Paul Romness, CEO of OS Therapies, discusses the Plausible Mechanism Framework draft guidance and how it will affect the approval process of OST-HER2 LM for the treatment of osteosarcoma.

Osteosarcoma is the most common type of bone cancer, typically occurring in adolescence. Although osteosarcoma tends to occur in the larger bones, such as the shin, thigh, and upper arm, it can occur in any bone. A number of variants of osteosarcoma exist, including conventional types (osteoblastic, chondroblastic, and fibroblastic), telangiectatic, multifocal, parosteal, and periosteal. The exact cause of osteosarcoma is not known, however, at least one gene has been linked to increased risk.

The OST-HER2 LM vaccine is an immunotherapy that targets HER2-positive cancers such as osteosarcoma, breast, and esophageal cancer. It is designed to activate the immune system, triggering T cells to seek out and destroy cancer cells. The immunotherapy shows potential in preventing or eliminating recurrences of osteosarcoma, particularly through translational research and trials involving canines diagnosed with the disease. OST-HER2 LM is currently under review via the US Food and Drug Administration’s (FDA) Plausible Mechanism Framework.

The FDA’s Plausible Mechanism Framework:

The US FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research recently issued the Plausible Mechanism Framework draft guidance. The guidance is designed for sponsors seeking approval for targeted individualized therapies by generating substantial evidence of effectiveness and safety when randomized controlled trials are not feasible due to small patient populations. The goal is to remove barriers and exercise regulatory flexibility to encourage scientific advances and the delivery of more cures and meaningful treatments for patients suffering from rare diseases.

The guidance focuses on therapies that target a specific genetic, cellular or molecular abnormality and are designed to address the underlying cause of disease. Key criteria include:
Identifying the disease-causing abnormality.
Demonstrating the therapy targets the root cause or proximate biological pathway.
Relying on well-characterized natural history data in untreated patients.
Confirming successful target drugging or editing.
For traditional approval, therapies should demonstrate improvement in clinical outcomes, disease course, or biomarkers if they are established to predict clinical benefit.

OS Therapies has an upcoming Type B meeting with the FDA to discuss biomarker data and accelerated approval of OST-HER2 LM. Following that meeting, Mr. Romness noted that there are plans for a phase 3 global trial to start by September 2026. In addition to being involved in the Plausible Mechanism Framework, OST-HER2 LM has also received Orphan Drug, Fast Track, and Rare Pediatric Disease Designations.

CHAPTERS
Introduction 00:00
Osteosarcoma Overview 00:53
OST-HER2 LM Immunotherapy 3:09
FDA’s Plausible Mechanism Framework 4:19
Next Steps 6:44

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Merlin G. Butler, MD, Medical Geneticist and Professor, Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, and one of the pioneers in Prader–Willi syndrome research, discusses the clinical features of this very rare disease and the critical importance of early identification.

Prader–Willi syndrome was first reported in 1956, and deletions in chromosome 15 were first identified in the 1980s. Dr. Butler has been working on the genetics of Prader–Willi syndrome since that decade.

Dr. Butler said that Prader–Willi syndrome was the first example of a disorder caused by “genetic imprinting,” in which it matters whether genes are contributed by the mother or the father. In 70% of the cases of this disorder, the father’s contribution is missing from chromosome 15q13, and 25% of cases are the result of both copies of chromosome 15 being from the mother (referred to as “disomy”).

Babies born with this genetic anomaly have severe hypotonia, and they have no interest in sucking or feeding. They often have decreased muscle mass and energy. “These infants look like they have a major problem at birth,” stated Dr. Butler. They need to be tube-fed. Once a genetic cause is suspected, Prader-Willi syndrome is quickly diagnosed; it is a very rare disease that also has very unique features. Pediatricians may see only one of these patients every 10 years. Therefore, according to Dr. Butler, “it is the parents who oftentimes make the diagnosis, through what they have seen on the Internet, prompting genetic testing.”

Despite their problems with feeding in the neonatal period, infants with Prader–Willi syndrome will begin to gain an interest in feeding by around age 2 to 3 years. By age 6 years, they develop hyperphasia. “Once their appetite is turned on,” he said, “it is never off.” Uncontrolled, this results in obesity and life-threatening conditions, such as type 2 diabetes and stomach rupture.

Early identification is key, and determining the genetic subtype is extremely important to building a multidisciplinary care team. There are seven different genetic subtypes, which can impact outcomes and management. Typically, the care team will include the medical geneticist and genetic counselors, endocrinologists (to manage the use of growth hormone and diabetes-related treatment), dietitians to manage and monitor caloric intake, mental health experts to address behavioral issues and the risk of self-injury, gastroenterologists, and potentially even sleep medicine professionals. The specialists comprising the care team will change over the patient’s lifespan; occupational therapy and speech therapy may well be required as the patient ages.

The treatment of hyperphagia associated with Prader–Willi syndrome, the number 1 issue, is a particularly active area of research. The idea is to avoid the onset of obesity, which can lead to most of the comorbidities and complications.

CHAPTERS
Introduction 00:00
Prader-Willi Syndrome Overview 00:48
Diagnostic Odyssey 6:30
Multidisciplinary Approach to Management 8:42
Emerging Therapies and Research 10:21
Key Message for Clinicians 11:58
Advice for Newly Diagnosed Families 17:37

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Cem Akin, MD, PhD, Professor, Allergy and Immunology at the University of Michigan, discusses with CheckRare systemic mastocytosis, and the results of the phase 2 PIONEER study, which tested the tyrosine-kinase inhibitor avapritinib (Ayvakit) against placebo in symptomatic patients. These results were presented at the 2026 AAAAI meeting in February 2026.

Mastocytosis is an incurable, heterogeneous disorder that is classified into two forms: cutaneous mastocytosis (seen in children) and systemic mastocytosis (mainly seen in adults). The systemic form is associated with an acquired (not inherited) genetic variant called KIT D816V, which is found in stem cells of more than 95% of affected patients.

Less than 15% of patients with systemic mastocytosis have advanced disease; the rest have nonadvanced types. Advanced disease is associated with decreased life expectancy and survival, whereas the other forms are not. However, patients with the more-common indolent or smoldering forms present with chronic symptoms (e.g., skin lesions, gastrointestinal and neurocognitive symptoms, osteopenia/osteoporosis). These symptoms are most often managed with antihistamines, leukotriene inhibitors, and mast-cell stabilizers. Due to the heterogeneity of the disorder, symptom burden may be relatively low or great; it can truly affect patients’ quality of life, daily activities, social life, and personal relationships.

Dr. Akin described the phase 2 PIONEER study, a double-blind, placebo-controlled investigation to evaluate the safety and efficacy of a selective tyrosine-kinase inhibitor avapritinib, which targets the KIT mutation. PIONEER had three components: (1) a dose-finding investigation, which settled on 25 mg/day orally as the primary dose tested; (2) the 6-month, randomized, placebo-controlled trial in patients with symptoms that were inadequately controlled with other medications; and (3) a long-term (follow-up is ongoing, up to 5 yr), open-label extension trial, which included switching the patients who receive placebo previously to active treatment with avapritinib.

The randomized, controlled portion of PIONEER proved that the avapritinib was clinically effective, as shown by various primary and secondary endpoints, including clearance or clinical improvement in skin lesions, reduction in symptoms scores, lower mast-cell load, and improvements in other biologic markers of the disease. Dr. Akin pointed out that the extension portion of PIONEER showed that these benefits were durable for up to 5 years with continued use.

In terms of safety, no additional safety concerns were observed through the extended follow-up phase. Peripheral and periorbital dema was seen in about 10% of patients (not serious, and no patient discontinued as a result).

In the open-label extension, a group of patients were allowed to increase their dose to 50 mg/mg based on their symptom burden, mast-cell markers, and the perceived patient response to the medication. Patients with the higher dose continued to improve symptomatically, with no additional safety concerns (their follow-up was up to 1 yr at this point).

Dr. Akin said that the PIONEER study provided confidence that the mutation is in fact the main driver of the disease, and if we can suppress expression of the mutation, we can change the outcome of systemic mastocytosis. “When disease markers and symptoms improve, we expect the response to be durable,” he stated. “Avapritnab kills the stem cells carrying the mutation, and when therapy is stopped, we expect that the systemic mastocytosis symptoms and markers will return. It is important to make the point that this is a chronic therapy.” PIONEER provided the reassurance that avapritinib is safe and effective over the long term.

CHAPTERS
Introduction 00:00
Mastocytosis Overview 00:42
Burden of Disease 2:30
PIONEER Clinical Trial Design 3:37
Four-Year Follow-Up Data 5:13
Durability of Symptom Improvements 8:40
GI Symptoms, Bone Health, and Other Manifestations 9:31
Effect of Ayvakit on Underlying Disease 11:58
Selection of Patients 13:39
Unanswered Questions for Future Studies 17:12

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CheckRare conducted a joint interview with two key opinion leaders in spinal muscular atrophy (SMA), Kristin J. Krosschell, DPT, MA, Professor of Physical Therapy and Human Movement Sciences, Pediatrics and Nancy L. Kuntz, MD, Child Neurologist and Professor, Pediatrics (Neurology and Epilepsy), both at Ann and Robert H. Lurie Children's Hospital of Chicago & Northwestern Feinberg School of Medicine. Dr. Kuntz is also Medical Director of the Mazza Foundation Neuromuscular Disorders Program, the PPMD Duchenne Care Center and the MDA Care Center at the Children’s Hospital. In this interview, Drs. Krosschell and Kuntz describe how disease-modifying therapies have changed the landscape of SMA management, discuss their study on the impact of newborn screening and early treatment, and reflect on some of the challenges facing SMA patient care today.

Summary copy:
The ability of providers to diagnose, treat, and manage SMA is dramatically different than 10 years ago, said Dr. Kuntz. “Not only are some of these new treatments very effective in improving outcomes, but timing of their administration is critical.” In fact, those infants who receive a confirmed genetic diagnosis of SMA before symptoms are apparent, and who begin treatment have better outcomes than infants who only receive these new therapies after the emergence of symptoms. Newborn screening is extremely effective, identifying 95% to 97% of all infants with SMA.
Dr. Krosschell added that the objective of their latest study was to determine what difference early treatment meant to motor function development and progression. The investigation comprised 21 infants who received care at the Ann and Robert H. Lurie Children’s Hospital in Chicago. All were diagnosed at younger than 3 months of age. Among this study group were three infants who were diagnosed with SMA prenatally and received treatment within the first 3 weeks postdelivery.
Based on the results of the CHOP INTEND, TIMPSI, and WHO Motor Milestone surveys, all infants demonstrated gross motor function improvements, and their progression followed a normative development curve, but at a slightly lower level.
It appears that increasing access to genetic testing and reducing the time to obtain testing are very important variables in obtaining optimal outcomes in SMA. They acknowledge that if the fetus cannot be tested prior to delivery, testing within the first 2 weeks of delivery is crucial.
Now that prenatal diagnosis is possible, work is just beginning on whether any specific prenatal care may be additionally useful in these patients. Drs. Kuntz and Krosschel acknowledge that the individual treatments now available are not curative, but knowing whether a particular therapy would be appropriate upon delivery would be time-saving. For example, some mothers may have antibodies to the viral vector used in gene therapy, which may help better guide treatment choices for the baby.
Dr. Krosschel added that we now know it is beneficial to treat SMA as early as possible. “We need longer-term studies in real-world settings to identify where there may be treatment delays and gaps. We need to understand what slows down the process” of getting these SMA-confirmed patients into treatment.
Dr. Kuntz said that based on the research and presentations at the MDA meeting, “It’s an incredibly exciting time. It’s not the end of the journey, only the beginning.”




CHAPTERS
Introduction 00:00
Understanding the Current Landscape of SMA 1:12
Effects of Disease Modifying Treatments 2:35
Real World Data of Early Treated Infants 2:59
The Future of SMA Screening and Treatment 13:22
Take Home Message 19:32

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Geraldine Bliss, Co-Founder and President of CureSHANK, and Jenny Graham Beeson, Board Member for CureSHANK, discuss research in Phelan-McDermid syndrome (PMS) and the Start Genetic initiative.

PMS is a chromosome disorder caused by deletions at 22q13.3. The loss or the variation of the SHANK3 gene is likely responsible for many of the common features associated with PMS. Common symptoms include hypotonia, intellectual disability, developmental delays, and epilepsy. Differences in physical features may include long eyelashes, down slanting eyes, large ears, ears without normal folding, bulb-like tip of nose, pointed chin, large hands, and toenails that flake off as infants and then become hard and brittle as age. Unusual behaviors may include mouthing or chewing on non-food items, decreased perception of pain, and autistic-like behaviors such as flapping of hands and repetitive motions.

CureSHANK is a non-profit organization focused on finding a cure for PMS. It is currently involved in a variety of research studies focused on the development of novel therapies for PMS and getting them into clinical trials. Through collaboration with Neuren, the first patient was dosed in February 2026 in a phase 3 clinical trial of IGF-1 analog, NNZ-2591. As Ms. Bliss highlights, this marks the organization’s first phase 3 trial for PMS, helping to establish regulatory pathways for future treatments. Additionally, Jaguar Gene Therapy’s SHANK3 minigene replacement therapy has been officially dosed in five patients with no serious adverse events related to the therapy and early signs of improvement. The next step is a dose escalation study (NCT06662188).

CureSHANK is also working to facilitate natural history studies and the development of new biomarkers. Ms. Bliss explains this area of unmet need is caused by the diverse behavioral phenotypes of PMS that pose challenges in establishing outcome measures due to their subjectivity of improvement.

Genetic testing is also an area of focus for the organization, with their board members coming together to form Start Genetic. This initiative spreads awareness of genetic testing for a variety of genetic disorders through a Genetic Testing Action Day of July 25.

CHAPTERS
Introduction 00:00
PMS Overview 2:29
Current Management 5:09
Clinical Research 7:47
Next Steps 10:50
Genetic Testing 12:30
Take Home Message 14:52

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Amy Shapiro, MD, a pediatric hematologist and the Medical Director and CEO of the Indiana Hemophilia and Thrombosis Center in Indianapolis, provides CheckRare an overview on type 1 plasminogen deficiency (PLGD-1).

Plasminogen is a key enzyme that lyses fibrin throughout the body. When the body’s production of plasminogen is significantly impaired, the accumulation of fibrin causes ligneous growths in the eyes, airways, gastrointestinal tract, and in virtually any mucous membranous tissue.

The very rare, inherited genetic disorder PLGD-1 or plasminogen deficiency type 1, is characterized by the body’s inability to produce adequate quantities of plasminogen. Caused by a defect in the PLG gene, if one person is diagnosed, the other family members should be evaluated for this disorder as well.

If left untreated, PLGD-1 may result in severe complications, including vision loss/blindness, tooth loss with associated bone degradation, hearing impairment/loss, airway obstruction, and infertility. Furthermore, this disorder can present at birth with an immediate and severe manifestation—obstruction of the spinal fluid outflow tract, causing hydrocephalus (pressure build-up in the brain). Interestingly, Dr. Shapiro pointed out, patients with PLGD-1 do not experience excessive blood clotting, which might be expected in those unable to break up fibrin clots.

Most commonly, patients present in childhood (within 1 yr of age) with eye lesions, which can obscure the eye, irritate the cornea, and can cause vision loss. These lesions are often misdiagnosed as conjunctivitis. If the problem is resistant to treatment or if the ligneous growth, once removed, grows back, that is a key sign that PLDG-1 is the cause.

In patients with PLGD-1, the presentation can be quite variable, according to Dr. Shapiro, who has seen people with PLGD-1 who don’t present with symptoms until adulthood. As a result, diagnosis may take years because of an unusual presentation, and prognosis may be difficult to predict. At a prevalence of approximately 1.6 cases per 1 million population, most physicians are unfamiliar with PLGD-1.

Before 2021, management of these patients was focused on resolving each symptom or lesion. Patients who manifested hydrocephalus were given shunts to drain excess fluid, but these often became obstructed without adequate treatment. Systemic treatment was based on the infusion of fresh frozen plasma, which has low concentrations of plasminogen (thus requiring frequent infusions).

In 2021, a plasminogen concentrate, from human blood, was approved by the U.S. Food and Drug Administration. It rapidly increases plasminogen in blood. Today, many patients can be treated with home administration. Importantly, this agent treats all of the manifestations of PLGD-1 throughout the body.

The Plasminogen Deficiency Foundation is a valuable organization comprising people with affected family members or are patients themselves. It helps patients and care providers with disease education and support groups where they share experiences and network with others affected by this disorder.

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Amy Shapiro, MD, a pediatric hematologist and the Medical Director and CEO of the Indiana Hemophilia and Thrombosis Center in Indianapolis, provides CheckRare an overview on type 1 plasminogen deficiency (PLGD-1).

Plasminogen is a key enzyme that lyses fibrin throughout the body. When the body’s production of plasminogen is significantly impaired, the accumulation of fibrin causes ligneous growths in the eyes, airways, gastrointestinal tract, and in virtually any mucous membranous tissue.

The very rare, inherited genetic disorder PLGD-1 or plasminogen deficiency type 1, is characterized by the body’s inability to produce adequate quantities of plasminogen. Caused by a defect in the PLG gene, if one person is diagnosed, the other family members should be evaluated for this disorder as well.

If left untreated, PLGD-1 may result in severe complications, including vision loss/blindness, tooth loss with associated bone degradation, hearing impairment/loss, airway obstruction, and infertility. Furthermore, this disorder can present at birth with an immediate and severe manifestation—obstruction of the spinal fluid outflow tract, causing hydrocephalus (pressure build-up in the brain). Interestingly, Dr. Shapiro pointed out, patients with PLGD-1 do not experience excessive blood clotting, which might be expected in those unable to break up fibrin clots.

Most commonly, patients present in childhood (within 1 yr of age) with eye lesions, which can obscure the eye, irritate the cornea, and can cause vision loss. These lesions are often misdiagnosed as conjunctivitis. If the problem is resistant to treatment or if the ligneous growth, once removed, grows back, that is a key sign that PLDG-1 is the cause.

In patients with PLGD-1, the presentation can be quite variable, according to Dr. Shapiro, who has seen people with PLGD-1 who don’t present with symptoms until adulthood. As a result, diagnosis may take years because of an unusual presentation, and prognosis may be difficult to predict. At a prevalence of approximately 1.6 cases per 1 million population, most physicians are unfamiliar with PLGD-1.

Before 2021, management of these patients was focused on resolving each symptom or lesion. Patients who manifested hydrocephalus were given shunts to drain excess fluid, but these often became obstructed without adequate treatment. Systemic treatment was based on the infusion of fresh frozen plasma, which has low concentrations of plasminogen (thus requiring frequent infusions).

In 2021, a plasminogen concentrate, from human blood, was approved by the U.S. Food and Drug Administration. It rapidly increases plasminogen in blood. Today, many patients can be treated with home administration. Importantly, this agent treats all of the manifestations of PLGD-1 throughout the body.

The Plasminogen Deficiency Foundation is a valuable organization comprising people with affected family members or are patients themselves. It helps patients and care providers with disease education and support groups where they share experiences and network with others affected by this disorder.

0 0

Amy Shapiro, MD, a pediatric hematologist and the Medical Director and CEO of the Indiana Hemophilia and Thrombosis Center in Indianapolis, provides CheckRare an overview on type 1 plasminogen deficiency (PLGD-1).

Plasminogen is a key enzyme that lyses fibrin throughout the body. When the body’s production of plasminogen is significantly impaired, the accumulation of fibrin causes ligneous growths in the eyes, airways, gastrointestinal tract, and in virtually any mucous membranous tissue.

The very rare, inherited genetic disorder PLGD-1 or plasminogen deficiency type 1, is characterized by the body’s inability to produce adequate quantities of plasminogen. Caused by a defect in the PLG gene, if one person is diagnosed, the other family members should be evaluated for this disorder as well.

If left untreated, PLGD-1 may result in severe complications, including vision loss/blindness, tooth loss with associated bone degradation, hearing impairment/loss, airway obstruction, and infertility. Furthermore, this disorder can present at birth with an immediate and severe manifestation—obstruction of the spinal fluid outflow tract, causing hydrocephalus (pressure build-up in the brain). Interestingly, Dr. Shapiro pointed out, patients with PLGD-1 do not experience excessive blood clotting, which might be expected in those unable to break up fibrin clots.

Most commonly, patients present in childhood (within 1 yr of age) with eye lesions, which can obscure the eye, irritate the cornea, and can cause vision loss. These lesions are often misdiagnosed as conjunctivitis. If the problem is resistant to treatment or if the ligneous growth, once removed, grows back, that is a key sign that PLDG-1 is the cause.

In patients with PLGD-1, the presentation can be quite variable, according to Dr. Shapiro, who has seen people with PLGD-1 who don’t present with symptoms until adulthood. As a result, diagnosis may take years because of an unusual presentation, and prognosis may be difficult to predict. At a prevalence of approximately 1.6 cases per 1 million population, most physicians are unfamiliar with PLGD-1.

Before 2021, management of these patients was focused on resolving each symptom or lesion. Patients who manifested hydrocephalus were given shunts to drain excess fluid, but these often became obstructed without adequate treatment. Systemic treatment was based on the infusion of fresh frozen plasma, which has low concentrations of plasminogen (thus requiring frequent infusions).

In 2021, a plasminogen concentrate, from human blood, was approved by the U.S. Food and Drug Administration. It rapidly increases plasminogen in blood. Today, many patients can be treated with home administration. Importantly, this agent treats all of the manifestations of PLGD-1 throughout the body.

The Plasminogen Deficiency Foundation is a valuable organization comprising people with affected family members or are patients themselves. It helps patients and care providers with disease education and support groups where they share experiences and network with others affected by this disorder.

0 0

Amy Shapiro, MD, a pediatric hematologist and the Medical Director and CEO of the Indiana Hemophilia and Thrombosis Center in Indianapolis, provides CheckRare an overview on type 1 plasminogen deficiency (PLGD-1).

Plasminogen is a key enzyme that lyses fibrin throughout the body. When the body’s production of plasminogen is significantly impaired, the accumulation of fibrin causes ligneous growths in the eyes, airways, gastrointestinal tract, and in virtually any mucous membranous tissue.

The very rare, inherited genetic disorder PLGD-1 or plasminogen deficiency type 1, is characterized by the body’s inability to produce adequate quantities of plasminogen. Caused by a defect in the PLG gene, if one person is diagnosed, the other family members should be evaluated for this disorder as well.

If left untreated, PLGD-1 may result in severe complications, including vision loss/blindness, tooth loss with associated bone degradation, hearing impairment/loss, airway obstruction, and infertility. Furthermore, this disorder can present at birth with an immediate and severe manifestation—obstruction of the spinal fluid outflow tract, causing hydrocephalus (pressure build-up in the brain). Interestingly, Dr. Shapiro pointed out, patients with PLGD-1 do not experience excessive blood clotting, which might be expected in those unable to break up fibrin clots.

Most commonly, patients present in childhood (within 1 yr of age) with eye lesions, which can obscure the eye, irritate the cornea, and can cause vision loss. These lesions are often misdiagnosed as conjunctivitis. If the problem is resistant to treatment or if the ligneous growth, once removed, grows back, that is a key sign that PLDG-1 is the cause.

In patients with PLGD-1, the presentation can be quite variable, according to Dr. Shapiro, who has seen people with PLGD-1 who don’t present with symptoms until adulthood. As a result, diagnosis may take years because of an unusual presentation, and prognosis may be difficult to predict. At a prevalence of approximately 1.6 cases per 1 million population, most physicians are unfamiliar with PLGD-1.

Before 2021, management of these patients was focused on resolving each symptom or lesion. Patients who manifested hydrocephalus were given shunts to drain excess fluid, but these often became obstructed without adequate treatment. Systemic treatment was based on the infusion of fresh frozen plasma, which has low concentrations of plasminogen (thus requiring frequent infusions).

In 2021, a plasminogen concentrate, from human blood, was approved by the U.S. Food and Drug Administration. It rapidly increases plasminogen in blood. Today, many patients can be treated with home administration. Importantly, this agent treats all of the manifestations of PLGD-1 throughout the body.

The Plasminogen Deficiency Foundation is a valuable organization comprising people with affected family members or are patients themselves. It helps patients and care providers with disease education and support groups where they share experiences and network with others affected by this disorder.

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