Moving emerging therapies through clinical trials and across the finish line is often challenging—and in some cases, harrowing. Many treatments never make it.
In early 2022, the future looked bleak for ProQR Therapeutics’ two RNA therapies in clinical trials. The biotech company reported that sepofarsen, its RNA therapy for LCA10 (IVS26 mutation in CEP290), did not meet its primary endpoint of improvement of at least three lines in best-corrected visual acuity or BCVA. (Improvement in BCVA was only on average two lines in the Phase 2/3 trial.) That news came despite vision improvements, some significant, for many patients. The endpoint misled ProQR to stop development of its ophthalmology assets—sepofarsen and ultevursen (exon 13 mutations in USH2A)—and attempt to find a company to acquire them.
Mike Schwartz, who was then vice president, global project leader, at ProQR, said, “That was devastating for me, the doctors, and the patients.” He noted that one patient with LCA10 in the trial with only light perception gained enough vision after receiving sepofarsen to see letters on an eye chart. Another LCA10 patient in the study returned to his work as a carpenter after treatment.
Fortunately, a year and a half later, the large European eye care company Théa acquired sepofarsen and ultevursen and formed the Sepul Bio business unit to move the therapies back into clinical trials. Many former ProQR staff went to Sepul Bio, including Mr. Schwartz, who is now their chief operating officer.
The global HYPERION Phase 3 clinical trial for sepofarsen and the LUNA Phase 2 trial for ultevursen are now underway. Using what was learned from the ProQR trials, the Sepul Bio team made significant changes to the designs (protocols) for the clinical trials, changes they believe will greatly improve chances for success. Mr. Schwartz thanked the Hope in Focus team for providing input from patients for the sepofarsen clinical development program.
One major change in the new sepofarsen clinical trial protocol has to do with the placebo. In most clinical trials with regulatory authorization, the treatment group is compared to a placebo or control group to ensure that efficacy is indeed a result of the treatment. In the original sepofarsen trial, treated eyes of LCA10 patients were compared to the eyes of untreated LCA10 patients (i.e., the control group). Comparing treated patients to untreated patients was less than ideal because of significant variations in vision loss among LCA10 patients. So, in the new trial, each LCA10 patient will have one eye injected with sepofarsen and the other will get a saline placebo injection. The patient won’t know which eye is getting the treatment. Sepul Bio believes comparing untreated and treated eyes for the same patient will lead to less variation and a stronger efficacy signal.
Keep in mind that sepofarsen injections are made into the vitreous, the soft gel in the middle of the eye. These intravitreal injections are performed routinely (e.g., monthly) and safely in doctors’ offices for treating age-related macular degeneration. In the sepofarsen clinical trial, patients will receive injections every six months.
Sepul Bio’s RNA therapies, known as antisense oligonucleotides (ASOs), are tiny pieces of genetic material that fix mutations in RNA—the genetic messages that cells read to make proteins critical to the cells’ health and function.
Stay tuned. We will report on updates from the trials as soon as we receive them.
For more information on the sepofarsen or ultevursen trials, send an email to: contact@sepulbio.com.
Gene therapy is unequivocally the most advanced approach for treating retinal diseases like Leber congenital amaurosis (LCA). Of course, there’s LUXTURNA® which is FDA-approved and has restored significant vision for people with LCA caused by RPE65 mutations. But several other emerging gene therapies are, or will soon be, in clinical trials. Excitingly, some are restoring vision early in human studies.
I had the honor and privilege of moderating an expert research panel at the 2025 Hope in Focus Conference last June in Minneapolis to discuss some of the exciting developments in LCA gene therapies. The three panelists were Kenji Fujita, MD, chief medical officer, at Atsena Therapeutics; Sarah Tuller, JD, chief regulatory officer at Opus Genetics; and Bikash Pattnaik, PhD, a professor at University of Wisconsin-Madison.
Atsena’s LCA1 Gene Therapy Moving into Phase 3
Dr. Fujita delivered the exciting news that Atsena’s LCA1 (GUCY2D) performed very impressively in a Phase 1/2 clinical trial. “We were super-thrilled with the results,” he said. “The gene therapy worked better than we expected.” Thanks to the excellent results, the gene therapy is moving into Phase 3 in a co-development partnership with Nippon Shinyaku which brought a few of their representatives to Minneapolis.
The Phase 1/2 trial enrolled nine adults in Part A (the dose escalation group) to evaluate initial safety and determine the optimal dose. An additional three adults and three pediatric patients were subsequently dosed. Patients receiving the highest dose (all were treated in one eye) had 100-fold improvement in retinal sensitivity, as measured by full-field sensitivity (FST). Some had10,000-fold improvement. Patients were also able to navigate a multi-luminance mobility test (MLMT) in dimmer light (two lux levels lower) after treatment. “This was a transformative difference, on par what we have seen with LUXTURNA,” said Dr. Fujita.
The Phase 3 clinical trial will enroll a larger group of patients and treat both eyes. Some patients will be in a deferred treatment group, serving initially as controls.
The Foundation Fighting Blindness, through its RD Fund, is an original investor in Atsena.
Opus Reports Vision Improvements in LCA5 Gene Therapy Clinical Trial
Opus Genetics, a company established by the Foundation Fighting Blindness in 2021, launched its first clinical trial in 2023 for an LCA5 gene therapy. LCA5 is a severe retinal degeneration diagnosed in a child’s first year. It is also very rare, affecting only about 200 patients in the US.
Opus reported excellent results for the first three patients (adults) in the trial with improvements in FST and virtual maze navigation. The company is now dosing pediatric patients and expects to report on them in the third quarter of 2025. “We are trying to move forward as aggressively as the FDA will allow,” said Ms. Tuller.
She acknowledged the great work of Dr. Tomas Aleman, the principal investigator on the trial, who was also at the meeting and had an engaging discussion with Sarah McCabe, one of the first patients to receive an RPE65 gene therapy.
A CRISPR Therapy is Emerging for LCA 16
Dr. Pattnaik reviewed his team’s emerging CRISPR gene editing approach for correcting the W53X mutation in the gene KCNJ13 which causes LCA16. He explained that the treatment works like molecular scissors to cut out the mutation.
Dr. Pattnaik is using lipid nanoparticles ⎯ which are like microbubbles ⎯ to deliver the treatment into retinal pigment epithelial (RPE) cells. Unlike most other genetic therapies which use engineered viruses to get genetic cargo into cells, nanoparticles have the advantage of being able to deliver therapeutic cargo of any size. Also, they are less likely to cause an immune reaction than viral systems.
Dr. Pattnaik tested the approach in cells and small animal models, and is now evaluating it in a large animal. He said the FDA is very positive about their current development plan.
The CRISPR therapy is currently funded through a grant from the National Institutes of Health (NIH) and was previously supported by the Foundation Fighting Blindness.
Dr. Pattnaik is also a co-founder of Hubble Therapeutics which is advancing a KCNJ13 gene augmentation therapy developed in his lab.
The development of diverse treatment approaches for Leber congenital amaurosis (LCA) is necessary because no single modality will work for everyone affected. While development of gene augmentation therapies (i.e., replacing mutated genes with healthy genes) has much momentum, other approaches also show promise as they move into and through clinical trials. Three of those emerging alternatives were discussed by a panel of experts at the Minneapolis meeting in June. The panel was moderated by Amy Laster, PhD, chief scientific officer, Foundation Fighting Blindness.
Optogenetics is a gene-independent approach for restoring some vision for people with advanced inherited retinal diseases (IRDs) who have lost most or all their photoreceptors (rods and cones), the retinal cells that make vision possible. Ray’s therapies deliver genes that express a light-sensing protein called channelrhodopsin to either bipolar or ganglion cells ⎯ cells that are normally not light sensitive but survive after photoreceptors are lost. In essence, the therapies enable bipolar or ganglion cells to work like a back-up system for photoreceptors. The therapies are delivered by a one-time injection into the vitreous, the soft gel in the middle of the eye. These non-invasive injections are performed thousands of times every day in retinal doctors’ offices for treatment of AMD and diabetic retinopathy.
While Ray’s clinical trials are at an early stage, Dr. Agrawal said early reports for safety and efficacy have been encouraging. Stay tuned.
Sepul Bio’s RNA Therapies for LCA10 and USH2A
In early 2022, the biotech company ProQR reported that sepofarsen, its RNA therapy for LCA10 (IVS26 mutation in CEP290), did not meet its primary endpoint in a Phase 2/3 clinical. That news came despite vision improvements, some significant, for many patients in the trial. The endpoint miss led ProQR to stop development of its ophthalmology assets ⎯ sepofarsen and ultevusen (exon 13 mutations in USH2A) ⎯ and find a company to acquire them.
Mike Schwartz, who was then vice president, global project leader, at ProQR, said, “That was devastating for me, the doctors, and the patients.” He noted that one patient with LCA10 in the trial with only light perception gained enough vision after receiving sepoafarsen to see letters on an eye chart. Another LCA10 patient in the study was able to return to his work as a carpenter after treatment.
Fortunately, a year and a half later, the large European eye care company Théa acquired sepofarsen and ultevursen and formed the Sepul Bio business unit to move the therapies back into clinical trials. Many former ProQR staff went to Sepul Bio including Dr. Schwartz who is now their chief operating officer.
A Phase 2 clinical trial for ultevursen is underway and a global Phase 3 trial for sepofarsen is imminent. Using what was learned from the ProQR trials, the Sepul Bio team made significant changes to designs for the forthcoming trials ⎯ changes they believe will greatly improve chances for success. Mr. Schwartz thanked the Hope in Focus team for providing input from patients for the sepofarsen clinical development program.
Sepul Bio’s RNA therapies, known as antisense oligonucleotides (ASOs), are tiny pieces of genetic material that fix mutations in RNA, the genetic messages that cells read to make protein that’s critical to the cells’ health and function. Both sepofarsen and ultevursen are delivered by intravitreal injections every six months.
The development of cell therapies for IRDs has been challenging for numerous reasons. Therapeutic cells haven’t been easy to source and enabling them to survive and integrate when transplanted into patients’ retinas has been difficult.
As a panelist for the session, I had the privilege of discussing a promising photoreceptor replacement therapy from BlueRock Therapeutics which came out of the lab of stem cell pioneer David Gamm, MD, PhD, University of Wisconsin-Madison. Excitingly, BlueRock’s therapy just moved into a clinical trial for people with RP and cone-rod dystrophy. Dr. Gamm said the cells might at some point be relevant to LCA patients.
The photoreceptor precursors used in the trial came from induced pluripotent stem cells (iPSC). The iPSC were derived from a small sample of mature blood or skin cells from a healthy donor. The cells were genetically tweaked to revert back to a stem cell state. The iPSC were then coaxed forward to develop into the photoreceptor precursors. As precursors, they aren’t fully mature. Dr. Gamm research showed that precursors have the best chance at survival and integration after transplantation.
BlueRock has the backing of two prominent companies: Bayer and Fuji Film. The Foundation Fighting Blindness funded Dr. Gamm’s previous iPSC-related lab research.
The BlueRock trial is moving forward methodically so that investigators can ensure safety for patients and best understand which patients and conditions can benefit most from the approach.
The development of gene therapies for inherited retinal diseases (IRDs) took off when young adults and children showed significant vision improvements in an early clinical trial for what would become LUXTURNAⓇ for LCA2 (RPE65 mutations). That was 2008. LUXTURNA became the first FDA-approved IRD gene therapy in 2017. Thanks to that success, dozens of gene therapy clinical trials are underway. Some target specific genes. Others are gene-agnostic, designed to preserve photoreceptors or harness non-light-sensing cells in the retina, an approach called optogenetics.
Cell-based therapies for IRDs have not advanced so quickly, with just a few clinical trials being launched. Gene therapies, which use human-engineered viruses to deliver the therapeutic gene, are not easy to develop or administer. But cell therapies, especially those for replacing lost photoreceptors, present additional challenges that have been difficult to overcome. These include determining the source and manufacturing of the cells, promoting their survival after transplantation, and enabling their integration into the host retina.
The launch of a Phase 1/2 clinical trial for OpCT-001, an emerging photoreceptor replacement therapy from BlueRock Therapeutics, is a big step forward for the IRD cell therapy field. The trial will initially enroll people with IRDs such as retinitis pigmentosa and cone-rod dystrophy. But the approach could also be relevant for forms of LCA that primarily affect photoreceptors.
OpCT-001 is comprised of photoreceptor progenitors—photoreceptors that haven’t fully matured. Researchers believe that progenitors have the best chance of integrating and surviving once they are transplanted and mature. The progenitors are developed from induced pluripotent stem cells (iPSC). To produce iPSCs, investigators take a small blood or skin sample from an adult human donor. The cells are then genetically tweaked to revert to a stem-cell-like state. As stem cells, they can be coaxed to develop into virtually any cell type in the body, including photoreceptors. Furthermore, billions of cells (many therapy doses) can be produced from the cell sample. The study will assess several dose levels of the therapy and is expected to enroll participants in sites across the U.S.
BlueRock Therapeutics is a wholly owned subsidiary of Bayer AG. The company licensed OpCT-001 from FUJIFILM and Opsis Therapeutics, a company co-founded by David Gamm, MD, PhD, a world-renowned retinal cell therapy pioneer at the University of Wisconsin-Madison. The Foundation Fighting Blindness provided significant funding over several years to Dr. Gamm and his team for the development of retinal and photoreceptor cell therapies derived from iPSC.
One should never get too excited about any emerging therapy in an early-stage clinical trial, especially for something as cutting-edge as a photoreceptor progenitor treatment. But if there is one scientist on the planet who can get photoreceptor replacement to work, it is Dr. Gamm.
In March 2024, the company announced vision improvements for the first three adult patients in its Phase 1/2 LCA5 gene therapy clinical trial. Some patients, who had been almost totally blind since birth, can now see and identify objects for the first time. The company has also reported positive safety data for the trial thus far.
Though LCA5 patients have severe vision loss at birth, they have some surviving retinal structure that researchers believe can be harnessed for improved vision using gene therapy.
Known as OPGx-001, the gene therapy uses a human-engineered adeno-associated virus (AAV) to deliver healthy copies of the LCA5 gene to patients’ retinas, augmenting the mutated copies that cause vision loss. The therapy is administered through a one-time injection underneath the retina. Researchers believe gene therapies will be effective for many years, perhaps for the patient’s lifetime.
Opus plans to administer the next highest dose of its LCA5 gene therapy to the next cohort of adult patients in mid-2024. The company also has plans to dose patients as young as 13 years old sometime in the future.
Courtney Coates, Hope in Focus’s Director of Outreach and Development, stated, “We are thrilled that patients in this trial are having early success with the low-dose treatment. We look forward to hearing more as the next cohort is enrolled for the mid-dose.”
The LCA5 gene therapy clinical trial is the first launched by Opus, a company founded in 2021 by the RD Fund, the venture arm of the Foundation Fighting Blindness, which is investing in companies near or in early-stage clinical trials for their retinal degenerative disease treatments.
In December 2023, ProQR sold its sepofarsen (LCA10) and ultevursen (USH2A) programs to Théa, a large European biotechnology company focused on ophthalmology. Théa, through its new dedicated business unit, Sepul Bio, will continue developing sepofarsen and ultevursen. I asked representatives at Sepul Bio a few questions about their emerging therapies, plans, and efforts. Here are their answers.
What are sepofarsen and ultevursen? Who developed these therapies, and how did they perform in clinical trials?
Sepofarsen is an experimental mRNA therapy designed to improve visual function for patients with Leber congenital amaurosis 10 (LCA10). Sepofarsen targets a specific genetic mutation (c.2991+1655A>G) in the CEP290 gene. This mutation stops the cell from producing an essential protein needed for the cells in the retina to function. By addressing this mutation with a piece of genetic material called an antisense oligonucleotide (AON), sepofarsen aims to restore cell function in the retina. The AON is delivered by an intravitreal injection. Sepofarsen is entering Phase 3 clinical development.
Ultevursen is an experimental mRNA therapy designed to stabilize visual function for patients with Usher syndrome type 2A or non-syndromic retinitis pigmentosa caused by mutations in exon 13 of the USH2A gene. These mutations stop the cell from producing usherin, an essential protein needed for the cells in the retina to function. By addressing this mutation with an AON, ultevursen aims to restore cell function in the retina. The AON is delivered by an intravitreal injection. Ultevursen is entering Phase 2 clinical development.
Both sepofarsen and ultevursen were first clinically developed at the biotechnology company ProQR Therapeutics, based in the Netherlands. Both emerging therapies improved vision in some patients participating in ProQR’s previous clinical trials.
What is Sepul Bio? What is its mission?
Sepul Bio is a dedicated business unit of Théa. The team is at the forefront of advancing transformative RNA therapies for inherited retinal diseases, particularly emphasizing the further development of sepofarsen and ultevursen.
Sepul Bio’s projects are driven by the vision of a future where patients with inherited eye diseases have treatment options for their eye condition. Through ongoing research and rigorous development, Sepul Bio hopes to bring new therapies to patients. Learn more at www.sepulbio.com.
As part of the divestment from ProQR, the dedicated team at Sepul Bio includes former members of the previous clinical development teams. This structure maintains consistency and brings previous experience with the programs to the new clinical development steps. The new business unit underlines Théa’s firm commitment to advancing therapeutic products for eye disorders, particularly where medical needs are unmet.
What are the lessons learned from the ProQR trials? What will Sepul Bio do differently to improve the two therapies’ chances of success?
The Sepul Bio team previously worked on the sepofarsen and ultevursen programs at ProQR. This experience has enabled the team to learn from previous regulatory and clinical interactions in formulating new plans for the programs.
All the previous learnings from the years of clinical development have been incorporated into the new designs, with further validation from key physicians and inherited retinal disease specialists. A key area of focus has been new tests and novel study designs that are more suited for developing therapies for rare retinal diseases.
Luxturna®, the only approved treatment for one of 27 identified forms of Leber congenital amaurosis (LCA), cost $500 million to develop and took more than 12 years to come to market.
With such an enormous investment in time and money, it would make sense to use that same platform for developing new treatments to improve vision or halt progression of blindness.
Every individual clinical study must complete a set of rigorous requirements – which cost time and money – to receive regulatory approval from the Food and Drug Administration (FDA).
Chad R. Jackson
The Foundation’s translational research program steps up the pace of preclinical studies toward clinical studies involving humans through proactive management and industry-level advice to drive research leading to prevention, treatment, and vision restoration for degenerative retinal diseases.
A Hope in Focus partner, the Foundation has raised nearly $900 million since its founding in 1971 and funds more than 90 programs worldwide, including no-cost genetic testing and the My Retina Tracker® patient registry. The Foundation also launched a Retinal Degeneration Fund (RD Fund) to help accelerate life-changing outcomes for people with retinal degenerations through direct mission-related investments in therapeutic companies.
Chad and other presenters shared information about drug development, gene therapies, and non-gene therapies during two sessions of the Hope in Focus 2023 LCA Family Conference* in Indianapolis this summer.
More than 100 people attended the forum to hear the latest in LCA research and to network with families living with LCA and other rare inherited retinal diseases (IRDs).
Bringing a drug from inception to market takes 10 to 15 years, Chad said, and costs tens and tens of millions of dollars. He said bringing a developing drug from preclinical studies to the FDA requires three steps:
Identify your target to know what you’re seeking to do; conduct invitro studies by expressing patient cells in a lab or as it’s referred to, retinas in a dish; and perform animal-model studies, which save time and money to determine whether emerging therapies are safe and perhaps ready to move toward clinical trials using humans.
Gene-Agnostic Therapies
Chad moderated a panel discussion about research moving beyond single-gene correction to gene-independent therapies to help delay progression of blindness or restore levels of vision.
Eric Daniels
Kiora Pharmaceuticals’ Chief Development Officer Eric J. Daniels, MD, MBA, discussed the company’s first-in-human study for a non-gene therapy treatment for retinitis pigmentosa (RP), a group of inherited eye diseases that cause progressive vision loss. It is characterized by the gradual death of light-sensitive photoreceptor cells in the retina, known as rods and cones, responsible for converting light into neutral signals sent to the brain.
Dr. Daniels said his company’s technology shifts retinal ganglion cells from their off state, in which they respond to decreases in light. Kiora has discovered a way to shift these cells into their on state in the presence of light through channeled photoswitch molecules.
According to Kiora, the mutation-agnostic treatment has the potential for use in any of the various genetic forms of RP, as well as other retinal degenerative diseases; its intravitreal injection allows for more consistent and tolerable administration, and the small molecule can be manufactured and provided to patients at a much lower expense than the $450,000 per eye cost of Luxturna.
Huma Qamar, MD, MPH, CMI, the head of Clinical Development and Medical Affairs for Ocugen, discussed the biotech’s work on treatments for LCA10 (CEP290), RP, and other IRDs. One of their clinical trials involves a novel gene therapy, OCU400, consisting of a functional copy of a nuclear hormone receptor gene delivered to target retinal cells using an adeno-associated viral (AAV) vector. Expression of this receptor within the retina may potentially help stabilize cells and rescue photoreceptor degeneration, Dr. Qamar said.
Huma Qamar
Ocugen demonstrated the potential of a novel modifier gene therapy to elicit broad-spectrum benefits in early and intermediate stages of RP and LCA, based on animal studies, showing the potential for a mutation-agnostic treatment.
Since the conference, Ocugen reported an update on its Phase 1/2 clinical trial for OCU400 for 12 patients who had follow-ups from six to 12 months after a subretinal injection in one eye. The developing drug had a favorable safety profile in this trial phase. Also eight of the 12 patients showed stabilization or improvement in the visual function measures of best corrected visual acuity, low-luminance visual activity, and navigating a multi-luminance mobility test.
The trial is currently enrolling patients, including pediatric patients with LCA10.
Gene Therapies
In the conference’s final session, moderated by Foundation Vice President of Science Communications Ben Shaberman, four panelists discussed their work on LCA gene therapies.
Shannon E. Boye
Shannon Boye, PhD, Co-Founder, Director, and Acting Chief Science Officer of Atsena Therapeutics, said the road to drug development is long and bumpy. She helped design early studies on LCA1 (GUCY2D) in 2001.
With the process going so slowly, Shannon reached out to then-Foundation CEO Ben Yerxa, who helped push her and her husband into starting their own company.
In 2019 doctors dosed the first patient. Earlier this year, in a Phase 1/2 clinical trial, their LCA1 gene therapy, known as ATSN-101, showed clinically meaningful improvements in vision at the highest dose with no drug-related serious adverse events at six months after treatment.
Ash JayagopalBen Yerxa
At Opus Genetics, Chief Scientific Officer Ash Jayagopal, PhD, discussed the biotech’s progress for various programs in, or advancing toward, early-stage clinical trials.
Opus, headed by CEO Ben Yerxa, PhD, is the first spin-out company internally conceived and launched by the Foundation’s RD Fund. The Fund’s purpose is to accelerate advancing research into gene therapy for several forms of LCA and other retinal degenerative diseases.
Opus’ most advanced program for LCA5 (lebercilin), OPGx-LCA5, is dosing patients, while two other LCA programs involving LCA13 (RDH12) and LCA9 (NMNAT1) are in preclinical development.
Thomas Mendel, MD, PhD, talked about his research at The Ohio State University, where he is Assistant Professor of Ophthalmology and Vitreoretinal Surgery at the university’s Havener Eye Institute, Department of Ophthalmology & Visual Sciences. He is building a research program to develop and implement gene therapies for Professor of Ophthalmology and Vitreoretinal patients with inherited retinal disease.
Bikash R. Pattnaik
Thomas Mendel
The goal is to build a translational lab with a team and accelerate development and clinical trials with gene-based treatments.
Bikash R. Pattnaik, PhD, told the audience about his work at the University of Wisconsin-Madison (UWM), where he is a professor and Clinical Director for Electrophysiology in the departments of Pediatrics, Ophthalmology, and Visual Sciences.
This summer, the National Institutes of Health awarded UWM a $29 million grant to develop gene-editing therapies for two inherited retinal conditions: LCA16 (KCNJ13) and Best disease. Bikash said the LCA16 treatment in development could be in clinical trials next year.
*Please go to our Hope in Focus website to see our previous three stories detailing sessions from our 2023 LCA Family Conference. Click here to see a video about the conference.
Through global data sharing and analysis, the nonprofit RARE-X (the research arm of Global Genes) is working to accelerate treatments for rare diseases, including Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs).
Hope in Focus featured Karmen Trzupek, RARE-X’s Senior Director of Scientific Programs, in its webinar episode “Let’s Chat About…RARE-X.’ Our Director of Outreach and Development Courtney Coates discussed with Karmen RARE-X’s mission and goals, and its recent merger with Global Genes. The March 7, 2023, session can be viewed here.
“Let’s Chat About…” is our free webinar series bringing together researchers, advocates, industry leaders, and people living with LCA and other rare IRDs for conversations important to the rare retinal disease community.
RARE-X and its founding
Nicole Boice founded Global Genes to support patients, families, and patient advocacy groups dedicated to rare diseases. At Global Genes, Nicole and others recognized a tremendous need to solve data collection and sharing problems for patient communities affected by rare diseases, and founded RARE-X to address those critical data issues
Rare disease patients’ data often is collected somewhere and sits privately in a silo where it is inaccessible to others. Or, the patient community actively manages the data in a format precious to a particular researcher, but unhelpful to others. Or, the data doesn’t exist, as is the case with many rare diseases.
RARE-X began addressing these issues through its data collection platform that enables rare disease communities to start gathering data in a highly structured and streamlined way that aligns with existing research philosophies.
“We work very hard at RARE-X to make sure that every single question asked of patients and families is a valid data point,” Karmen said. “Then we also share that data. With patient permission, all the data collected on the platform gets migrated to a data-analysis platform, and any qualified researcher can access that data.”
Collecting the data
“When someone first comes onto the RARE-X platform and starts entering data, it will ask them for their self-reported diagnosis. Do you have a genetic test? It asks about symptoms and the progression of those symptoms over time.
“We have people upload a copy of their genetic test results for the genetic testing data. Then we have a genetic curation team that reviews those, pulls out that data and makes sure that that data is in discrete data points. That’s useful to researchers because a researcher coming onto the platform does not want to pour through a whole bunch of PDFs and sometimes pictures from somebody’s phone of their test results, so we curate all of that data and make sure that that’s available on the research portal.”
Collaborations through RARE-X
Karmen develops programming and strategic collaborations to ensure the company makes the best use of the data that patients and families entrust to them.
In one program, she’s managing an “Open Science Data Challenge” with data from about 30 patient advocacy groups in the pediatric neurodevelopmental space, in collaboration with families of children with disorders causing seizures and global developmental delays.
“We are pulling the data and aligning it with other partner data, and then making it widely available to an extensive research community under a challenging environment, like a hackathon, to try to generate valuable insights and create research proposals for grants.”
Karmen also is looking at how RARE-X develops partnerships for additional data sources and uses of the data that circle back to benefit the patient community. Other groups on the platform include some adult-onset neurodegenerative disorders and some inherited retinal disorders.
“Usher syndrome, for example, that community is actively collecting data on the platform. And then other related inherited ocular conditions that aren’t retinal but share overlapping issues and needs, like Leber hereditary optic neuropathy, are collecting data.”
The company also plans to make digital optical coherence tomography (OCT) data available side-by-side with patient reported data.
“Those images are proprietary to the software and the hardware used. Multiple companies make OCTs, and we’re working with an artificial intelligence group that has developed ways to bring that data together and make it cross-comparative.”
RARE-X plans future LCA community data collection
“The platform has been live for about a year and a half, and we are very much building this plane as we fly it,” she said. “We’re working in the vision consortium to ensure that we’re adding the right kinds of surveys and patient-reported outcome measures to the platform that are most useful to this patient community.
“We’re continuing to talk with Hope in Focus and other groups within the LCA family of diseases. As soon as we start to have some more vision-specific surveys, we’ll begin collecting data pretty actively.”
From genetic counselor to RARE-X’s mission
Karmen’s career began as a genetic counselor in inherited retinal diseases. She worked at the Casey Eye Institute and then InformedDNA, where she developed ways to share the experience and information received by patients and families seen at a major academic research center with patients and families unable to physically get to a major center. Telemedicine and collaborations and partnerships with local retinal specialists accomplished much of that.
But she realized a much greater need overall for rare disease information sharing and for funding. Through the Usher Syndrome Coalition, Karmen met Nicole and Charlene, the RARE-X founders.
“I loved the mission and that they’re enabling even the smallest patient groups to start becoming very actively involved in clinical research,” she said.
“They are flipping that paradigm where a patient community doesn’t have to wait for a clinical trial or a natural history study for their data to be valuable. But flipping where the patient communities drive the research agenda and begin to say, ‘look, we have the data, and we have started to de-risk this disease as a disease that would be valuable to pharma to invest in.’ I love that paradigm shift. I love getting to be part of that.”
Merger benefits the rare disease community
“Coming together and joining Global Genes helps the entire journey of the patient advocate. If you think about a rare disease patient or parent, you start on your diagnostic journey searching for the diagnosis, right?
“You get that diagnosis, and maybe a patient foundation or community already exists. Maybe not, if it’s an ultra-rare disease. Those patients and families going through that have lots of needs. Those questions might include: Where do I go from here? How do I best support my child in the school system?
“The patient-advocacy journey is something that Global Genes, for a long time, has been very involved in. RARE-X has been developing this platform and developing partnerships to use this data, and now we can provide an extension of that patient advocate journey.
“So much of what both Global Genes and RARE-X have been doing is related to how we educate and support patient advocates in becoming more active participants in research and helping to drive that research agenda. I think there was a lot of overlap that was beginning to develop there. It made sense to merge.”
data from an ongoing natural history study as essentially a control arm.
“That brought up a lot of excitement and questions around patient-generated data because the patient community drove that natural history study. RARE-X and Global Genes have an opportunity to be part of this story and its evolution,” Karmen said.
“Now I am not suggesting that clinical data and traditional natural history studies will be replaced. There’s so much value in those studies, but we also know that they only ever capture a small percentage of the patient community who can travel.
“How can we make that kind of research more broadly available to a much larger population of patients and find something that’s a little bit more hybrid? That is a massive part of where I see us going in the next five years.”
The community of people living with Leber congenital amaurosis caused by mutations in the RDH12 gene moved closer to realizing the shared goal of establishing a clinical trial to find a treatment for the blinding disease.
More than 40 people gathered for the Second Global RDH12 Scientific Conference in Baltimore. The daylong meeting in November offered perspectives from clinicians, patients, parents, advocates, academia, regulators, and industry.
Silvia Cerolini, founder of Eyes on the Future, one of three organizations under the umbrella of the Global RDH12 Alliance, said the conference made tremendous progress toward a common goal: Designing a successful clinical trial to find a treatment to improve or stabilize vision in people living with RDH12. Current LCA13 RDH12 research is in preclinical stages, with the hope that the first clinical trials may start in 12 to 24 months.
Silvia Cerolini and her 9-year-old daughter, Vicky
As one woman living with RDH12 voiced during the conference: “Any quantity of vision is everything for us.”
This recent conference brought together an international group of scientific, medical, advocacy, and industry experts to identify and prioritize potential elements in designing a clinical trial and its key components: Outcome measures and endpoints.
Outcome measures are used to assess a patient’s vision. Performed at the start of a clinical trial, the measures provide baseline information that can be compared with the same outcome measures done after an intervention or treatment, determining progress and efficacy.
Participants in the Second Global RDH12 Scientific Conference
Endpoints are outcome measures selected as the most relevant and clinically meaningful measurements that can be measured objectively to determine whether the intervention being studied is beneficial.
Selecting the most appropriate and patient-relevant outcome measures as endpoints for each specific IRD is a big challenge for the entire field of inherited retinal dystrophies.
The heterogeneity (diverseness) of IRD phenotypes (characteristics) poses significant challenges to understanding disease pathology, predicting treatment benefit, and selecting outcome measures and endpoints for clinical trials. Challenges in recent clinical trials failing to demonstrate treatment efficacy show the need for innovation in trial design and outcome measures’ selection.
Organizers cited four key challenges unique to treating RDH12 mutations: (1) Severe impairment of retina/vision from early life; (2) Uncertain expectations of stabilization/preservation versus improvement/restoration of vision; (3) Heterogeneity of the RDH12 phenotypes (and IRDs in general); and (4) Slow expected pace of detectable changes after treatment.
Conference highlights included stories from people living with the disease and the constructive dialog among industry representatives, clinicians, scientists, and regulators, Coates said.
“Most significant were the RDH12 patients and parents sharing their experiences with progressive vision loss and their hopes for a treatment,” she said. “The day marked a meaningful step toward successful trials and, hopefully, will become a model as other gene-mutation studies progress to trials.”
For Maria Fiore, mother of 17-year-old Bella who lives with RDH12, the day brought hope.
“The input – from the academic side, opinions from the regulatory side, and the competitive nature of having multiple interests on the industry side – gives me a lot of hope that we’re getting closer to an RDH12 clinical trial,” said Fiore, a member of the Board of Directors for RDH12 Fund for Sight.
“We appear to be closer than ever, and events like the conference help to keep the motivation and drive to bring this to the finish line a real possibility.”
Bella and Vicky are part of the global RDH12 community that includes more than 200 families from 20 countries. Children and adults living with the rare inherited retinal disease hail from the United States, Europe, South America, China, India, and Russia.
The families communicate through Facebook and an email newsletter, with some local groups emerging to involve more people and remove language barriers.
The Global RDH12 Alliance organizes twice-yearly virtual community calls to review progress on clinical developments and discuss common challenges. Collectively, the three RDH12 organizations have raised more than $3.5 million since 2011 to advance research and find treatments.
Click here to see a video of people living with RDH12 introducing themselves.
Cerolini said it had been far from easy to wrestle all the participants down for one full day.
“But we came together as one big team to optimize the chances of trial success for our RDH12 community. There is still work to do to give Vicky and all our RDH12 community hope to see the world,” she said.
“It is not easy. But we are as close as ever to the first human clinical trials and we need to keep going. What we are learning about RDH12 can help the entire IRD field.”
The gathering watched a video of children and adults with RDH12 describing difficulties with sight loss and the hope that research will lead to a treatment.
Coates said people from several countries expressed their desires to have a chance to better their vision or at least maintain it.
“The heartfelt presentation reminded everyone in the room why we were there.”
Individuals and their families at the conference comprised a group of nine, sharing worldwide perspectives about trial design and outcome. They said they would accept stabilizing visual function as a “significant win” in the pursuit of a treatment.
Adult patients talked about the importance of keeping whatever light perception they have and shared stories of struggles in knowing where they are in their space, including the perils of bumping and bruising their foreheads when navigating spaces.
As one woman characterized the quest: “Any quantity of vision is everything for us.”
Their comments led to discussions with regulators and clinicians about the complexities of retinal function and the validity of certain endpoints and outcomes.
Clinicians and academics shared unpublished data on RDH12 natural history and thought-provoking perspectives from the latest IRD trials.
Tomas S. Aleman, MD, PhD, presented insight from an RDH12-associated IRD natural history study and the latest expectations for treatment. He talked about differences between the LCA13 RDH12 and LCA2 RPE65 mutations, and the structural and functional relationship in the RDH12 mutation that causes central vision loss resulting in blurring.
L-R: Debra A. Thompson, Jean Bennett, Maria Fiore, Allison Galloway, and Tomas S. Aleman
Despite functional and structural degradation of photoreceptors, he said, RDH12 gene therapy may have the potential to improve outcomes, even in adults, once certain toxins can be degraded.
Dr. Aleman is Professor of Ophthalmology and Director of the Hereditary Retinal Degeneration Clinics at the Scheie Eye Institute’s Perelman Center for Advanced Retinal and Ocular Therapeutics (CAROT) at the University of Pennsylvania.
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Jean Bennett, MD, PhD, discussed outcomes and endpoints from studying the RPE65 gene mutation while developing voretigene neparvovec, known as LUXTURNA®, and whether they can be translated to RDH12 clinical trials.
The U.S. Food & Drug Administration (FDA) in 2017 approved LUXTURNA to help improve vision for people living with RPE65. The therapy remains the first and only approved ocular gene therapy and the only gene therapy treatment for any inherited disease in the United States.
The breakthrough treatment developed at Children’s Hospital of Philadelphia (CHOP) and Spark Therapeutics in Cambridge began with the successful treatment of a special being, Lancelot, the first in a line of Briard herding dogs, who helped drive research to bring the gene therapy to market.
Dr. Bennett told the group the development of a novel patient-relevant endpoint – a multi-luminance mobility test (MLMT) to measure functional vision, or how a person navigates in a vision-related activity across a range of light levels in daily living – was instrumental in demonstrating how voretigene neparvovec could improve vision in RPE65 patients, leading to LUXTURNA’s approval.
The navigational test, though, can be cumbersome and time-consuming, given the elaborate setup with lighting controls, videotaping, analysis, and such. Alternatively, researchers are working on virtual-reality tests, created as time-savers with more versatility. The task would be to design a functional vision test using a virtual-reality obstacle course.
Drs. Bart P. Leroy, Jean Bennett, and Daniel C. Chung
Dr. Bennett is Professor of Ophthalmology at CAROT and the F.M. Kirby Emeritus Professor of Ophthalmology at the Perelman School of Medicine at UPenn.
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Dr. Robert E. MacLaren, Professor of Ophthalmology at the University of Oxford, discussed lessons drawn from recent IRD clinical trials and vector delivery. He is working on a trial assessing the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding genome particles.
LUXTURNA gene therapy employs a human-engineered AAV vector containing copies of a normal gene injected under the retina to express a protein necessary for vision.
Prof. MacLaren discussed opening the door to a new concept in the IRD space where researchers look for statistically significant improvements that show the vector is working and be more flexible in the immediate argument of whether that has a clinically significant improvement in that patient’s visual function, there and then.
Professor Bart P. Leroy, MD, PhD, discussed information learned from recent IRD clinical trials and gene therapies in clinical practice.
He co-authored the PERCEIVE study that analyzed the Year 2 interim research on LUXTURNA, concluding the drug demonstrated safety and effectiveness when used in clinical practice following its regulatory approval. The study also identified a new adverse drug reaction called chorioretinal atrophy, causing inflammation in some patients. So far, the reaction has not affected visual function and will be tracked as the study progresses.
He emphasized working toward shared goals and communicating with regulatory agencies on design and outcomes for IRD clinical trials. Saying children are not little adults, Dr. Leroy said questions about specific designs and patient-reported outcomes need to be adapted to the study population.
Dr. Leroy is Professor of Ophthalmology, Ophthalmic Genetics, and Visual Electrophysiology at Ghent University, and Head of the Ophthalmology Department at Ghent University Hospital, Ghent, Belgium.
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Adam M. Dubis, PhD, Associate Professor, University College of London Institute of Ophthalmology Global Business School for Health, and Advanced Human Retinal Imaging Specialist at Moorfields Eye Hospital, presented information on work planned around data-driven solutions for RDH12 clinical trial support.
Meira GTxCEO RobertK. Zeldin, MD, PhD, updated the group on the biotech’s RDH12 clinical development. The company is enrolling participants in the US, UK, and Europe for a natural history study and is planning a Phase 1/2 trial to assess safety and tolerability of potential gene therapy treatment.
Opus Genetics’ CEO Ben Yerxa, PhD, discussed capitalizing on key lessons in LUXTURNA’s development. Opus has three LCA-related projects in its pipeline, including one in early stages for RDH12. The company concentrates on preclinical projects in, or advancing toward, early-stage clinical trials to move research forward, with the goal of a successful trial or trials.
The FDA’s Dr. Wiley A. Chambers and the EMA’s Jane Moseley discussed trial-design parameters and outcome measures. They articulated their points of view, offering actionable advice on novel endpoints, including structural versus functional measures, virtual-reality mobility mazes, and patient-reported outcomes.
Todd A. Durham, Foundation Fighting Blindness Sr. VP of Clinical & Outcomes Research, talked about Patient-Reported Outcome Measures (PROMS), questionnaires designed to capture how a patient feels or functions, without input or interpretation from anyone else.
PROMS are developed using qualitative information, such as experiences, priorities, and contextual information from well-defined patient populations. Durham described ways the information could help advance research into treatments for people living with RDH12 and other IRDs, and he recommended steps toward creating a draft PROM strategy to begin conversations with regulators and payors.
Elin Haf Davies, PhD, CEO of Aparito, presented information on patient-centered clinical outcome assessments and the importance of quality of life for people living with rare diseases, such as RDH12.
Attendee Perspectives
The conference, chock-full of experts in myriad aspects of working to find a treatment for people living with RDH12, manifested hope and excitement toward its goal of launching clinical trials. Here are a few reflections from people in attendance:
Vicky, Silvia Cerolini’s daughter
“The level of engagement and willingness to share knowledge, experiences, and perspectives from this multi-stakeholder group was inspiring and motivating,” Astraea’s Sue Lacey said. “And I’m sure this will translate into increased momentum and robust clinical development programs for RDH12.”
From Prof. Bart P. Leroy: “A big thank you for organizing a day that took RDH12-IRD patients considerably closer to gene therapy. The maturity and respect during the day allowed for an open and fruitful discussion.”
Dr. Daniel C. Chung with SparingVision thanked organizers for putting together a great meeting and said, “The free exchange of thoughts and points of view was incredibly enriching. We look forward to continuing this conversation and developing concrete solutions for further development until one day a patient will have the option of a treatment.”
