Marc, before joining AstraZeneca, you had already worked in the rare disease space. What made you return to it, knowing the challenges involved?
When I started my career in 1975, I was already involved in registering an orphan drug. Even back then, orphan drugs had distinct regulatory pathways and reimbursement systems, making them a special category of medicine. That early experience gave me an understanding of the unique challenges and opportunities in rare diseases.
In 2010, I started a rare disease unit within GSK. And I continued in this space when AstraZeneca acquired Alexion in 2021. The challenge of rare diseases is enormous—there are 10,000 known conditions, and we cannot work on all of them simultaneously. That is why Alexion’s focus on the complement cascade was so strategic. Since its early days, Alexion pioneered this field, taking 15 years of research before launching its first product in 2007. Watching this unfold from the outside, I saw the potential in targeting fundamental biological mechanisms that can address multiple conditions, which is one reason why I returned to the space.
Does Alexion’s approach of targeting the complement system provide a sort of solution to the problem of targeting multiple rare diseases?
Yes, that is a fair way to look at it. There are multiple ways to develop solutions for rare diseases. Out of the 10,000 identified rare diseases, about 80% have a genetic cause. Most rare disease therapies in the future will likely focus on correcting, replacing, or targeting specific genetic mutations. However, Alexion's approach differs because we focus on fundamental biological mechanisms, such as the complement system, which can apply to many different conditions.
Unlike a typical rare disease drug, which is often designed for a single indication, Alexion’s therapies regulate core biological processes involved in various diseases. This approach allows for scalability, enabling innovative R&D to have a greater impact, and reach, despite the small patient populations.
How has the field of rare diseases evolved over the past decade? Is there more optimism that we are on the right path?
Absolutely. Rare diseases have become a critical area for exploring new treatment modalities because, in many cases, there is no existing therapy, or even a model. For patients who have no options, innovative approaches are important. That is why many groundbreaking scientific advances—such as gene therapy and oligonucleotides—saw their first advancements in rare diseases before expanding to broader patient populations.
Rare disease research often involves small patient groups, but the potential impact is immense. Since these diseases frequently lack treatment, regulators and researchers have more flexibility in trial design and benefit-risk assessment. This environment has allowed for faster adoption of new technologies. Many of the advances seen today, such as gene editing and RNA-based therapies, originated in rare disease research before moving into larger indications.
Can you highlight some of Alexion’s most promising ongoing programs?
We continue to focus on complement biology, which has already led to multiple approved products. However, we also continue to build a diversified pipeline across disease areas with significant unmet need, using an array of innovative modalities. For example, we have expanded into areas like amyloidosis, a condition historically known as a genetic disorder but now recognized as affecting a larger, aging population as well. For instance, transthyretin amyloidosis, or ATTR, was once thought to be caused solely by genetic mutations, but we now know that aging alone can trigger similar disease mechanisms. Until recently, many of these patients were misclassified as heart failure patients and treated accordingly, without addressing the underlying amyloidosis.
With new diagnostics and therapies, we now see that treatments developed for the genetic form of the disease can also benefit this broader aging population. This is a perfect example of how rare disease research can expand into more commonconditions over time.
Additionally, we have expanded into genomic medicine with a number of early-stage assets, marking an exciting step in broadening our capabilities beyond complement biology.
Diagnosis remains a major challenge in rare diseases. How is Alexion addressing this issue?
Diagnosis is crucial because many rare diseases are often misidentified or go undiagnosed for years. A recent study analyzing the economic burden of rare diseases in Europe found that 25% of rare disease patients experience a misdiagnosis, and for those who are misdiagnosed, their journey to receiving an accurate diagnosis can take three-times longer. For example, while diagnosing transthyretin amyloidosis requires specialized testing at reference centers, the key challenge is getting physicians to suspect the condition in the first place. Heart failure patients, for instance, may have amyloidosis but remain undiagnosed due to a lack of awareness or diagnostic tools.
To address this, we are exploring methods to flag potential cases earlier. For instance, certain heart thickening patterns detected via echocardiography have the potential to suggest amyloidosis. While no single test provides a definitive answer, combining multiple clinical indicators through AI-powered algorithms may help physicians identify at-risk patients. Once flagged, these patients could be referred for confirmatory testing, significantly improving diagnostic rates.
Do you believe AI and new technologies will play a transformative role in diagnosing and treating rare diseases?
Yes, and we are already seeing the impact. AI can analyze multiple diagnostic parameters simultaneously, improving accuracy and efficiency. As we develop new treatments, we are also advancing diagnostic tools to identify the right patients. AI-based risk models can help prioritize patients for further testing, potentially ensuring that those who would benefit most from treatment are identified sooner. This integration of AI and medical diagnostics is a game-changer for rare diseases, where early intervention can significantly alter outcomes.
Continuing with amyloidosis as an example, by integrating data from echocardiography, MRI, and cardiovascular function tests, AI can identify patterns that may not be obvious when looking at a single parameter. This probabilistic approach allows for earlier suspicion and intervention.
Recently, AstraZeneca discontinued two of Alexion’s programs. What lessons have you learned from those decisions?
Innovation always involves some level of risk. The more pioneering the approach, the greater the likelihood that some programs will not succeed. When working with new mechanisms or endpoints, early-stage studies often have smaller patient groups, leading to variability in outcomes.
Our priority is to allocate resources effectively. If a drug does not show a strong enough potential benefit, we prefer to discontinue it early rather than invest in late-stage trials with a high risk of failure. Our goal is not just to bring a new drug to market, but to ensure it provides a meaningful benefit and improvement over existing options, if any exist. Strategic portfolio management is essential in rare disease research, where development costs are high and patient populations are small.
Where do you see the field of rare diseases evolving in the next five years?
There are 10,000 known rare diseases, but less than 10% have an approved treatment. This means the field is still in its early stages, with vast opportunities for scientific advancements. While much attention is given to the diseases with available treatments, the majority of rare diseases remain unaddressed.
Scientific progress has accelerated over the past decade, especially in areas like gene therapy. The field is now in what I would call the third or fourth wave of gene therapy, moving from early clinical failures to real-world successes. Today, there are only eight approved gene therapy products, but by 2025, that number could double. Meanwhile, over 200 late-stage trials are ongoing. Not all will succeed, but the increasing success rate signals a turning point in the field. As delivery systems and payload mechanisms improve, we expect an acceleration in personalized solutions for genetic diseases, fundamentally changing the landscape of rare disease treatment.
