrosis program, 4D-710, and the recent associated funding?
4D-710 is our investigational genetic medicine for cystic fibrosis (CF), an inherited, progressive lung disease. We use a directed evolution-derived vector designed for low-dose, safe, and efficient delivery of the CFTR gene – the defective gene in CF – to the small airways. It’s aerosolized with a commercially available nebulizer – the same kind used in routine care – so it distributes throughout the lung.
Historically, nobody had ever achieved efficient gene delivery to patients’ lungs, especially in CF, where the mucus makes it a tough target. So, we’re thrilled with our Phase 1 data, which looks at four dose levels in 16 patients. We’re seeing very strong CFTR expression one to two months after dosing in all patients, well above the physiologic threshold for efficacy. The safety profile has been excellent, and we’re already seeing encouraging early signs in lung function and quality of life.
We’ll report the Phase 1 data from the AEROW clinical trial in late 2025, and enrolment in the Phase 2 stage of the AEROW clinical trial is currently underway. We’ll be measuring endpoints like lung clearance index, FEV1, and quality of life. Meanwhile, we’re advancing manufacturing and planning for Phase 3 discussions with regulators.
The Cystic Fibrosis Foundation has been a phenomenal partner – they’ve funded us for more than a decade, nearly $32 million to date, and they bring both capital and technical depth. We’ve just expanded that collaboration through a new joint steering committee to help guide the next phase of development.
And what do you see as the next big breakthroughs in retinal gene therapy?
I think we’re on the cusp. We now understand the molecular drivers, and if we can express the right regulators continuously – 24 hours a day, seven days a week, for years – that’s going to be transformative.
For wet AMD, we’ve already seen patients experience the benefit of our genetic medicine. These aren’t just theoretical possibilities; they’re realities taking shape today.
Just earlier this month we were thrilled to unveil positive, long-term data from the PRISM trial, which continues to demonstrate the remarkable consistency and durability of 4D-150's clinical benefits over 1.5 and 2 years in wet AMD patients. The data solidifies 4D-150’s potential as a backbone therapy, not just for wet AMD but potentially for other retinal vascular diseases as well. The depth of enthusiasm we’re seeing among patients and physicians is reflected in the enrolment of our Phase 3 4FRONT clinical trials, which is already outpacing expectations.
That’s the promise of gene therapy in ophthalmology: sustainable, long-term benefit from a single dose – and with each partnership and positive data set, we’re now seeing that promise become a reality.
