On this week’s episode of The CheckRare Brief, we discuss FDA's approval of Orzeyful (oveporexton) to treat patients with narcolepsy type 1, CAMP4’s first-in-human clinical trial for patients with SYNGAP1-related disorders, and BioMarin’s termination for their ENPP1 deficiency program following mixed results from their phase 3 clinical trial.

The US Food and Drug Administration (FDA) approved Takeda’s Orzeyful (oveporexton) for narcolepsy type 1 on August 5, 2026. The approval came nearly two months ahead of its September 30th PDUFA date. Oveporexton is an orexin receptor 2 agonist designed to directly target the pathway involved and the underlying biology of narcolepsy. This novel mechanism of action could dramatically change how patients with narcolepsy are managed, giving patients more choices. Plans to dispense the drug via specialty pharmacies following the DEA's review are underway.

CAMP4 is advancing CMP-002 into a first-in-human phase 1/2 trial for SYNGAP1-related disorder, a genetic condition that causes debilitating autistic-like behaviors, seizures, gastrointestinal problems, and intellectual disabilities. There are currently no treatments approved for this rare condition. CMP-002 is an antisense oligonucleotide that binds to regulatory RNA to increase activity of the SYNGAP1 gene and restore SYNGAP1 protein to normal levels.

This clinical trial is a good example of how the rare disease landscape has changed. Advances in genetic testing and the work of patient advocacy groups helped identify these patients and give a once unknown condition a name. Identifying a patient population is crucial to understanding the natural history of the disease, developing clinical trials, and ultimately attracting investment in treatments.

Finally, BioMarin has terminated the development of enzyme replacement therapy BMN 401 after their phase 3 trial in ENPP1 deficiency failed to meet one of its two co-primary endpoints. ENPP1 deficiency is a genetic disorder that results in a reduction of pyrophosphate, causing rickets or soft bones. While the trial showed the drug improving pyrophosphate levels, improvements in bone health, the clinically relevant measure required by the FDA, were not observed. This failed trial is very disheartening for the ENPP1 community, but will hopefully aid in providing the foundation for more robust clinical trials going forward.

Sources
FDA approves Orzeyful (oveporexton)
https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-full-range-narcolepsy-type-1-symptoms

SYNGAP 1 Clinical Trial To Begin
https://www.globenewswire.com/news-release/2026/07/27/3333378/0/en/camp4-therapeutics-secures-australian-regulatory-clearance-to-initiate-first-in-human-clinical-trial-of-cmp-002-in-patients-with-syngap1-related-disorder.html

EENP1 Clinical Program Terminated
https://www.prnewswire.com/news-releases/biomarin-reports-second-quarter-2026-financial-and-operating-results-302845167.html

2026 Orphan Drugs: PDUFA Dates and FDA Approvals
https://checkrare.com/2026-orphan-drugs-pdufa-dates-and-fda-approvals/

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On this week’s episode of The CheckRare Brief, we discuss FDA’s approval of Orzeyful (oveporexton) to treat patients with narcolepsy type 1, CAMP4’s first-in-human clinical trial for patients with SYNGAP1-related disorders, and BioMarin’s termination for their ENPP1 deficiency program following mixed results from their phase 3 clinical trial.

The US Food and Drug Administration (FDA) approved Takeda’s Orzeyful (oveporexton) for narcolepsy type 1 on August 5, 2026. The approval came nearly two months ahead of its September 30th PDUFA date. Oveporexton is an orexin receptor 2 agonist designed to directly target the pathway involved and the underlying biology of narcolepsy. This novel mechanism of action could dramatically change how patients with narcolepsy are managed, giving patients more choices. Plans to dispense the drug via specialty pharmacies following the DEA’s review are underway.

CAMP4 is advancing CMP-002 into a first-in-human phase 1/2 trial for SYNGAP1-related disorder, a genetic condition that causes debilitating autistic-like behaviors, seizures, gastrointestinal problems, and intellectual disabilities. There are currently no treatments approved for this rare condition. CMP-002 is an antisense oligonucleotide that binds to regulatory RNA to increase activity of the SYNGAP1 gene and restore SYNGAP1 protein to normal levels. 

This clinical trial is a good example of how the rare disease landscape has changed. Advances in genetic testing and the work of patient advocacy groups helped identify these patients and give a once unknown condition a name. Identifying a patient population is crucial to understanding the natural history of the disease, developing clinical trials, and ultimately attracting investment in treatments.
Finally, BioMarin has terminated the development of enzyme replacement therapy BMN 401 after their phase 3 trial in ENPP1 deficiency failed to meet one of its two co-primary endpoints. ENPP1 deficiency is a genetic disorder that results in a reduction of pyrophosphate, causing rickets or soft bones. While the trial showed the drug improving pyrophosphate levels, improvements in bone health, the clinically relevant measure required by the FDA, were not observed. This failed trial is very disheartening for the ENPP1 community, but will hopefully aid in providing the foundation for more robust clinical trials going forward.

Sources
FDA approves Orzeyful (oveporexton)
https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-full-range-narcolepsy-type-1-symptoms

SYNGAP 1 Clinical Trial To Begin
https://www.globenewswire.com/news-release/2026/07/27/3333378/0/en/camp4-therapeutics-secures-australian-regulatory-clearance-to-initiate-first-in-human-clinical-trial-of-cmp-002-in-patients-with-syngap1-related-disorder.html

EENP1 Clinical Program Terminated
https://www.prnewswire.com/news-releases/biomarin-reports-second-quarter-2026-financial-and-operating-results-302845167.html
2026 Orphan Drugs: PDUFA Dates and FDA Approvals
https://checkrare.com/2026-orphan-drugs-pdufa-dates-and-fda-approvals/


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Caterina Garone, PhD, MD, Associate Professor at the University of Bologna, describes the identification of TK2 deficiency and early signs and symptoms.

View the whole story at https://checkrare.com/safety-and-efficacy-of-kygevvi-in-thymidine-kinase-2-deficiency/

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Alexandra Miller, MD, PhD, Chief of Neuro-Oncology and Co-Director of the Brain and Spine Tumor Center at the Perlmutter Cancer Center at NYU Langone Health, discusses follow-up data on the safety and efficacy of safusidenib in patients with IDH-mutant gliomas.

Gliomas are the most common type of brain cancer in adults worldwide. IDH is a rare metabolic gene that causes tumor initiation in many gliomas and other cancers. IDH is necessary for the conversion of α-ketoglutarate (α-KG), however, when mutated, it reduces α-KG to oncometabolite D-2-hydroxyglutarate, causing elevated levels that can impact metabolism, cancer biology, and therapeutic sensitivity of gliomas. Approximately 2,500 patients in the U.S. are diagnosed with IDH-mutated Gliomas, of whom 95% of IDH1 mutations.

Recently, positive long-term follow-up data from the Phase 2 (J201) study of safusidenib in patients with chemotherapy- and radiotherapy-naïve grade 2 IDH1-mutant glioma were announced. Safusidenib is an investigational, oral, brain-penetrant, selective inhibitor of mutant IDH1.

The updated data includes 27 patients in Japan at a median of 38.8 months of follow-up. The centrally assessed confirmed overall response rate (ORR), per Response Assessment in Neuro-Oncology (RANO) for low grade gliomas (LGG) criteria, was 51.9%. Median progression-free survival (PFS) was not reached, and the 36-month PFS rate was 79.1%. Additionally, responses were durable, with only one patient who had previously responded experiencing subsequent disease progression. No new safety signals were identified.

Also announced were significant expansions of the clinical development program for safusidenib. Two new studies to evaluate safusidenib across the broader landscape of IDH1-mutant glioma will be initiated with the goal of evaluating safusidenib across the broader landscape of IDH1-mutant glioma and to provide an additional treatment option for patients whose cancer progresses after initial therapy and who wish to delay chemotherapy.

G307 (NCT07712757) is a phase 3, randomized, placebo-controlled study that will enroll approximately 140 patients with newly diagnosed grade 2 IDH1-mutant glioma who have not yet received chemotherapy or radiation. The study will be conducted at sites outside the US in regions where vorasidenib is not yet approved or accessible. The primary endpoint is PFS as assessed by blinded independent central review (BICR). Secondary endpoints include ORR, time to next intervention, duration of response, and time to response.

G209 (NCT07703436) is a phase 2, multicenter study that will enroll up to 40 patients in the US with grade 2 or 3 IDH1-mutant glioma who have experienced disease progression after treatment with vorasidenib and who remain in need of another option to delay radiation or chemotherapy. This study seeks to establish proof-of-concept for safusidenib in a setting of high unmet need. The primary endpoint is ORR by BICR, with a number of secondary endpoints, including tumor growth rate, an emerging way of assessing early anti-tumor activity.

CHAPTERS
Introduction 00:00
IDH-Mutant Gliomas Overview 00:42
Safusidenib Overview 1:46
Key Takeaways From the Data 3:04
Effect on Treatment Landscape 5:56
G209 and G307 Studies 7:43
Take Home Message 8:42

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Ajay K. Nooka, MD, MPH, FACP, Director of the Myeloma Program at the Emory University School of Medicine, discusses topline results from the MonumenTAL-6 clinical trial testing Tecvayli (teclistamab) in adults with relapsed/refractory multiple myeloma (RRMM).

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. Most patients with MM require multiple lines of therapy as patients are prone to the cancer relapsing and/or be refractory to initial therapies.

Recently, positive topline results from the three-arm investigational phase 3 MonumenTAL-6 clinical trial (NCT06208150) were presented. The study evaluated teclistamab plus Talvey (talquetamab) (Tec-Tal) or talquetamab plus pomalidomide (Tal-P) in adult patients with relapsed/refractory MM who received 1 to 4 prior lines of therapy, including an anti-CD38 antibody and lenalidomide.

Teclistamab is a first-in-class, bispecific T-cell engager antibody therapy designed to activate the immune system by binding to the CD3 receptor and the B-cell maturation antigen (BCMA) that are expressed on T-cells and multiple myeloma cells. The treatment first received accelerated approval from the US Food and Drug Administration (FDA) in October 2022. Talquetamab is a bispecific T-cell engaging antibody designed to bind to the CD3 receptor and G protein-coupled receptor class C group 5 member D (GPRC5D). The treatment first received accelerated approval from the U.S. FDA in August 2023.

In the MonumenTAL-6 study, both regimens met the primary endpoint of progression free survival (PFS), demonstrating statistically significant and clinically meaningful improvements versus standard of care. Risk of progression or death was reduced in the Tec-Tal arm by 89% and 73% in the Tal-P arm.

Additionally, the overall safety profiles for the Tec-Tal and Tal-P treatment arms were consistent with the known safety profiles of each monotherapy.

CHAPTERS
Introduction 00:00
MonumenTAL-6 Clinical Trial Key Results 1:07
Importance of Targeted Approach 6:05
Patients Most Likely to Benefit 7:06
How This Changes the Treatment Landscape 7:39
Treatment Toxicities 8:27

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Guy Young, MD, Director of the Hemostasis and Thrombosis Program at Children's Hospital Los Angeles, discusses an ATLAS-OLE subgroup analysis of fitusiran in patients with hemophilia.

Hemophilia is a rare bleeding disorder that slows the blood clotting process. People with this disorder experience prolonged bleeding following an injury or surgery. In severe cases, heavy bleeding occurs after minor trauma or in the absence of injury. Serious complications can result from bleeding into the joints, muscles, brain, or other internal organs. The major types of this disorder are hemophilia A and hemophilia B, caused by a deficiency of factor VIII and IX, respectively.

Fitusiran is the first antithrombin (AT)-lowering therapy approved by the FDA for the treatment of patients ages 12 years and older with hemophilia A and B, with or without factor VII or IX inhibitors. Fitusiran is a small interference RNA drug that inhibits antithrombin and promotes thrombin generation, restoring homeostasis and increasing blood clotting. It is administered subcutaneously with a 50mg dose.

A study presented at the 2026 International Society on Thrombosis and Haemostasis (ISTH) Congress aimed to assess the safety and efficacy of fitusiran AT-DR in a subgroup analysis by age group from the phase 3 open-label extension study ATLAS-OLE (NCT03754790).


A total of 286 males aged 12 years and older with severe hemophilia A and B, with and without inhibitors, received the AT-DR and were included in the safety analysis. The proportion of participants with any treatment-emergent (TEAEs) and serious adverse events were similar, irrespective of age. There were no treatment discontinuations due to TEAEs in the adolescent population. One of 60 adolescents, three of 266 adults and none of the three elderly participants experienced a thrombotic event. Additionally, no transaminase elevations greater than 3x ULN were reported in adolescents.


Efficacy analyses included 213 participants. Observed median annualized bleeding rate (ABR) were 3.7 in the adolescent population and 3.7 in both the adult and overall populations. A total of 40% of adolescents had no bleeds compared to 28.9% of adults. ABR and number of bleeds were significantly lower in the elderly population. However, it is noted that the sample size remains too small to support definitive conclusions.

CHAPTERS
Introduction 00:00
ATLAS-OLE Results 00:19
Fitusiran as a Long-Term Treatment Option 3:39
Addressing Gallbladder Issues 6:20
Hemophilia Indications 7:58

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Caterina Garone, PhD, MD, Associate Professor at the University of Bologna, discusses the summary of safety and efficacy data on Kygevvi (doxecitine and doxribtimine) in patients with thymidine kinase 2 deficiency (TK2d).

TK2d is a rare genetic disease characterized by progressive and severe muscle weakness. It is often fatal. Patients who develop symptoms before the age of 12 years tend to show rapid disease progression and are at high risk of premature death. Other common symptoms include breathing difficulties, weakness in the eye muscles, and trouble chewing and swallowing. TK2d is caused by genetic mutations in the TK2 gene.

Kygevvi is a combination of two pyrimidine nucleosides, doxecitine and doxribtimine, that target and restore mitochondrial DNA in the skeletal muscle. It is the first and only treatment, approved by the U.S. Food and Drug Administration (FDA) in November 2025, for patients with TK2d.

New data published in Brain Communications examines the safety and efficacy of Kygevvi in TK2d and highlights the progressive disease burden in untreated patients.

Safety and efficacy data were pooled from retrospective (NCT03701568, NCT05017818) and prospective (NCT03845712) studies and expanded access programs of patients treated with Kygevvi. Untreated patients were pooled from literature reviews and a retrospective chart review study (NCT05017818).

A total of 218 patients were included (104 treated; 114 untreated) and most patients had an age of symptom onset at or before 12 years. In the age-of-symptom-onset-12-years-or-earlier subgroup, restricted mean survival time was 29.2 years over the 30 years after symptom onset for treated patients and 14.4 years for untreated patients.

Loss of 1 or more acquired motor milestones was more frequent before treatment start than after. Substantially more patients regained 1 or more lost motor milestone after treatment start than before. Ventilatory and feeding support were used across all age-of-symptom-onset subgroups, but some patients reduced or discontinued support after starting treatment and fewer patients initiated support after treatment start than before.

Most treatment-emergent adverse events (AEs) did not lead to discontinuation. The most frequent AE was diarrhoea, which was generally mild or moderate and resolved with dose reduction. Serious AEs occurred in 56% of patients and 8% were considered to be drug related. In total, three patients experienced a fatal serious AE, which were not considered to be drug related.

CHAPTERS
Introduction 00:00
Thymidine Kinase 2 Deficiency Overview 1:48
Effect of Kygevvi on Survival 4:52
Importance of Early Diagnosis 7:02
Key Takeaways for Clinicians 9:01
Remaining Challenges 10:25

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Doug Kerr, MD, PhD, MBA, Chief Medical Officer of Dyne Therapeutics, discusses the initiation of the phase 3 FORZETTO trial of zeleciment rostudirsen (z-rostudirsen, also known as DYNE-251), in individuals with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.

DMD is a rare genetic, neuromuscular condition characterized by progressive muscle wasting. Symptoms of DMD include progressive weakness and atrophy of both skeletal and heart muscle. Early signs may include delayed ability to sit, stand, or walk and difficulties learning to speak. DMD is caused by genetic changes in the DMD gene.

Z-rostudirsen is an investigational therapeutic consisting of a phosphorodiamidate morpholino oligomer (PMO) conjugated to an antigen-binding fragment (Fab) that binds to the transferrin receptor 1 (TfR1). It is designed to enable the production of near full-length dystrophin in muscle and the central nervous system to provide functional improvement.

The design of the FORZETTO clinical trial was presented at the 2026 International Congress on Neuromuscular Diseases (ICNMD).

FORZETTO is a global, randomized, placebo-controlled, double-blind, confirmatory phase 3 trial designed to assess the efficacy, safety, and tolerability of z-rostudirsen administered intravenously to ambulatory male participants with DMD amenable to exon 51 skipping. The trial will enroll approximately 90 participants ages 4 to 18 years who will be randomized to receive 20 mg/kg of z-rostudirsen or placebo every four weeks. The first trial site is activated and open to enrollment.

The primary endpoint is the change from baseline to week 73 in rise from floor (RFF) velocity, or time to rise (TTR) velocity, a clinically meaningful measure of muscle strength and motor coordination. Secondary endpoints include changes from baseline in stride velocity 95th centile, North Star Ambulatory Assessment total score, 10-meter walk/run velocity, four-stair climb velocity and forced vital capacity percent predicted. Following the 72-week double-blind placebo-controlled treatment period, participants will be eligible to enroll in a 96-week open-label long-term extension.

CHAPTERS
Introduction 00:00
DMD Overview 00:16
The DMD Gene 1:18
Therapy Development 3:08
FDA Submission 5:05
Age Range Effectiveness 8:38
Extent of Treating Patients 11:08
What Physicians Should Know 13:26

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Priya Kishnani, MD, Professor and Chief of the Division of Medical Genetics at Duke University, discusses the GALILEO-3 clinical trial of FLT201 in adults with Gaucher disease type 1 (GD1).

GD1 is the most common form of Gaucher disease. It is caused by a deficiency of glucocerebrosidase (GBA), an important enzyme that breaks down a fatty chemical called glucocerebroside. Because the body cannot break down this chemical, fat-filled Gaucher cells build up in areas like the spleen, liver and bone marrow. Unlike type 2 and 3, GD1 does not usually involve the central nervous system. Symptoms of GD1 include enlarged spleen and liver, low blood cell counts, bleeding problems and bone disease. Gaucher disease is caused by changes in the GBA gene.

It was recently announced that the first patient has been dosed in the GALILEO-3 clinical trial (NCT07223944). This study is a phase 3 non-randomized, global, multicenter study evaluating the safety and efficacy of FLT201in adult patients with GD1 currently on stable standard-of-care therapies.

The study hopes to enroll approximately 45 adults with GD1 who have been stable on enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) for at least two years. Participants will receive a single intravenous infusion of FLT201 alongside a prophylactic immunosuppressive regimen.

The primary endpoint is the proportion of participants maintaining stable hemoglobin concentration at week 52. Secondary endpoints include safety and tolerability, stability of platelet counts, spleen and liver volumes, biomarker changes, bone marrow burden and mineral density changes, and patient-reported quality-of-life outcomes.

FLT201 is a proprietary, liver-tropic capsid and an engineered beta-glucocerebrosidase (GCase85), designed to deliver continuous, sustained enzyme exposure beyond what is achievable with ERT. This allows for a low vector genome dose, necessary for a favorable safety profile. FLT201 has both Orphan Drug and RMAT (regenerative medicine advanced therapy) designations from the FDA.

Clinical trial eligibility is as follows:

Key Inclusion Criteria:
Aged ≥18 years at time of screening.
Clinical diagnosis of Gaucher disease type 1
Stable hemoglobin concentration at baseline
Stable platelet count at baseline
Receiving ERT or SRT without interruption for at least 2 years

Key Exclusion Criteria:
Diagnosed or suspected Gaucher disease type 2 or type 3
Positive for AAVS3 neutralizing antibodies.
Abnormal lab values, conditions or diseases that would make the participant unsuitable for the study
Positive pregnancy test or lactating
History of hematopoietic stem cell transplant (HSCT)/bone marrow transplant or any solid organ transplant.
History of receiving any gene therapy or cell therapy.
History of total splenectomy. Note: Additional protocol defined Inclusion and Exclusion criteria apply

CHAPTERS
Introduction 00:00
Current Treatment Options 00:15
The Need for Better Options 1:51
FLT201 Overview 3:43
Lower Age Limit Criteria 5:17
GALILEO-3 Clinical Trial 5:37
Take Home Message 6:12

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