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Dr. Laurent Fischer, CEO of Adverum, sits down with Onyx for a feature length interview.
To start, could you give us an insight into your personal career journey prior to Adverum?
Absolutely. I trained as a physician in Switzerland and later joined Hoffmann-La Roche in Basel during the mid-nineties, right at the peak of the AIDS epidemic. I was fortunate to be involved in launching the first protease inhibitor for HIV—the first AIDS cocktail while I lived in New York. Back then, patients had to take up to 20 pills three times a day, with and without food, and the regimen was poorly tolerated. Many couldn't keep up, leading to viral resistance, AIDS and death.
We came up with a concept using ritonavir, which inhibits a liver enzyme responsible for metabolizing these drugs, to boost the levels of the HIV medication. This allowed patients to take their meds once a day, keep their viral loads suppressed, allow their immune systems to recover, and, ultimately, survive. Interestingly, this approach is still relevant today; for instance, Paxlovid for COVID-19 uses ritonavir in a similar fashion.
Why does this matter? We're developing amazing drugs that can have huge impacts on patients' lives, but they're only effective if patients can actually take them. That insight led me to Adverum, my fifth role as a biotech CEO in areas of unmet medical need. I saw the potential to preserve sight for life in patients suffering from wet age-related macular degeneration (wet AMD), which is the leading cause of vision loss in the elderly.
Once diagnosed, patients essentially sign up for a lifetime of anti-VEGF injections into the eye every four to eight weeks. Despite some improvements over the past 20 years, the burden remains significant leading to chronic under-treatment. More concerning is the fact that, about 40% of patients stop treatment altogether within three years, leading to loss of vision. The treatments are painful and require frequent visits to retina specialists—it's just too burdensome for many patients.
At Adverum, we identified a way to deliver a nti-VEGF differently. We've designed a viral vector that encodes the gene for aflibercept (Eylea®). By injecting it once into the eye, we essentially train the patient's cells to produce their own anti-VEGF, blocking the disease in its tracks. One of our first patients was treated over five years ago. He had received 109 injections over 10 years, and five years later, he's been free of injections with stable vision and no fluid in the eye.
In our first-in-human study, all of these hardest to treat patients have been followed out to three years or beyond. More than half of them are free of injections with stable vision. This is truly unprecedented. We've been fortunate to receive PRIME designation in Europe, ILAP designation in the UK, and RMAT designation from the FDA—regulatory mechanisms that prioritize groundbreaking regenerative therapies.
We presented 26-week data from our Phase II study, showing that 76% of patients required no supplemental anti-VEGF injections at all at six months. In patients who required 6 or less anti-VEGF injections before enrolling in our study, which is more representative of the general population, approximately 90% were free of injections. With the doses we're looking at, this gene therapy could be very cost-effective for healthcare systems—not the millions of dollars per patient we see for rare diseases and systemic gene therapy, but a much smaller cost for millions of patients. We hope to make this treatment accessible globally because, while patients in developed countries have access to these medications, that's not the case elsewhere. Protecting vision for millions around the world is particularly inspiring to me.
In terms of your overall pipeline, are you able to delve into timelines for data readouts and Phase III trials?
The data readout for the 52-week results from our Phase II LUNA trial will be in the fourth quarter of 2024. We'll also discuss the size and specific patient population we plan to enroll in our Phase III program, which we aim to start in the first half of 2025.
Our vector, which is proprietary, is being used in two clinical trials, including with a French company called GenSight. We and partners are also exploring using the same vector in other programs, both for rare diseases and optogenetics—an early part of our pipeline aimed at regenerating sight in patients who've lost vision.
How would you best characterize the population you're most interested in and who are most applicable in these studies?
As is often the case in gene therapy, we first focus on the hardest-to-treat patients—those who have stable vision but require upwards of 10 annualized injections. These patients showed great benefit, with more than half remaining free of injections out to three years in our longest- term reported data in this first-in-human trial. In our LUNA Phase II trial, 76% of similarly heavily treated patients were injection free at six months at the lower dose. When we looked at less heavily treated patients needing up to six injections in the year before our trial, we achieved up to 90% free of injections across both doses at six months with preserved vision and no active fluid or active disease.
Eventually, we aim to help every patient who needs it. Real-world evidence shows that while newly treated patients gain vision initially, they start losing those gains beginning at 12 to 18 months. If we can protect vision for patients with 20/50 or even 20/20 vision, we can have a transformative impact. In our studies, 88% of patients said they would prefer the gene therapy over their prior treatment, and 93% said they would use it in the other eye if they developed bilateral disease. Interestingly, some also report improved functional vision at night, improved color vision and ability to see well enough to go back to activities like cross-word puzzles.
We've spoken to others interested in gene therapy in the ophthalmic space. Is there a particular reason why the eye seems to be yielding such positive results in gene therapy?
That's an excellent question. The eye has two advantages. First, it's a relatively compartmentalized part of the body, allowing us to inject a much smaller amount of viral vector compared to systemic gene therapy—roughly a thousand to ten thousand times less. This means there's less risk of an immune response. Second, the eye is somewhat immune-privileged, so we see less of an immune response. We've been able to control the immune response with just local steroid eye drops. These factors make ocular gene therapy particularly attractive.
Given the benefits, how does this all square up in terms of cost and scalability?
We're using a suspension-based virus manufacturing system, similar to what's been used in some COVID vaccines. Our gene therapy product is manufactured by a contract organization with experience in commercial products and is already at our planned commercial launch scale. We're in very good shape to deliver this to the market cost-effectively and at scale. Manufacturing is one of the challenges with complex biologics, but we've built strong internal teams and partnerships to ensure we're prepared for commercialization.
What's your commercialization strategy, and how are you balancing national and international ambitions?
We recently hired a Chief Commercial Officer who was at Apellis, which launched the first treatment for dry AMD approved in the US. The market is relatively concentrated, with a few thousand specialists, of which a few hundred to a thousand specialists drive most of the adoption. In the US, we can launch without a partner. For the rest of the world, we'll look to find partners to help commercialize the product. Given that even a small market share represents a significant opportunity—a few percentage points can represent a billion dollars—we anticipate interest from parties looking to enter this therapeutic area.
Having launched several products in HIV/AIDS that had a global impact, I was attracted to Adverum because we have the potential to make this product available globally at a reasonable cost. We'll focus initially on the US, Europe, and Asia. We're also trying to find ways to make this treatment available over time in parts of the world where it's more challenging. For example, in China, the government only reimburses for a couple of anti-VEGF injections, which isn't sufficient for a life-long disease. Our goal is to protect vision for millions of people around the world.
Looking ahead to 2025, what are your main goals and milestones for Adverum?
Our main goal is to initiate the Phase III trial and enroll patients as rapidly as possible. These trials follow patients for one year compared to the standard of care. We'll also start setting up the commercial infrastructure to be ready once we meet our Phase III milestones and can file for approval in the US and Europe. Additionally, we'll continue to advance our pipeline with promising early candidates. Earlier this year, we hired a Chief Scientific Officer experienced in ocular gene therapy including in the first approved product, Luxturna, and we're exploring areas of unmet medical need where we can have an impact with our platform.
As we look ahead, are there any trends or developments in the wider industry that you think will be crucial to watch?
Gene therapy is finally coming to maturity. For ocular gene therapy, the future is bright, and I believe it will be readily adopted due to its manageable side effects and great efficacy. Gene editing and mRNA editing are also starting to come of age. Regenerative medicines addressing currently undruggable targets are particularly exciting, especially with advances in machine learning that can improve and potentially accelerate target identification and drug discovery. There's a bright future ahead with many exciting new therapies coming to market and I am honored to be involved with many cutting edge technologies across multiple companies.
From a leadership perspective, with your decades of experience, what would you say is the secret sauce for leading a successful team?
I love that question. The culture and the team you hire are everything. A team that works well together, brings diversity of experience and thinking, and fosters a collaborative yet challenging environment is incredibly important. I've worked with some people for over a decade across multiple companies, and we've always led an incredibly positive culture. We even frequently see people even come back after leaving because they miss it so much.
The mission we're on—trying to preserve vision for life—is something people can aspire to. But it's also about doing it in a way that's exciting and collaborative. What we do is difficult and challenging; there are always setbacks. But having the ability to see through these setbacks and continue to achieve transformative outcomes is what gets people excited.
For me, it's about hiring people you want to work with and spend time with, who bring their own personal and professional experiences to the table and engage fully. During COVID, it was challenging not being able to spend time together, but we're happy to be back in the office and at medical conferences. It's that collegial and collaborative spirit that creates great teams. That's the secret—identifying the right people, bringing diverse personalities together, and fostering an environment where everyone can contribute their best.
