RARECast

Hunter syndrome is caused by the body’s inability to produce a critical enzyme needed to break down cellular waste. The condition can cause damage to organs throughout the body as well as to the brain. A new generation of therapies in development, including a gene therapy currently under review by the U.S. Food and Drug Administration, that has the potential to address the neurological symptoms of the disease. Still, patient advocates have been frustrated by regulatory delays and are seeking to push the FDA and Congress to take action. We spoke with Kristin McKay, CEO of the Hunter syndrome patient advocacy organization Project Alive, about the need for new therapies, the importance of early detection, and the patient community’s concerns with regulatory delays in approving needed treatments. An editor’s note: Since recording this podcast, the FDA granted accelerated approval to Stealth Biotherapeutics’ Forzinity for Barth syndrome, which is referenced in the discussion.

Developmental and epileptic encephalopathies are a group of rare disorders that are characterized by frequent seizures that often don’t respond to existing medications. These are complex conditions that involve progressive cognitive and behavioral manifestations that can pose significant burdens on patients and their families. In both clinical practice and within the biopharmaceutical industry, there has been a tendency to focus on seizure control, while often overlooking the non-seizure burdens of developmental and epileptic encephalopathies. We spoke to Amelie Lothe, global medical community head for rare epilepsies at UCB, about the need to view these developmental and epileptic encephalopathies as complex neurodevelopmental conditions, the need to go beyond seizure frequency when it comes to clinical trial outcome measures, and what drug developers can do to improve their research focus to include broader patient and caregiver experiences.

Achondroplasia is the most common form of dwarfism. Beyond short stature, people living with achondroplasia can experience serious health complications, including compression of the brainstem and upper spinal cord due to impaired development of the skull. Tyra Biosciences is developing a next-generation medicine to precisely target FGFR3, an overactive growth factor that causes achondroplasia. We spoke to Todd Harris, CEO of Tyra Biosciences, about the company’s experimental once-daily, oral medicine for achondroplasia; what’s known about it from studies conducted to date, and why he believes it will offer competitive advantages over existing therapies.

Recurrent high-grade glioblastoma is a rare and aggressive brain tumor, which today is generally treated with surgery and chemotherapy. Outcomes are poor, with survival ranging from three to nine months and five-year survival rates less than 10 percent. Candel Therapeutics is developing viral immunotherapies that both kill tumor cells directly and enlist the patient’s own immune system in the fight against cancer. It’s experimental therapy CAN-3110 uses a modified herpes simplex virus that carries a viral gene that is designed to allow the virus to replicate in tumor cells while avoiding healthy cells. We spoke to Paul Peter Tak, president and CEO of Candel, about its viral immunotherapy, how it works, and what clinical studies have shown to date. 

While there has been enormous innovation in the treatment of cancer over the past two decades, much of this has been focused on adult cancers. Despite the advent of targeted therapies and immunotherapies, the treatment of childhood cancers relies largely on chemotherapy and radiation, both of which can create lifelong side effects in developing bodies. And cancer remains the leading cause of death by disease in children in the United States and the United Kingdom. C-Further, an international consortium created by LifeArc and Cancer Research Horizons, is working to advance innovative treatments for childhood cancers. It not only provides funding to discover and develop transformative therapies to treat childhood cancers but also leverages its network to help advance promising therapies. We spoke to David Jenkinson, head of childhood cancer translational challenge at LifeArc, about the approach C-Further is taking, the scientific and economic challenges of developing treatments for childhood cancers, and why new models for advancing these therapies are needed.

Avion was a healthy and athletic 15-year-old who became critically ill when he was admitted into a pediatric intensive care unit. For Robin Williams, assistant professor of pediatric hematology/oncology at the University of Minnesota Masonic Children's Hospital, Avion offered a medical puzzle she couldn’t crack on her own. His immune system was on overdrive and it was attacking healthy cells and organs within his body. Though testing ruled out blood cancers, it was only when Williams consulted a friend outside the hospital that she realized Avion was suffering from TAFRO, a subtype of the ultra-rare disorder idiopathic multicentric Castleman’s disease, a condition that has characteristics of both blood cancers and autoimmune disease. We spoke to Williams about the challenges physicians face in diagnosing patients with rare diseases, the thought process she went through in Avion’s case, and why she’s working to educate other physicians about the ultra-rare condition.

Recurrent respiratory papillomatosis is a potentially life-threatening disease of the upper and lower respiratory tract caused by chronic infection with human papillomavirus type 6 or type 11. In the absence of approved therapies, people with the condition often undergo repeated surgeries to clear their airways. The U.S. Food and Drug Administration in August approved Precigen’s Papzimeos, an immunotherapy that targets the underlying cause of the RRP, as the first approved therapy to treat the condition. We spoke to Kim McClellan, president of the Recurrent Respiratory Papillomatosis Foundation and Simon Best, associate professor of otolaryngology-head and new surgery at Johns Hopkins Medicine, about recurrent respiratory papillomatosis, the daily impact the condition can have on the lives of people with the disease, and what the approval of this therapy means for people living with the condition. 

Tris Dyson founded Challenge Works to incentivize innovators to solve societal problems. Dyson, who was diagnosed with amyotrophic lateral sclerosis, is now using the platform to find new treatments for the progressive neurodegenerative disease. The $10 million Challenge Works' Longitude Prize on ALS harnesses AI, open collaboration, and big data to find new treatments for the condition. We spoke to Dyson, managing director of Challenge Works, about his diagnosis of ALS, the case for using a prize to spur innovation, and the potential for leveraging AI to find treatments for the disease. 

When Daniel Fischer’s daughter Natasha was diagnosed with the rare genetic epilepsy, Dravet syndrome, his search for treatments eventually led him to tRNA therapies, an emerging area of genetic medicines that work to correct so-called nonsense mutations. Nonsense mutations prematurely cause the translation of a gene to stop before a protein is fully formed. What’s particularly compelling about the approach is that a single therapy has the potential to correct any nonsense mutation, regardless of the size of the gene or the gene in which the mutation occurs. We spoke to Fischer, CEO of Tevard, about his own journey as the parent of a child with a rare disease, how it led to his co-founding Tevard and its pursuit of tRNA therapies, and why this type of genetic medicine holds promise for so many people with rare diseases. 

Prader-Willi syndrome is a rare and complex genetic condition, the hallmark of which is hyperphagia, an intense and insatiable hunger. Hunger and appetite, though, are different things, particularly from a biological perspective. Aardvark Therapeutics is developing an experimental therapy to treat Prader-Willi syndrome by targeting hunger as opposed to appetite. We spoke to Tien Lee, CEO of Aardvark Therapeutics, about Prader-Willi syndrome, the company’s experimental therapy to treat the condition, and why it may have broader applications in other forms of obesity.

Rare disease advocates have long made the case that studying rare diseases can provide insights into more common ones. Actio Biosciences has turned that into a business model. The company is leveraging genetics and precision medicine to develop drugs for rare diseases in the hopes of expanding the indications for them to include more common disease that share underlying biology. We spoke to David Goldstein, founder and CEO of Actio Biosciences, about the company’s Rare Disease Target Atlas, how it identifies the indications it will pursue, and why pricing represents a challenge for such a business model.

When people with a rare disease accomplish a lot, someone might say they did so “despite their condition.” In the case of Khartik Uppalapati, it might be more appropriate to say “because of his conditions.” Uppalapati, a 16-year-old Virginia high school student, is a co-founder of the RareGen Youth Network, an organization designed to give voice to young people affected by rare diseases. He’s also an entrepreneur, scientific researcher, and international rights activist, all stemming from his experience as a someone with a rare disease. We spoke to Uppalapati about his journey as a rare disease patient, his work as an advocate, and why he thinks it essential that there be greater youth representation in healthcare policy and advocacy.

One of the challenges for developing gene therapies for inherited eye diseases is that a large number of individual mutations to a gene can drive the same disease. That makes conventional gene replacement therapy a difficult approach to treat a large number of patients. Ocugen is developing gene therapies that target master regulators of genetic networks and can work across different mutations. We spoke to Arun Upadhyay, chief scientific officer and head of research and development at Ocugen, about inherited retinal diseases, the company’s platform technology that can work across different genetic mutations, and its potential applications beyond the eye. One note before we begin. Since recording this podcast, Ocugen announced that Carisma Therapeutics and Ocugen’s subsidiary OrthoCellix, entered into a definitive merger agreement to create a Nasdaq-listed, late clinical stage regenerative cell therapy company focused on orthopedic diseases. That transaction is not discussed in this interview. 

Tepezza became an instant blockbuster when it hit the market as the first targeted therapy for thyroid eye disease, a rare autoimmune condition that causes eyes to bulge, vision problems, and can lead to long-term damage to the eyes. The success of Tepezza drove Amgen’s $27.8 billion acquisition of Horizon Therapeutics, announced at the end of 2022. Now, Viridian Therapeutics is developing veligrotug, a potential challenger to Tepezza. It’s betting that its demonstrated efficacy, greater dosing convenience, and data showing an ability to resolve double vision associated with thyroid eye disease will make it a fierce competitor. We spoke to Steve Mahoney, CEO of Viridian, about the complexities of thyroid eye disease, the challenges of living with the condition, and why veligrotug has the potential to provide a new alternative for people living with the condition.

When Ben Davies was born, he had difficulty breathing. He also suffered from recurrent infections. It took five years of being in and out of hospitals, and the persistence of his mother Traci Davies, who brought him to different doctors, before a physician diagnosed him with primary immunodeficiency. The rare condition leaves people with weakened immune systems. Years later, Traci herself would discover that she too suffered from the same rare condition. We spoke to Ben Davies and Traci Davies about their experiences with primary immunodeficiency, what it's like to be both a caregiver and patient, and why they have both become patient advocates. 

When Melanie Kandzierski took on the role of being mother to her granddaughter Rosie, she didn’t know how it would change her world. Rosie began experiencing seizures and she would eventually be diagnosed with a Dravet syndrome, a rare form of epilepsy that not only causes seizures, but developmental delays, motor issues, and behavioral challenges. Kadzierski discusses how she has learned to care for a child with Dravet syndrome, care for herself, and to advocate not only for Rosie but others with complex medical conditions.

One of the challenges of delivering gene therapies to the eye is that once a subretinal injection is made, the therapy’s distribution is confined to the margins of the pocket of fluid that is created, known as a bleb. Atsena, which is developing gene therapies for X-linked retinoschisis and Leber congenital amaurosis 1, uses its AAV.SPR technology that allows the gene therapy to spread laterally after injection. We spoke to Patrick Ritschel, CEO of Atsena Therapeutics, about the challenges of gene therapies for inherited retinal diseases, how the company’s unique vector technology addresses this, and how it allows for safer and more effective delivery of gene therapies to the retina. 

In a medical first, a team at Children’s Hospital of Philadelphia and Penn Medicine has successfully treated an infant diagnosed with a rare genetic disorder by using a customized CRISPR gene editing therapy. The work, led by Penn Medicine’s Kiran Musunuru and CHOP’s Rebecca Ahrens-Nicklas, points to the potential to use bespoke gene editing therapies to treat others with rare genetic diseases for which no available medicines exist. We spoke to P.J. Brooks, deputy director of the Office of Rare Disease Research at the National Institutes of Health’s National Center for Advancing Translational Sciences, about the breakthrough treatment, how the researchers were able to move from diagnosis to treatment with great speed, and what it would take to scale such an approach.

The Children’s Tumor Foundation has been effective in working with drug developers to advance new therapies for neurofibromatosis, a group of rare, genetic conditions that cause tumors to grow on nerves throughout the body. Part of its success has been its ability to get biopharmaceutical companies to reposition assets once in development for other conditions as potential treatments for neurofibromatosis. We spoke to Annette Bakker, CEO of the Children's Tumor Foundation, about the complexities of neurofibromatosis, the foundation's role in advancing research and drug development, and what other patient organizations can learn from its strategic approach. 

Epicrispr Biotechnologies is using CRISPR to modulate the expression of disease-causing genes without making cuts to DNA. Its lead program is in development to treat FSHD, a genetic disorder that causes progressive weakness in the muscles of the face, shoulders, and upper arms. We spoke to Amber Salzman, CEO of Epicrispr, about how its one-and-done therapies work to target the epigenome, the company’s lead program in FSHD, and the broader applications for its therapeutic approach.