Chadi Nabhan, MD, Hematologist and Oncologist, Chief Medical Officer at Ryght AI, and Vivek Subbiah, MD, Professor of Medicine at Stanford University and Executive Medical Director of Novel Therapies & Clinical Trial Network at Stanford Health Care, discuss the need for better classification systems in precision oncology.

The 1983 Orphan Drug Act (ODA) defined rare diseases as those affecting fewer than 200,000 Americans, resulting in regulatory incentives that transformed drug development. Since then, oncology has accounted for 38% of all orphan designations and approvals sanctioned by the US Food and Drug Administration (FDA).

An editorial published in the Journal of Clinical Oncology seeks to address the implications this framework and definition have on modern precision oncology and its original intention to enable and advance progress. Drs. Nabhan and Subbiah propose in their thesis that every cancer is effectively a rare disease and should be recognized as such, fundamentally challenging how malignancies are classified, studied, regulated, and treated.

In oncology today, cancers are grouped by subtype, often depending on the specific gene mutations involved. Each of these subtypes have their own unique natural history, treatment responses, and outcomes. When defined at this level, nearly all cancers could be defined as a rare disease, thus requiring new systems of treating cancer.

While drug development often focuses on these rare populations, there is a disconnect in how these diseases are framed in clinical practice, health care delivery, and public discourse. This results in misaligned expectations in clinical trials, inadequate molecule biomarker testing, and misaligned investment incentives for pharmaceutical development.

One concern in labeling most or all cancers are rare is that could weaken the current framework that was designed to advance orphan drug development. Defining all diseases as rare because of their molecular subdivisions may render the term “rare” meaningless. Treating every cancer as rare could also overwhelm regulatory systems and orphan designation reviews could take years. Additionally, this classification would exacerbate already struggling health care delivery to stay current with genomic testing and targeted therapies. Finally, taking this mindset to its logical conclusion every patient can be labeled as having a rare disease based on their unique molecular profile, ultimately defeating the purpose of disease classification entirely.

To overcome these concerns, Drs. Nabhan and Subbiah propose a new way to define and classify rare cancers. They propose a Tiered Rarity Classification System (TRCS) which defines diseases as: Common (prevalence threshold of less than 50 per 100,000), Uncommon (10-50 per 100,000), Rare (less than 6 per 100,000 (US/EU), Ultra-Rare (less than 1 per 100,000), Exceptionally Rare (less than 0.1 per 100,000; Case reports/series level; molecular subsets), and Compounded Rarity (less than 0.1 per 100,000; Ultra-rare cancer plus ultra-rare biomarker).

However, it is stressed that the real solution is not formally reclassifying all cancers as rare diseases, but in building systems that effectively respond to molecular rarity, clinical trial design, regulation of therapies, and delivery of care.

CHAPTERS
Introduction 00:00
Should Every Cancer Be Considered Rare? 00:27
Clinical Trial and Regulatory Implications 6:22
Proposed Incentive Structure 9:42
Next Steps 17:50

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Andrew Kuykendall, MD, Clinical Researcher at Moffitt Cancer Center, discusses the role of rusfertide in decreasing phlebotomies in patients with polycythemia vera (PV).

PV is a condition characterized by an increased number of red blood cells. Affected people may also have excess white blood cells and platelets. The excess cell levels lead to thicker blood and increased risk for blood clots. PV occurs more frequently in men than it does in women. The condition has been associated with genetic changes in the JAK2 and TET2 genes.

Rusfertide is a first-in-class hepcidin mimetic peptide observed to reduce the need for phlebotomy and control hematocrit levels by regulating iron distribution and restricting iron availability for red blood cell production in patients with PV.

Dr. Kuykendall explains how phlebotomies have become so ingrained in the treatment of PV, that the burden it places on patients has not been adequately addressed. However, a recent focus on patient burden is bringing the impact of this treatment strategy to light. Frequent doctor’s office and hospital visits to get labs checked and then get phlebotomies every two to three weeks greatly limit patient’s freedom and autonomy.

While these phlebotomies may help the overproduction of red blood cells in these patients, they do not address the iron deficiency and consequent fatigue, brain fog, and other disabling symptoms that affect patient’s daily lives. Dr. Kuykendall explains how the development of rusfertide was based on mimicking a high-hepcidin state to increase iron levels, control hematocrit, and decrease the need for phlebotomy by reestablishing balance of iron regulation, thus improving fatigue and disease-related symptoms. Additionally, rusfertide may be added to patients on cytoreductive therapy doses that are higher than are comfortably tolerated, to help more optimally dose patients.

Unmet needs still exist for patients with PV, including the development of therapies that address the underlying JAK2 mutation that causes disease, as well as those that prevent progression.

Finally, Dr. Kuykendall highlights that rusfertide was developed by listening to patients and that it should be used in practice the same way, stressing the importance of focusing on how the disease affects them and how this treatment could fit into patients’ lives.

To learn more about PV and other rare hematologic conditions, visit https://checkrare.com/diseases/hematologic-disorders/

CHAPTERS
Introduction 00:00
Burden of Phlebotomies in PV 00:37
Patients’ Input in Developing Rusfertide 2:14
Unmet Needs in PV 4:49
Impact of Potential Rusfertide Approval 7:19
Take Home Message 9:39

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Logan Schneider, MD, Adjunct Clinical Associate Professor of Psychiatry and Behavioral Sciences at Stanford University, discusses treatment with Xywav (low sodium oxybate) in patients with narcolepsy and idiopathic hypersomnia.

Narcolepsy is a chronic neurological disorder characterized by an inability of the brain to control sleep-wake cycles. Patients with narcolepsy typically enter REM sleep more quickly, causing the boundaries between wakefulness and sleep to blur. This causes fragmented sleep at night as well as muscle weakness and dream activity while awake. Common symptoms include excessive daytime sleepiness, cataplexy, sleep paralysis, and hallucinations.

Idiopathic hypersomnia is a rare neurological sleep disorder characterized by chronic excessive daytime sleepiness. In addition to excessive daytime sleepiness, symptoms may include severe sleep inertia or sleep drunkenness (a core symptom of idiopathic hypersomnia), as well as prolonged, non-restorative nighttime sleep, cognitive impairment, and long and unrefreshing naps.

At SLEEP 2026, data was presented from a variety of studies evaluating Xywav oral solution in patients with narcolepsy and idiopathic hypersomnia. Xywav is a central nervous system depressant used to treat cataplexy and excessive daytime sleepiness in patients with sleep disorders. It was approved by the US Food and Drug Administration (FDA) in July 2020 for patients 7 years and older with narcolepsy and was expanded to treat adults with idiopathic hypersomnia in August 2021.

As Dr. Schneider explains, the main takeaway from the abstracts presented was the importance of 24-hour management in patients with sleep disorders, citing a study that observed the treatment’s ability to make patients sleep at night which benefitted patients daytime symptoms. He further stressed that focusing on one aspect of disease in these patients is not enough and more robust treatment plans are necessary.

Another analysis showed the ability of Xywav to enable individualized treatment regimens with flexible dosing. Through a post-hoc analysis, it was observed that incremental dose adjustments can yield once- or twice-nightly regimens that can be uniquely tailored to patients.

CHAPTERS
Introduction 00:00
Narcolepsy Landscape Overview 00:40
SLEEP 2026 Abstract Data 2:56
Patient Advocates in Study Design 7:53
Take Home Message 8:48

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Vlado Perkovic, MD, Professor of Medicine and Provost at the University of New South Wales Sydney, discusses results from the VISIONARY clinical trial testing Voyxact (sibeprenlimab) in patients with IgA nephropathy (IgAN).

IgAN is due to the accumulation of IgA protein in the kidneys. In the early stages, IgAN has no symptoms. The first sign of this condition may be blood in the urine. End-stage kidney disease may develop if the disease is not treated properly. In most instances, the cause of this condition is unknown; however, certain disorders have been linked with IgAN, such as cirrhosis of the liver, celiac disease, and HIV infection. The condition can also often be triggered by a viral illness.

Sibeprenlimab is a humanized monoclonal antibody that binds to and blocks A-PRoliferation-Inducing Ligand (APRIL), reducing levels of serum galactose-deficient IgA1 (Gd-IgA1). The therapy is a self-administered, subcutaneous injection dosed once every four weeks, and was granted accelerated approval by the US Food and Drug Administration (FDA) in November 2025.

Interim results from the phase 3 VISIONARY clinical trial were presented at the European Renal Association (ERA) Congress 2026. This study is ongoing and is evaluating the long-term safety and efficacy of sibepreblimab in preserving kidney function in patients with IgAN.

In the 152 patients treated with sibeprenlimab, an increase in the mean estimated glomerular filtration rate (eGFR) change from baseline of +0.7 mL/min/1.73 m² was observed, compared to a decline of -4.8 mL/min/1.73 m² in the placebo-treated arm. At 12 months, sibeprenlimab showed a mean eGFR change from baseline that meets the KDIGO treatment goal to reduce the annual kidney function decline to the normal physiological rate of less than 1 mL/min/1.73 m2/year. Additionally, the annualized slope of eGFR showed -3.0 mL/min/1.73 m²/year with sibeprenlimab compared to -7.6 mL/min/1.73 m²/year with placebo over 12 months.

Sibeprenlimab was well tolerated with a favorable safety profile in line with previously reported data. The most common adverse events were infections and injection site reactions.

Additional longer-term assessments are planned in the Phase 2/3 open-label extension study (NCT05248659).

CHAPTERS
Introduction 00:00
IgAN Overview 00:16
Shifts in Management 1:37
Autoimmune Component of Disease 2:38
VISIONARY Clinical Trial 4:28
Slowing Damage and Potential for Reversing 8:15
Safety of Sibeprenlimab 9:14

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Eunice S. Wang, MD, Chief of Leukemia at Roswell Park Comprehensive Cancer Center, discusses long-term results of ziftomenib in combination with venetoclax and azacitidine in patients with acute myeloid leukemia (AML).

AML is a cancer that affects the blood and bone marrow. The signs and symptoms of AML vary but may include easy bruising, bone pain or tenderness, fatigue, fever, frequent nosebleeds, bleeding from the gums, shortness of breath, and/or weight loss. There are many potential causes of AML such as certain blood disorders, inherited syndromes, environmental exposures, and drug exposures; however, most people who develop AML have no identifiable risk factor.

Long-term results from the phase 1/2 KOMET-007 clinical trial (NCT05735184) evaluating ziftomenib in combination with venetoclax and azacitidine (intensive chemotherapy), 7+3, in newly diagnosed NPM1-m or KMT2A-r AML were presented at the European Hematology Association 2026 Congress.

Ziftomenib is a once-daily, oral menin inhibitor approved by the US Food and Drug Administration (FDA) for adult patients with relapsed or refractory AML with a susceptible NPM1 mutation who have no effective alternative treatment options.

The data presented included 64 response-evaluable patients with R/R NPM1-m AML, 27 of whom were treated in phase 1a dose escalation and 37 of whom were treated in phase 1b expansion, as of the January 16, 2026 data cutoff date. Patients had received 1 to 8 prior lines of therapy, and 37 patients had prior venetoclax exposure.

Overall, nearly two-thirds of all patients experienced clinically meaningful, deep, and durable responses. Rapid responses were also observed, with a median time to composite complete
remission (CRc) of 3.9 weeks.

In the venetoclax-naïve population, a 70% CRc rate was observed with 75% central measurable residual disease (MRD) negativity. The objective response rate was 87% with a median duration of CRc response of 9.2 months. Median overall survival was not reached after median follow-up of 10.7 months.

In the venetoclax-experienced population, a 24% CRc rate was observed with 60% central MRD negativity. The objective response rate was 48% with a median duration of CRc response of 8.6 months. The median overall survival was 7.4 months after a median follow-up of 9.9 months.

Overall, the combination therapy was well tolerated, with a safety profile consistent with that reported for venetoclax and azacitidine alone. 3% of patients experienced differentiation syndrome that resolved with protocol-specified mitigation and there was one case of ziftomenib-related QTc. Median time to neutrophil and platelet recovery were similar to venetoclax-based regimens alone.

CHAPTERS
Introduction 00:00
Ziftomenib Combination Therapy Effects 1:48
Treatment in Patients With NPM1-m AML 3:46
Take Home Message 7:20
Addressing Needs Further 8:21

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Saad Usmani, MD, Hematologist-Oncologist at Memorial Sloan Kettering Cancer Center, discusses results from the CEPHEUS clinical trial of daratumumab combination therapy in patients with newly diagnosed multiple myeloma (MM).

MM is a rare blood cancer characterized by the expansion of malignant plasma cells in the bone marrow associated with excessive production of monoclonal immunoglobulins in blood and urine. Individuals with multiple myeloma develop significant osteolytic bone lesions and have immunodeficiency that compromise their longevity and quality of life. The exact underlying cause of disease is currently unknown.

Daratumumab is a monoclonal antibody targeting CD38, being investigated in combination with bortezomib, lenalidomide, and dexamethasone (VRd), an effective and well-tolerated therapy for patients with newly diagnosed MM.

The phase 3 CEPHEUS (NCT03652064) clinical trial established that daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) improved overall minimal residual disease (MRD)-negativity rates and progression-free survival compared to VRd in patients with transplant ineligible or transplant-deferred newly diagnosed MM.

At a median follow-up of 58.7 months, initial analysis of the DVRd transplant ineligible subpopulation showed a complete response or better rate of 80.6% and overall MRD-negativity rate of 60.4%. About 70% of patients were alive and progression free. This final analysis of the CEPHEUS transplant ineligible subpopulation describes a longer median follow-up of 76 months.

Of 395 patients enrolled, 289 with transplant ineligible newly diagnosed MM received either DVRd or VRd. The overall MRD-negativity rate at 10-5 was 61.1% for DVRd and 40.0% for VRd and at 10-6 was 46.5% for DVRd versus 27.6% for VRd. Sustained MRD-negativity rate at 10-5 was 49.3% for DVRd and 29.0% for VRd and at 10-6 was 37.5% for DVRd and 16.6% for VRd. Overall complete response or better rate was 80.6% for DVRd and 61.4% for VRd. Median investigator-assessed progression free survival was not estimable for DVRd and was 50.20 months for VRd, with 59.3% for DVRd versus 38.3% for VRd alive and progression free at 72 months.

Additionally, overall survival favored DVRd over VRd, particularly when censoring for COVID-19, which significantly impacted this study. The treatment effect was consistent across most subgroups.

For more information on MM and other rare cancers, visit https://checkrare.com/diseases/cancers/

CHAPTERS
Introduction 00:00
CEPHEUS Clinical Trial 00:21
Findings From the Final Analysis 1:18
Impact Compared to Standard Treatment 2:20
Notable Safety Findings 3:20
Take Home Message 4:01

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Fatima Scipione, Vice President of Global Patient Affairs at Blueprint Medicines, discusses the Colors of SM program.

Systemic mastocytosis (SM) is a rare disease usually caused by mutations of the KIT D816V gene. The disorder is characterized by uncontrolled mast cell proliferation and activation across multiple organ systems. Indolent SM accounts for approximately 90% of systemic mastocytosis. Common symptoms may include anaphylaxis, maculopapular rash, pruritis, diarrhea, brain fog, fatigue and bone pain. Most adults present with skin lesions, usually in the form of urticaria pigmentosa.

Colors of SM: Expressions of Life with Systemic Mastocytosis is a voluntary program dedicated to highlight the experiences of patients with SM. By partnering patients with artists who interpret a patients’ experiences into pieces of art, the initiative gives insights into what living with this rare disease really looks like. Artists and patients then showcase their work and experiences together at an annual art show.

Colors of SM was launched in partnership with Twist Out Cancer, a nonprofit organization that provides creative arts programs to people living with a variety of health conditions. The program aims to raise awareness about SM and the burden of disease on patients and foster an environment for change and advancement.

Ms. Scipione highlights how powerful it has been to see art communicate emotions, frustrations, resilience, and identity of these patients and how the program has provided visibility, connection, and understanding.

To learn more about SM and other rare autoimmune/anti-inflammatory conditions, visit https://checkrare.com/diseases/autoimmune-autoinflammatory-disorders/

CHAPTERS
Introduction 00:00
SM Overview 1:01
Colors of SM Program 3:29
Getting Involved 8:29

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Eric Lai, MD, Nephrologist at the West Coast Kidney Institute, discusses the importance of early diagnosis in IgA nephropathy (IgAN).

IgAN is a kidney disorder that occurs when IgA protein settles in the kidneys. In the early stages, IgAN has no symptoms. The first sign of this condition may be blood in the urine. End-stage kidney disease may develop. In most instances, the cause of this condition is unknown; however, certain disorders have been linked with IgAN, such as cirrhosis of the liver, celiac disease, and HIV infection. The condition can also often be triggered by a viral illness, such as a head cold or upper respiratory infection, that irritates the mucous membranes throughout the body.

Early diagnosis of IgAN is crucial for patients to receive proper treatment in efforts of preventing severe cirrhosis and end-stage kidney disease, often requiring kidney transplant. Dr. Lai explains that the easiest way to identify early signs of disease is through urine testing at a patient’s yearly physical. This test checks kidney function and signs of disease such as hematuria (blood in the urine) and proteinuria (protein in the urine). While this testing is mandated in other countries, physicians in the US are not required to perform this test.

The risk of progression in IgAN is dependent on the degree of proteinuria, making this marker the most important measure in gauging kidney prognosis and how well disease is being treated. Additionally, estimated glomerular filtration rate (eGFR) is also an important measurement in patients with IgAN.

Current treatment options consist mostly of symptom management. These may include angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, corticosteroids, and liver transplantation.

CHAPTERS
Introduction 00:00
IgAN Overview 00:15
Autoimmune Component 1:54
IgAN Triggers 3:44
Presentation of Disease 5:25
Risk Stratification 8:14
Importance of Urine Testing 14:40
What Physicians Should Know 15:56
Take Home Message 18:30

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Andrew Dauber, MD, Chief of Endocrinology at Children’s National Hospital, discusses results from a phase 3 study of Voxzogo (vosoritide) in children 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.

The CANOPY-HCH-3 (NCT06455059) clinical trial is a phase 3, double-blind, placebo-controlled, multicenter, open-label, long-term extension study evaluating the safety and efficacy of vosoritide in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide (CNP) analog approved by the US Food and Drug Administration (FDA) to promote linear bone growth in children with achondroplasia.

The trial met its primary endpoint, with vosoritide demonstrating a statistically significant increase in the change from baseline at week 52 in annualized growth velocity (AGV) compared to placebo. Treatment with vosoritide also showed a statistically significant increase in standing height and height Z-score versus placebo after one year of treatment. Additionally, significant improvements in arm span were observed.

The safety profile of vosoritide was consistent with the established profile in achondroplasia and no new safety signals were observed.

A supplemental New Drug Application (sNDA) submission to the FDA is planned for the third quarter of 2026.

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

CHAPTERS
Introduction 00:00
Hypochondroplasia Overview 00:24
CANOPY-HCH-3 Clinical Trial 2:07
Normal Growth Rates in Children 4:30
Approval in Achondroplasia 5:36
Potential Use in Other Indications 6:49

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