At First Sight

Over 100 years of scientific progress separate Gregor Mendel’s pea-crossing experiments from the moment US scientists Theodore Friedmann and Richard Roblin published their paper “Gene therapy for human genetic disease?” in Science. After they outlined the potential of replacing a disease-causing gene as a form of treatment for genetic disorders, it's no surprise that worldwide debate regarding its therapeutic potential and ethical considerations followed suit. But as with many facets of life, time reveals all – and their big question was answered. Today, gene therapy research – alongside many scientific and technological developments – is writing a new narrative that shows that disease can be confronted at its root cause. 

We’ve talked about the potential of gene therapy on many occasions in The Medicine Maker, but one area we haven’t explored in such detail is its relation to eye disease (a task we typically leave to our sister publication, The Ophthalmologist). There are several factors that make the eye a particularly attractive target for gene therapy, including its accessibility, immune privilege, and well-defined anatomy. And though the implications of gene therapy in this field are huge – and thus research activity is expanding rapidly – there is still so much to learn.

We hear from three companies – Cardinal Health, REGENXBIO, and Beacon Therapeutics – who are convinced gene therapy will broaden our treatment modalities against ocular conditions.

Broadening Perspectives with Cardinal Health

Located in Ohio, US, Cardinal Health is a global manufacturer and distributor of medical products, providing performance and data solutions for healthcare facilities to nearly 90 percent of US hospitals. At present, Cardinal Health has assisted numerous biopharma companies in establishing their own advanced therapies – the likes of which date back to the first CAR-T therapies of 2017. Covering clinical development to commercialization, their expertise in this field is widespread. Accordingly, we asked Fran Gregory, Vice President of Emerging Therapies at Cardinal Health, to give us a broad overview of the field – from challenges to future prospects.

Why is gene therapy significant for ophthalmology?
 

The first ophthalmic gene therapy was approved by the FDA in 2017. Though this treatment is limited to a highly specific gene mutation involved in Leber’s hereditary optic neuropathy, it’s a one-time therapeutic with the potential to restore the visual cycle entirely. Existing treatments for ophthalmic indications (i.e., macular edema, diabetic retinopathy, and wet age-related macular degeneration) belong to a class of medications called VEGF inhibitors. These treatments are injected into the eye several times a year, slowing the progression of disease or vision loss for patients who adhere to the dosing regimens.

With at least 25 treatments in phase I-III clinical trials, the advanced medicine pipeline is full of potential treatments for ocular conditions. The excitement for gene therapy is palpable, and for patients with genetic or inherited ocular conditions who have never before had treatment options, the future is promising.

What are the scientific challenges of developing gene therapies for ophthalmic conditions? 
 

Most retinal or ocular treatments on the market – or in development – target a specific genetic marker or mutation. However, the human genome is complex; there are many potential genetic mutations that could lead to ocular dysfunction. This makes identification of the dysfunctional, over-expressed, or under-expressed gene necessary for effective therapeutic intervention. As you can imagine, however, this is easier said than done.

There are millions of potential genetic mutations that lead to eye disease, and gene therapies cannot work for all patients. Only if the patient has the specific gene mutation contributing to their condition can the treatment work – but, even in such ideal circumstances, complications can occur. Ensuring gene therapies have the intended result is crucial. With substantial costs, repeated treatment is not a feasible option. Companies must achieve effective and durable responses that can for last years, or better yet, a lifetime.

What concerns do ophthalmology companies face in developing gene therapies?
 

Scientific challenges and population health considerations are at the forefront of company concerns. Since I’ve already discussed various scientific issues, let’s move on to the latter – we must think about overall population health. Who needs the treatment; can we identify them; and can we get the final product to the patients that can benefit from it.

All gene therapies in development treat a very specific gene, meaning that we must identify that genetic defect in every patient prior to treatment. If one is not already available today, a genetic test must become a standard-of-care. Once the patient’s genetic profile is understood, then the product must be an exact match for that patient. Finally, training the physician to identify genetic ocular conditions, perform the genetic testing needed, and refer the patient for gene therapy is another area of consideration. In an ideal world, physicians should be trained to perform ophthalmic surgery and be certified by the manufacturer to administer gene therapy.

Is there enough focus on developing advanced medicines for ophthalmic conditions? Or do indications like oncology take up most of the research effort?
 

There is certain positive evolution, based on the pipeline alone. This evolution doesn’t necessarily undermine oncology, but shows the space is more inclusive of additional therapeutic areas. While oncology will continue to have a presence (rightfully so), we will begin to see more therapies move along the development pathway for other, sometimes more prevalent conditions. Based on the gene therapy pipeline overtime, the percentage of non-oncology indications being studied will be short of 50 percent in the next 3–5 years.

Where should the priorities lie for the future growth of advanced medicine?
 

We’re only just starting to prove that these treatments are safe, effective and durable; gene therapy is in its infancy. Over time, it will be crucial to devise scalable manufacturing solutions and delivery methods of the gene therapy, all while assessing how impactful a single treatment could be. For example, the gene therapies in phase III and on the market all target a single gene, limiting broad population impact. Priorities, therefore, should be in manufacturing efficiency, development of new, potentially more cost-effective delivery methods, and broadening population impact.

Focusing on Wet AMD with REGENXBIO

REGENXBIO is a clinical-stage biotechnology company with a mission to improve lives through the curative potential of gene therapy. They got their start in 2009 by acquiring the rights to the NAV technology platform, which encompasses over 100 AAV vectors. With this step, they played an important role in reviving the AAV gene therapy field and helping set its current course towards producing one-time potential curative treatments for diseases of the eye, muscle, and brain. Indeed, they have a pipeline of investigational AAV-based therapeutics focused on retinal, neuromuscular, and neurodegenerative diseases – including late-stage programs. 

But, we wanted to learn more about a specific condition, namely wet age-related macular degeneration (AMD). Wet AMD occurs when abnormal blood vessels grow into the macula which leak blood or fluid, leading to scarring of the macula causing rapid loss of central vision. How could gene therapy be used to treat this condition? Steve Pakola, Chief Medical Officer at REGENXBIO, has the answers.

What are the limitations of current treatments for retinal diseases – and wet AMD specifically? 
 

Nobody enjoys injections to their eyes – nor do they enjoy the frequent visits needed to administer them. Most wet AMD patients need to receive injections that block vascular endothelial growth factor (VEGF) into the eye every four to 16 weeks indefinitely. Although these treatments have been shown to work in clinical trials, the requirement of frequent injections can place a heavy burden on patients and families alike. 

What is your approach to tackling wet AMD?
 

The wet AMD patient population is expected to increase to 5.7 million in the US, EU, and Japan in the next five years. So a one-time treatment that uses gene therapy to deliver sustained anti-VEGF activity is exciting to say the least. 

ABBV-RGX-314 is an investigational one-time AAV therapeutic that we are developing in collaboration with AbbVie for wet AMD, diabetic retinopathy (DR), and other chronic retinal conditions. It uses the NAV AAV8 vector to deliver a gene encoding a therapeutic antibody fragment to inhibit VEGF. Two separate routes of administration of ABBV-RGX-314 are currently being evaluated – a subretinal delivery procedure and a targeted, in-office administration to the suprachoroidal space.

ABBV-RGX-314 is involved in several clinical trials. For treatment of wet AMD delivered to the subretinal space, enrollment in phase III trials is ongoing. These are expected to support global regulatory submissions with the FDA and the EMA in late 2025, through the first half of 2026. To date, this is the largest gene therapy pivotal program ever executed. 

For wet AMD treatment delivered to the suprachoroidal space, positive interim data from our phase II AAVIATE trial was presented earlier this year, showing improved stable visual acuity and retinal thickness. 

And we expect to report additional interim data at upcoming medical meetings. For treatment of diabetic retinopathy delivered to the suprachoroidal space, positive interim data from our phase II ALTITUDE trial was also presented this year; again, we expect to report additional interim data at upcoming medical meetings.

Simply put, after one administration of ABBV-RGX-314, the eye will have what it needs to make its own anti-VEGF instead of relying on regular injections. In essence, our ABBV-RGX-314 candidate aims to turn the body into its own drug factory, eliminating the need for repeated treatment with injected therapies.

RGX-381, another candidate in our retinal portfolio, is an investigational one-time AAV therapeutic for the ocular manifestations of late-infantile neuronal ceroid lipofuscinosis Type 2 – or CLN2 disease, which is a form of Batten disease (a condition characterized by seizures, vision loss, problems with thinking and movement, and eventually death). It uses the NAV AAV9 vector to deliver the TPP1 gene directly to the retina. We recently announced the dosing of the first patient in the phase I/II trial of RGX-381, and we expect initial data to be shared in 2024.

If gene therapy is to be more widely used in ophthalmology, what challenges need to be overcome? 
 

An important consideration in ophthalmology drug development is demonstrating the ability to treat both eyes in diseases that affect both eyes, such as VEGF-driven retinopathies. We are starting to address this issue in the clinic, with the goal of demonstrating similar safety and efficacy when treating the second eye of patients with wet AMD.  

Another potential challenge with common diseases is having the capacity to manufacture sufficient doses for large numbers of patients. Again, we hope to address this through the addition of a specialized manufacturing facility that will enable us to boost manufacturing of NAV technology-based AAV vectors at scales up to 2,000 liters. The facility will implement our NAVXpress platform suspension cell culture process, which can increase product purity and yield.

Evidently, you see a significant role for gene therapy in retinal disease treatment in the future…
 

We are running the largest ever gene therapy program – not just in the field of retinal diseases but for any indication. The lessons we learn during the treatment of these patients will help inform future development of other gene therapies for retinal disorders. We are also the first company ever to evaluate gene therapy delivery via the suprachoroidal space, allowing for in-office delivery to a compartmentalized space close to the target tissue and thereby limiting exposure to other ocular tissues, including anterior eye structures. We believe that there is tremendous potential for our gene therapies to become a new standard of care to treat and prevent progression of vision threatening diabetic retinopathy.

New Beginnings with Beacon Therapeutics

Let’s say you’re a new company starting off in the ophthalmic space, what do you do? Take things slowly, limit your expertise to one treatment, or attack the market with numerous preclinical programs across multiple indications. Beacon Therapeutics – thanks to support from Syncona and additional investors – chose the latter. Targeting X-linked retinitis pigmentosa, dry age-related macular degeneration, and cone-rod dystrophy, Beacon is banking on a diverse pipeline to path their route to approval.

We were joined by both Dave Fellows, CEO at Beacon Therapeutics, and Nadia Waheed, Chief Medical Officer at Beacon Therapeutics to find out more.

What indications are you focusing on for gene therapy?
 

At the forefront of our clinical programs is AGTC-501 – a late-stage development candidate we’re using to treat X-linked retinitis pigmentosa (XLRP). XLRP is an inherited monogenic disorder that causes progressive vision loss in boys and young men, affecting approximately one in 40,000 young males. Since the condition is commonly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, AGTC-501 was designed to directly counteract this. Our drug expresses the full-length protein of the RPGR, thereby addressing the complement of photoreceptor damage caused by XLRP, including both rod and cone loss. 

We are also working on two additional preclinical programs. Our first preclinical asset is an intravitreally (IVT) delivered novel AAV based program for dry age-related macular degeneration (dry AMD). Approximately 200 million people worldwide are living with age-related macular degeneration (AMD), and this is expected to grow to 288 million by 2040. Dry AMD accounts for around 9 out of 10 cases. It is a leading cause of irreversible vision loss in people over 60 if left untreated. The second preclinical asset targets cone-rod dystrophy (CRD), which is caused by a null mutation in the Cadherin Related Family Member 1 (CDHR1) gene. This program was licensed from the laboratory of Robert MacLaren, Professor of Ophthalmology at the University of Oxford.

Many ophthalmic therapies require surgery to be delivered. XLRP is a rare disease with no current treatment or cure and the individuals suffering tend to be more tolerant of the necessary surgical procedure. However, with a more prevalent disease, such as dry AMD, a less invasive procedure is preferable. IVT delivery requires less clinician training and can be delivered in clinic rather than via surgery, making treatment more accessible to both patients and health care providers alike. 

These programs represent just the start of what we hope to achieve.

When it comes to commercialization of advanced therapies, what hurdles do you face?
 

A comprehensive clinical development strategy and program are essential in overcoming the demands of commercialization. We’re currently building a surgical training program and optimizing surgical procedures, while defining patient populations most likely to benefit from our therapies. 

The manufacturing of advanced therapies, like the adeno-associated virus (AAV) platform we use, can be more complicated than other pharmaceutical modalities. Accordingly, we invested in building our own manufacturing facility in Florida to transfer the knowledge and know-how we’ve gained during process development for delivering commercial products for patients. The facility will be split into two parts: a biotech accelerator featuring office space with wet and dry labs for product development by companies; and manufacturing space to make small batches of the companies’ products for use in clinical trials.

How challenging is it to develop ophthalmic gene therapies?

Ophthalmic treatments can make people feel squeamish, but diseases of the eye are actually a solid target for gene therapies – partly due to their potential for efficient delivery, as well as the lower risk of adverse immune responses. In fact, the reasons behind the rapid rise of gene therapy in this space is owed to three main characteristics. First, the eye is easily accessible for treatment via injections and surgical interventions. Second, an immune-privileged status means the eye can accommodate the antigenicity of a viral vector. And third, the tight blood-ocular barrier prevents other organs from unwanted contamination.