In this episode, we discuss Ultragenyx’s Priority Review Voucher that sold for $210 million, the efficacy of newborn screening on MLD, and ethical considerations needed to design and conduct clinical trials. 

This past week, Ultragenyx sold its Priority Review Voucher for $210 million.
The company received a PRV for the approval of their glycogen storage disease type Ia treatment, which was approved earlier this year.

As we have discussed on this podcast, the priority review voucher, or PRV, is an initiative the FDA introduced over a decade ago to encourage companies to develop therapies for pediatric conditions. And that program seems to be effective. 

We have followed several PRV transactions for years, and $210 million is toward the high end of the range, which has often been around $100 million to $150 million range. 

What's interesting is why these vouchers are so valuable. They allow a company to shorten the FDA review period from 10 months to 6 months. In a competitive market, getting a product approved four months sooner can be worth a tremendous amount of money.
For smaller biotech companies, selling a voucher can also provide meaningful capital to support broader development programs. So this is more than a regulatory story—it's also a story about how the economics of rare disease drug development work.

A recent publication looked at the efficacy of newborn screening to detect and treat metachromatic leukodystrophy, or MLD, in Europe. 

MLD is a rare neurodegenerative disorder. Children with the condition are born looking healthy but as toxins buildup and reach a threshold, cognitive, motor,  and behaviour abilities quickly decline. MLD does have a treatment available, but it is only indicated for patients who are diagnosed before that decline occurs. Which creates a bit of a catch-22; the baby looks healthy, so there is no reason to test them for this very rare condition. And once symptoms appear, it is too late to start treatment. Hence the need for newborn screening.

The study from Europe, shows that newborn screening dramatically changes the outcomes in these children. They found 7 babies with early onset MLD. All seven were treated and so far, their neurological functions are normal. That only happens if they get treated before symptoms appear. The treatment, developed by Orchard Therapeutics is an ex vivo gene therapy. And Orchard Therapeutics is working, along with several advocacy groups, to get MLD on NBS panels.

Identify patients that can benefit from treatment is a major challenge in rare disease. 
That's especially true for conditions like MLD, where treatment may be most effective before symptoms appear and irreversible neurological damage occurs.

Newborn screening can help close that gap by identifying affected babies before they become visibly ill. But getting a disease added to screening programs requires evidence, coordination, and time. The bigger lesson is that developing a treatment is only one part of the equation. We also need systems that identify patients early enough for that treatment to make a difference.

Another publication by the International Society of CNS Clinical Trials and Methodology (ISCTM) Orphan Diseases Working Group looked at ethical considerations needed to design and conduct clinical trials. 

This working group has its work cut out for it, but it's necessary. There are many ethical dilemmas for rare neurological diseases, especially those involving children.  

For example, we all want these trials to be placebo-controlled studies, but that can be difficult, or perceived to be unethical, if there is no standard treatment to act as the control group.  Other considerations, such as age and cognitive abilities, can also create ethical concerns that need to be addressed. 

Developing a therapy for an ultra-rare disease is already difficult because patient populations are small, recruitment is challenging, and the evidence base may be limited.

Companies also need a clear understanding of what constitutes an acceptable and scientifically meaningful clinical trial. Without that guidance, they face greater uncertainty about whether a study will generate evidence regulators can use to evaluate a treatment.

The goal isn't to lower the standards for evidence. It's to develop approaches that are both ethically sound and practical for these very small patient populations. That can help researchers generate meaningful results and give companies greater confidence to invest in diseases that might otherwise be overlooked.

References
Ultragenyx sells PRV for $210M
https://www.globenewswire.com/news-release/2026/10/07/3376457/20739/en/ultragenyx-enters-into-agreement-to-sell-rare-pediatric-disease-priority-review-voucher-for-210-million.html  

CheckRare’s Priority Review Voucher 
https://checkrare.com/priority-review-voucher/

Metachromatic leukodystrophy and newborn screening
https://link.springer.com/article/10.1186/s13023-026-04620-y 

Ethical considerat...

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In this episode, we discuss Ultragenyx’s Priority Review Voucher that sold for $210 million, the efficacy of newborn screening on MLD, and ethical considerations needed to design and conduct clinical trials.

This past week, Ultragenyx sold its PRV for $210 million.

The company received a PRV for the approval of their glycogen storage disease type Ia treatment, which was approved earlier this year.

As we have discussed on this podcast, the priority review voucher, or PRV, is an initiative the FDA introduced over a decade ago to encourage companies to develop therapies for pediatric conditions. And that program seems to be effective.

We have followed several PRV transactions for years, and $210 million is toward the high end of the range, which has often been around $100 million to $150 million range.

What's interesting is why these vouchers are so valuable. They allow a company to shorten the FDA review period from 10 months to 6 months. In a competitive market, getting a product approved four months sooner can be worth a tremendous amount of money.

For smaller biotech companies, selling a voucher can also provide meaningful capital to support broader development programs. So this is more than a regulatory story—it's also a story about how the economics of rare disease drug development work.

A recent publication looked at the efficacy of newborn screening to detect and treat metachromatic leukodystrophy, or MLD, in Europe.

MLD is a rare neurodegenerative disorder. Children with the condition are born looking healthy but as toxins buildup and reach a threshold, cognitive, motor, and behaviour abilities quickly decline. MLD does have a treatment available, but it is only indicated for patients who are diagnosed before that decline occurs. Which creates a bit of a catch-22; the baby looks healthy, so there is no reason to test them for this very rare condition. And once symptoms appear, it is too late to start treatment. Hence the need for newborn screening.

The study from Europe, shows that newborn screening dramatically changes the outcomes in these children. They found 7 babies with early onset MLD. All seven were treated and so far, their neurological functions are normal. That only happens if they get treated before symptoms appear. The treatment, developed by Orchard Therapeutics is an ex vivo gene therapy. And Orchard Therapeutics is working, along with several advocacy groups, to get MLD on NBS panels.

Identify patients that can benefit from treatment is a major challenge in rare disease.

That's especially true for conditions like MLD, where treatment may be most effective before symptoms appear and irreversible neurological damage occurs.

Newborn screening can help close that gap by identifying affected babies before they become visibly ill. But getting a disease added to screening programs requires evidence, coordination, and time. The bigger lesson is that developing a treatment is only one part of the equation. We also need systems that identify patients early enough for that treatment to make a difference.

Another publication by the International Society of CNS Clinical Trials and Methodology (ISCTM) Orphan Diseases Working Group looked at ethical considerations needed to design and conduct clinical trials.

This working group has its work cut out for it, but it's necessary. There are many ethical dilemmas for rare neurological diseases, especially those involving children.

For example, we all want these trials to be placebo-controlled studies, but that can be difficult, or perceived to be unethical, if there is no standard treatment to act as the control group. Other considerations, such as age and cognitive abilities, can also create ethical concerns that need to be addressed.

Developing a therapy for an ultra-rare disease is already difficult because patient populations are small, recruitment is challenging, and the evidence base may be limited.

Companies also need a clear understanding of what constitutes an acceptable and scientifically meaningful clinical trial. Without that guidance, they face greater uncertainty about whether a study will generate evidence regulators can use to evaluate a treatment.

The goal isn't to lower the standards for evidence. It's to develop approaches that are both ethically sound and practical for these very small patient populations. That can help researchers generate meaningful results and give companies greater confidence to invest in diseases that might otherwise be overlooked.

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Andrew Dauber, MD, MMsc, Chief of Endocrinology at Children’s National, discusses the efficacy of vosoritide to treat persons with hypochondroplasia.

Hypochondroplasia is a rare skeletal disease characterized by very short stature, similar to achondroplasia, but with milder features. People with hypochondroplasia usually have very short stature, large head, accentuated lordosis, short arms and legs, and broad, short hands and feet. Other features include a limited range of motion in the elbows, lordosis, and bowed legs. Uncommon symptoms may include learning difficulties and convulsions. Hypochondroplasia is often caused by genetic changes in the FGFR3 gene.

Vosoritide is a C-type natriuretic peptide analogue being investigated for the treatment of hypochondroplasia. It is currently approved for the treatment of achondroplasia.

In the phase 3, multicenter CANOPY-HCH-3 (NCT06455059) clinical trial, children with hypochondroplasia who were 3 to less than 18 years of age were randomly assigned to receive once-daily subcutaneous injections of vosoritide or placebo for 52 weeks per weight-band dosing regimen.

A total of 81 participants were randomly assigned to receive vosoritide or placebo. At week 52, the least squares mean (LSM) change from baseline in annualized growth velocity was 1.95 cm/year with vosoritide versus −0.39 cm/year with placebo. Dr. Dauber also explains that patients in the vosoritide group also showed an increase in arm span of more than a centimeter compared to the placebo group.

87.8% of participants in the vosoritide group and 72.5% of the placebo group experienced at least one adverse event. There were no reports of grade 3 or higher adverse events, adverse events leading to treatment discontinuation, or deaths.

For more information, visit The New England Journal of Medicine Evidence.

To learn more about hypochondroplasia and other rare musculoskeletal conditions, visit https://checkrare.com/diseases/musculoskeletal-diseases/

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Daniela Rogoff, MD, PhD, Chief Medical Officer, Skeletal Dysplasia of BridgeBio, discusses the efficacy of infigratinib to treat persons with achondroplasia.

Achondroplasia is a disorder of bone growth that prevents the changing of cartilage to bone, particularly in the long bones. It is characterized by dwarfism, limited range of motion at the elbows, macrocephaly, and small fingers. Achondroplasia can cause health complications such as apnea, obesity, recurrent ear infections, and lordosis. More serious problems include spinal stenosis and hydrocephalus. Some patients may have delayed motor development early on, but cognition is normal. Achondroplasia is caused by genetic changes in the FGFR3 gene.

Positive topline results from the PROPEL 3 clinical trial (NCT06164951) of oral infigratinib in children living with achondroplasia were recently announced. PROPEL 3 was a phase 3, global, one-year, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of infigratinib in children with achondroplasia, ages 3 to 18 years, with open growth plates.

Infigratinib is a selective, reversible, ATP-competitive tyrosine kinase inhibitor primarily targeting the fibroblast growth factor receptors FGFR1, FGFR2, and FGFR3.

Key results from the study through week 52 included a change from baseline in annualized height velocity (AHV) superior to placebo, with an LS mean treatment difference of +1.74 cm/year and a mean treatment difference of +2.10 cm/year. Absolute AHV at week 52 also showed a significant improvement with infigratinib compared to placebo. Change from baseline in height Z-score was superior to placebo, with an LS mean treatment difference of +0.32 standard deviations (SD) and the LS mean change from baseline on the treatment arm of +0.41 SD.

In an exploratory analysis of children younger than 8, oral infigratinib showed statistical significance against placebo in change from baseline in upper-to-lower body proportionality at week 52, demonstrating an LS mean decrease of -0.05 against placebo. In the overall population, infigratinib achieved an LS mean decrease of -0.05, with a favorable LS treatment difference of -0.02 versus placebo at week 52.

Infigratinib was well-tolerated, with no discontinuations and no serious adverse events related to the study drug.

Based on these results, plans for submission of a New Drug Application (NDA) and Marketing Authorization Application (MAA) for infigratinib are underway. BridgeBio is currently enrolling participants in the observational run-in for the phase 3 trial and has an ongoing clinical trial of infigratinib for the newborn to 3 year old age groups in achondroplasia in the PROPEL Infant & Toddler trial (NCT07169279).

For more information, visit https://www.globenewswire.com/news-release/2026/09/09/3358343/0/en/oral-infigratinib-shows-meaningful-benefits-beyond-growth-within-52-weeks-in-children-with-achondroplasia-in-the-phase-3-propel-3-trial.html

To learn more about achondroplasia and other rare musculoskeletal conditions, visit https://checkrare.com/diseases/musculoskeletal-diseases/

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Jane Salmon, MD, Professor of Medicine at Weill Cornell Medical College, discusses antiphospholipid syndrome (APS), its impact on pregnancy, and emerging research into Cimzia (certolizumab pegol) as a potential approach to preventing serious pregnancy complications.

APS is an autoimmune condition characterized by an increased risk of thrombosis and serious pregnancy complications (e.g., preeclampsia, placental insufficiency, growth restriction, intrauterine fetal death, and recurrent early miscarriages). Thrombosis may also cause severe, life-threatening complications such as stroke. Diagnosis involves testing for three types of antibodies: anti-cardiolipin, anti-beta 2 GP1, and the lupus anticoagulant, with the latter carrying the highest risk for thrombosis and pregnancy complications. Despite the significant burden of the condition, there are currently no FDA-approved therapies and patients are typically managed with low-dose aspirin and heparin.

The US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to certolizumab pegol for the prevention of placenta-mediated adverse pregnancy outcomes in pregnant women who have APS and are positive for lupus anticoagulant. Certolizumab pegol is a tumor necrosis factor (TNF) blocker currently indicated for a variety of autoimmune conditions.

Breakthrough Therapy Designation is granted to treatments intended to address serious or life-threatening conditions when preliminary clinical evidence indicates the therapy may demonstrate substantial improvement over available treatments on one or more clinically significant endpoints. The designation is designed to facilitate development and expedite the FDA review of promising new therapies. The designation for certolizumab pegol is supported by preliminary clinical evidence from the IMPACT clinical trial (NCT03152058).

The trial met its primary endpoint, reducing the adverse outcome rate to 20% in the study population, compared to a 44% historical adverse outcome rate. Furthermore, 95% of the women in the trial had live-born babies who survived to hospital discharge, marking a significant improvement over the 37% rate observed in the participants' previous pregnancies. Although the intervention did not completely eliminate adverse outcomes, it made them significantly less severe by allowing for later gestational ages at the time of delivery.

For more information, visit https://www.prnewswire.com/news-releases/ucb-receives-us-fda-breakthrough-therapy-designation-for-cimziacertolizumab-pegol-in-pregnant-women-with-antiphospholipid-syndrome-aps-302873706.html

To learn more about rare autoimmune conditions, visit https://checkrare.com/diseases/autoimmune-autoinflammatory-disorders/

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Kyle Loh, PhD, Associate Professor at Stanford Medicine, discusses research that could help scientists better understand spinal muscular atrophy (SMA) by generating new motor neurons from human hindbrain cells in the laboratory.

SMA is a genetic neuromuscular disorder characterized by the loss of motor neurons, causing progressive muscle weakness and loss of movement due to atrophy. SMA mainly affects the muscles involved in walking, sitting, arm movement, and head control. Breathing and swallowing may also become difficult as the disease progresses. SMA is caused by genetic mutations in the SMN1 gene. Extra copies of the nearby related gene, SMN2, modify the severity of SMA, with type 1 being the most severe and type 4 the least severe.

The study by Dr. Loh and his colleagues examined how different parts of the brain develop and use that knowledge to create new ways to generate new cells, including motor neurons. While the brain is often viewed as a single organ originating from one source, it is actually built from two distinct sources: one creating the forebrain/midbrain and another creating the hindbrain. As Dr. Loh explains, this distinction is critical for understanding the evolution of the brain and for developing human neurons in a laboratory setting.

Neurons in the hindbrain have received less attention than the well-studied spinal cord motor neurons. However, these hindbrain neurons are essential for life-sustaining functions, including eating, swallowing, speech, and facial movements. To study these neurons, specific genes that mark different progenitor cells were identified: OTX2 for forebrain/midbrain and GBX2 for the hindbrain. By directing stem cells toward these specific progenitor states, hindbrain motor neurons can be generated in a petri dish.

This study includes the creation of human induced pluripotent stem cell lines from patients with type 1 SMA to observe how the condition affects the growth of hindbrain motor neurons.

Dr. Loh is also interested in exploring the pathophysiology of SMA further. For example, the SMN1 gene is ubiquitously expressed in every cell in the body, its loss specifically impacts a small subset of motor neurons in patients with SMA. Further work is also needed to investigate why certain motor neurons, such as those innervating the diaphragm, appear resilient in patients with SMA while muscles nearby are impacted. Understanding this natural resilience could offer a new approach to therapy that moves beyond simply replacing the missing gene.

For more information, visit https://www.nature.com/articles/s41593-026-02433-7

To learn more about SMA and other rare neurological conditions, visit https://checkrare.com/diseases/neurology-nervous-system-diseases/

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Michael Benatar, MD, PhD, Department of Neurology and ALS Center, University of Miami Miller School of Medicine, discusses the use of plasma proteomics in predicting clinical manifestations of amyotrophic lateral sclerosis (ALS).

ALS is a rare motor neuron disease characterized by problems with muscle control and movement. Early symptoms may include muscle twitching, cramping, stiffness, or weakness, slurred speech, and/or difficulty chewing or swallowing. There are various types of ALS depending on symptoms, and sometimes, genetic cause. Most people with ALS have a sporadic form of ALS. It is believed that these cases are caused by an interaction between genetic and environmental factors. Familial ALS may be caused by genetic changes in any one of several genes and the pattern of inheritance varies depending on the gene involved.

A study published in Nature Medicine looked at longitudinal plasma proteomics to predict phenoconversion to clinically manifest ALS. The study was conducted in patients with pre-symptomatic ALS to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when, with the hopes of designing more effective disease prevention trials.

A total of 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers, and 59 controls were included. 92 proteins were then identified with concentrations that changed before phenoconversion and the longitudinal trajectory of these proteins was characterized. A core panel of 19 proteins was identified which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons and resulted in estimates of time to phenoconversion with a mean absolute error of 1.6 years.

These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (including NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion.

To learn more about ALS and other rare neurological conditions, visit https://checkrare.com/diseases/neurology-nervous-system-diseases/

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Keisha L. Gibson, MD, MPH, pediatric nephrologist at the UNC School of Medicine, discusses the approval of Gazyva (obinutuzumab) for patients with childhood-onset idiopathic nephrotic syndrome (INS).

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Keisha L. Gibson, MD, MPH, pediatric nephrologist at the UNC School of Medicine, discusses the approval of Gazyva (obinutuzumab) for patients with childhood-onset idiopathic nephrotic syndrome (INS).

INS is a rare, autoimmune kidney disease that is often managed by corticosteroids and/or mycophenolate mofetil. The disease and treatment however, is characterized by unpredictable relapses that cause fatigue, swelling, weight gain and increased susceptibility to infections and clotting. These flare-ups or relapses also lead to anxiety, depression and reduced self-esteem, brought on by the fear of relapse and social isolation. It is usually diagnosed in early childhood and is the most common form of primary glomerular disease in children.

Obinutuzumab is a humanized type II anti-CD20 monoclonal antibody that binds to the CD20 antigen, a proven target for CD20+ B cells. It is the first treatment option for INS to be approved in 70 years. It is currently indicated to reduce the risk of relapse in adult and pediatric patients 2 years of age and older with frequently relapsing or steroid dependent childhood-onset INS who are in complete remission.

The approval is based on results from the phase 3 INShore clinical trial (NCT05627557). More obinutuzumab-treated patients experienced no relapses after week 8 and were in complete remission at one year (95%) compared with mycophenolate mofetil (MMF) (73%). Analysis of key secondary endpoints showed statistically significant and clinically meaningful benefits with obinutuzumab with an increase in those with overall relapse-free survival, median time to first relapse or death, and fewer relapses from baseline to week 52, all compared with MMF. Additionally, no new safety signals were observed.

This approval is significant to patients and families living with INS because it provides an alternative treatment option to daily oral medications and the toxicities associated with chronic steroid use.

For more information on this approval, visit https://www.gene.com/media/statements/ps_092526 or https://checkrare.com/fda-approves-gazyva-obinutuzumab-for-treatment-of-childhood-onset-idiopathic-nephrotic-syndrome/

To learn more about INS and other rare kidney conditions, visit https://checkrare.com/diseases/kidney-and-urinary-diseases/

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