Mike Flanagan, PhD, Chief Scientific Officer at Avidity Biosciences, discusses new data from the EXPLORE44 open-label extension of del-zota for treatment of patients with Duchenne muscular dystrophy (DMD) amenable to exon 44 skipping.

DMD affects the muscles, leading to progressive muscle wasting. DMD occurs primarily in males, though in rare cases may affect females. The 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.

Del-zota is a proprietary monoclonal antibody that binds to transferrin receptor 1 conjugated to a phosphorodiamidate morpholino oligomer (PMO) targeting exon 44, enabling dystrophin production. The EXPLORE44 clinical trial (NCT05670730) was a phase 1/2 evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of del-zota in 26 patients with DMD mutations amenable to exon 44 skipping. Participants then had the option to enroll in the EXPLORE44 open-label extension study.

The open-label extension (NCT06244082) was a multi-center trial evaluating the long-term safety, tolerability, pharmacokinetics, and pharmacodynamics, and efficacy of del-zota in 39 total patients with DMD amenable to exon 44 skipping.

Results with del-zota demonstrated statistically significant increases of about 25% of normal in dystrophin production and restored total dystrophin up to 58% of normal. Creatine kinase levels were also rapidly reduced by greater than 80% compared to baseline and were sustained at near normal levels throughout the duration of evaluation (up to 16 months). Half of the participants also had creatine kinase levels within the normal range at one year of treatment.

Additionally, patients in the open-label extension demonstrated improvements in four-stair climb by 2.1 seconds from baseline, 10-meter walk/run test by 0.7 seconds from baseline, time to rise from floor by 3.2 seconds from baseline, North Star Ambulatory Assessment remained stable, and performance of upper limb by 1.5 points from baseline. Compared to natural history data, these results were significant improvements.

Finally, del-zota continued to demonstrate favorable long-term safety and tolerability in this open-label extension. The majority of treatment emergent adverse events were mild or moderate and the most common were upper respiratory tract symptoms, diarrhea, fall, back pain, and headache. There was one discontinuation following an event of hypersensitivity.

Next steps involve plans for a Biologics License Application (BLA) submission for Accelerated Approval to the U.S. Food and Drug Administration (FDA) by the end of 2025.

Chapters:
Introduction 00:00
DMD Landscape Overview 00:28
Del-Zota Overview 2:12
Clinical Trial Data 2:57
Next Steps 6:05

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Clint Allen, MD, Senior Investigator, and Scott Norberg, DO, Associate Research Physician at Center for Cancer Research at the National Cancer Institute, discuss results from a study testing the safety and efficacy of zopapogene imadenovec to treat patients with recurrent respiratory papillomatosis (RRP).

RRP is a rare viral disease where tumors grow in the respiratory tract. The tumors can cause a hoarse voice, chronic cough, and difficulty breathing. These tumors rarely become cancerous, but can cause long-term airway and voice complications. RRP is caused by two types of human papillomaviruses (HPV), HPV 6 and HPV 11. There are currently no systemic treatments for this condition.

A recent study published in The Lancet Respiratory Medicine aimed to assess the safety and clinical activity of zopapogene imadenovec (PRGN 2012) in adult patients with RRP. Zopapogene imadenovec is a gorilla adenovirus vector-based gene therapy that targets robust T-cell immunity specific to HPV 6 or 11.

The study was a single-center, single-arm, phase 1/2 trial (NCT04724980) enrolling 38 patients who received a 12-week treatment course. The primary outcome measure was complete response rate, defined as the percentage of patients who did not require an intervention to control RRP in 12 months following treatment.

Of the 35 patients treated at the recommended phase 2 dose (5×1011 particle units), 51% demonstrated a complete response with the median duration of complete response yet to be reached. Complete responses were durable in 83% of those who achieved complete response, requiring no interventions in 12 months following treatment with a median follow up of 22 months.

Additionally, five patients had a partial response, defined as a 50% or greater reduction in clinically indicated interventions after treatment compared with before treatment. The objective response rate was 66%. Adverse events were mild and included grades 1-2 injection site reaction, fatigue, chills, and fever.

Based on these positive results, the U.S. Food and Drug Administration (FDA) approved zopapogene imadenovec in August 2025.

Chapters:
Introduction 00:00
RRP Overview 1:29
Pathophysiology and Natural History 2:46
Zopapogene Imadenovec Overview 4:28
Clinical Trial 6:15
Impact on Management 10:13

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Giselle Saulnier Sholler, MD, Division Chief for Pediatric Hematology/Oncology at Penn State University and Founder of the Beat Childhood Cancer Research Consortium, discusses the organization's work in neuroblastoma.

Neuroblastoma is a rare cancer that largely afflicts infants or children. It develops from neuroblasts in the sympathetic nervous system.The tumor most often develops in the adrenal gland, but may develop in the neck, chest, or spinal cord. In most cases, the tumor has metastasized by the time it is diagnosed. A neuroblastoma can cause a variety of signs and symptoms, including a lump where the tumor is growing, bone pain, diarrhea, and various neurological symptoms.

The Beat Childhood Cancer Research Consortium is a group of over 50 universities and children’s hospitals that provides a worldwide network of pediatric cancer clinical trials. Their mission is to continue the use of precision medicine and immunotherapy to bring forward new therapies for children with cancer with the goal of finding a cure for all patients.

The consortium consists of physicians, researchers, and parent advocates, who Dr. Sholler emphasizes as the most important contributor to the group’s mission. The group currently treat patients in the United States and Canada but plans are in place to reach the European and South American populations. By expanding their reach, the organization hopes to enroll and finalize clinical trials even quicker.

The consortium has led a few landmark studies over the past 15 years, including the development of difluoromethylornithine (DFMO) for high-risk neuroblastoma. DFMO specifically targets cancer stem cells left behind following treatment to prevent relapse, a main concern in patients with this condition. In a phase 2, single-arm trial, DFMO illustrated the ability to decrease relapse rates by over 50%. That study was instrumental in getting the drug approved by the U.S. Food and Drug Administration (FDA).

Additionally, the Beat Childhood Cancer Research Consortium is working to understand the specific biology of cancer in individual patients through the use of genomic sequencing. This method is being utilized with the goal of finding targeted, less toxic therapies that can be integrated into personalized treatment plans. A study done on this showed the ability to find effective treatment options in 70% of patients who otherwise have no treatment options left.

Currently, the consortium is currently enrolling eight clinical trials and more in the pipeline for next year. The group hopes to continue to move forward in precision medicine through the understanding of individual genomics and looking at using the immune system for specific targeting to reduce the toxicity of current treatment options.

Chapters:
Introduction 00:00
Beat Childhood Cancer Research Consortium 00:43
Importance of Clinical Trials 2:17
Landmark Studies 2:51
Treatment Landscape of Neuroblastoma 5:31
Importance of Collaboration 7:34
Current Clinical Trials 10:15
Future of Beat Childhood Cancer Research Consortium 10:30

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Araz Marachelian, MD, Pediatric Oncologist at Children’s Hospital Los Angeles, discusses the New Approaches to Neuroblastoma (NANT) Consortium and its work in neuroblastoma.

Neuroblastoma is a rare cancer that largely afflicts infants or children. It develops from neuroblasts in the sympathetic nervous system.The tumor most often develops in the adrenal gland, but may develop in the neck, chest, or spinal cord. In most cases, the tumor has metastasized by the time it is diagnosed. Neuroblastoma can cause a variety of signs and symptoms, including a lump where the tumor is growing, bone pain, diarrhea, and various neurological symptoms.

The NANT consortium is a network of universities and children’s hospitals with research and treatment programs focusing on neuroblastoma. It was established with the goal of providing collaboration opportunities for investigators developing novel therapies for high-risk neuroblastoma. The organization currently has two open, ongoing clinical trials with plans to initiate a few more in early 2026.

NANT has been involved in several landmark studies pioneering the dosing, safety, and feasibility for MIBG therapy. They have also been involved in laboratory trials of lorlatinib precision therapy that has since been led to pediatric patient trials with the Children’s Oncology Group. Dr. Marachelian highlights the impact of these collaborations and their necessity in accelerating access to innovation that provide hope for patients and families.

The neuroblastoma treatment landscape is constantly evolving and researchers are working to improve more targeted immunotherapies that will improve survival outcomes for patients. Dr. Marachelian explains how NANT’s expansion into Europe and other countries are aiding in the faster development of novel therapies and clinical trials.

Chapters:
Introduction 00:00
NANT Consortium 00:57
Landmark Studies 2:26
Treatment Landscape of Neuroblastoma 4:54
Impact of NANT Collaboration 6:28
Current Clinical Trials 11:41
Length of Clinical Trials 12:26
Advice for Newly Diagnosed Families 15:28
Future of NANT 17:07

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Jacky Smith, MB, ChB, FRCP, PhD, Chair of Respiratory Medicine at the University of Manchester, discusses topline results from the phase 2a RIVER trial for patients with refractory chronic cough (RCC).

Topline results and a responder analysis from the RIVER clinical trial were presented at the 2025 European Respiratory Society conference. This study was a phase 2a, double-blind, placebo-controlled, crossover study of nalbuphine ER versus placebo in patients with RCC. The trial enrolled 66 patients with RCC stratified by 24-hour cough frequency at screening (10-19 coughs per hour and 20 or more coughs per hour).

Patients were randomly assigned to 1 of 2 21-day treatment sequences: nalbuphine ER to placebo or placebo to nalbuphine ER, with a 21-day washout between treatment. Nalbuphine ER was titrated every 7 days from 27 mg twice daily to 108 mg twice daily. The primary endpoint was relative change from baseline in 24-hour objective cough frequency at day 21 in all patients measured by an objective digital cough monitor.

Results illustrated that at day 21, there was a 56% placebo-adjusted reduction in cough frequency with nalbuphine ER 108 mg. The responder analysis showed that 87% of patients achieved a 30% or greater reduction in 24-hour cough frequency with nalbuphine ER 108 mg at day 21, which is considered a clinically meaningful improvement. More than half of patients achieved a 75% reduction in cough frequency at day 21 with nalbuphine ER 108 mg twice daily.

No serious treatment-emergent adverse events were observed. 10 patients discontinued treatment due to treatment-emergent adverse events. The most common of these were constipation, nausea, somnolence, headache, dizziness, and fatigue.

Topline data: https://www.trevitherapeutics.com/wp-content/uploads/2025/09/Smith-et-al.-ERS-Congress-2025-RIVER-Primary.pdf

Responder analysis: https://www.trevitherapeutics.com/wp-content/uploads/2025/09/Smith-et-al.-ERS-Congress-2025-RIVER-Responder-Analysis.pdf


This drug is investigational and its safety and effectiveness have not been established by the FDA.

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Navin Pinto, MD, Professor of Pediatrics at the University of Colorado Anschutz Medical Campus and Colorado Children’s Hospital, discusses the Children’s Oncology Group and their work in neuroblastoma.

Neuroblastoma is a rare cancer that largely afflicts infants or children. It develops from neuroblasts in the sympathetic nervous system.The tumor most often develops in the adrenal gland, but may develop in the neck, chest, or spinal cord. In most cases, the tumor has metastasized by the time it is diagnosed. A neuroblastoma can cause a variety of signs and symptoms, including a lump where the tumor is growing, bone pain, diarrhea, and various neurological symptoms.

The Children’s Oncology Group (COG) was founded in 2000 and is the world’s largest organization dedicated to pediatric cancer research. As a member of the National Cancer Institute (NCI) National Clinical Trials Network, the group brings together over 12,000 experts across over 250 hospitals, universities, and cancer centers. Their mission is to cure and prevent pediatric cancer through scientific discovery and compassionate care. Today, the COG has over 100 active clinical trials.

Over the years, the COG has led a number of landmark studies. As an example, Dr. Pinto notes that the cure rates for acute lymphoblastic leukemia, the most common malignancy seen by pediatric oncologists, have been raised to over 95%. Within the neuroblastoma landscape, COG studies have led to the intensification and addition of immunotherapies that have improved outcomes. This includes being one of the first pediatric-only indications to be treated with a monoclonal antibody, dinutuximab.

Dr. Pinto also highlights the importance of collaboration in research and development for rare diseases. Through this network, clinical trials are developed quicker and more efficiently, allow access to more patients where populations are often small, and can lead to more standardized methods to treating diseases and advancing therapies.

The COG also works closely with the National Comprehensive Cancer Network (NCCN). Following the completion of trials and data readouts by the COG, that data is passed along to the NCCN, who develops recommendations for standard-of-care practices based on the data provided. This collaboration resulted in a rollout of guidelines for pediatric malignancies, such as neuroblastoma, earlier this year.

Over the past 25 years, the COG has worked to improve outcomes and survival for pediatric patients. Dr. Pinto explains that looking forward, the group hopes to continue this trend with the development of more targeted therapies that have less long-term effects and toxicities.

Chapters:
Introduction 00:00
The Children’s Oncology Group 00:57
Landmark Studies 2:52
Treatment Landscape of Neuroblastoma 5:47
Tandem Versus Monotherapy 7:30
Importance of Collaboration 8:45
Reflecting on the Past 25 Years 10:35
Length of Studies 12:16
Facing Cuts to Funding 15:40
Relationship with National Comprehensive Cancer Network 17:51
Take Home Message 19:35

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Kevin Eggan, PhD, Chief Scientific Officer at BioMarin, discusses new results from the PEGASUS clinical trial of Palynziq (pegvaliase) for treating patients with phenylketonuria (PKU).

PKU is a genetic metabolic disorder that increases the body's levels of phenylalanine. Phenylalanine is an amino acid of proteins. Humans cannot make phenyalanine, but it is a natural part of the foods we eat. However, people do not need all the phenyalanine they eat, so the body converts extra phenylalanine to another harmless amino acid, tyrosine. People with PKU cannot properly break down the extra phenylalanine to convert it to tyrosine. This means phenylalanine builds up in the person's blood, urine, and body. Without treatment, children with classic PKU develop permanent intellectual disability. Light skin and hair, seizures, developmental delays, behavioral problems, and psychiatric disorders are also common. In most cases, PKU is caused by genetic changes in the PAH gene.

The phase 3 PEGASUS clinical trial was a multicenter, open-label, randomized, controlled study evaluating the safety and efficacy of pegvaliase compared to diet alone in 55 patients ages 12 to 17 years with PKU. Pegvaliase is a substitute for the deficient PAH enzyme in PKU that contains a PEGylated version of phenylalanine ammonia lyase to break down blood phenylalanine (Phe). It is currently approved for the treatment of adults with PKU. New data from the study was recently presented at the 15th International Congress of Inborn Errors of Metabolism.

The primary endpoints of the study are change in blood Phe concentration and characterization of the safety profile in adolescents. Secondary endpoints include change in total dietary protein intake and pharmacokinetics. The study consists of two parts: a primary treatment phase lasting 72 weeks and an extension phase lasting for an additional 80 weeks of monitoring.

Results from the study show the ability of pegvaliase to significantly lower Phe compared to diet alone. At baseline, mean blood Phe was 1026.4 µmol/L and 49.1% of participants had blood Phe levels above 1000 µmol/L. After the 72 week primary treatment phase, 45.2% of participants in the pegvaliase group achieved reductions in blood Phe concentrations of 50% or more from baseline, with many reaching guideline-recommended and normal Phe target levels.

Additionally, the safety profile and overall efficacy in adolescents were consistent with the known profile of pegvaliase in adults. The majority of adverse events were manageable and only 5.6% were considered serious and led to study discontinuation.

Chapters:
Introduction 00:00
PKU Overview 00:39
Current Management 1:31
PEGASUS Clinical Trial 3:21
Takeaway Message 5:05

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Amer Zeidan, MBBS, MHS, Professor of Internal Medicine at Yale School of Medicine and Chief of the Division of Hematologic Malignancies at Yale Cancer Center, discusses plans for a phase 2/3 clinical trial testing bexmarilimab plus standard of care in patients with myelodysplastic syndromes (MDS).

MDS are a group of blood disorders characterized by abnormal development of blood cells within the bone marrow. People with MDS have abnormally low blood cell levels. Signs and symptoms may include dizziness, fatigue, weakness, shortness of breath, bruising and bleeding, frequent infections, and headaches. In some people with MDS, the condition progresses to bone marrow failure or develops into acute leukemia. MDS develops when a cell with a genetic change replicates, and the resulting copies begin to predominate in the bone marrow and suppress healthy stem cells. The genetic change may result from a genetic predisposition, or from injury to the DNA caused by an exposure such as chemotherapy or radiation. In many people with MDS there is no obvious exposure or cause.

The BEXMAB clinical trial is an open-label, phase 1/2 study evaluating bexmarilimab in combination with standard of care azacitidine in the aggressive hemtological malignancies of acute myeloid leukemia and MDS. The study included 20 frontline patients with higher risk MDS and 35 patients with relapsed/refractory MDS. The primary endpoint was to determine safety and tolerability.

Bexmarilimab is an investigational immunotherapy that targets myeloid cell function and stimulates the immune system. It has been designed to overcome resistance to existing treatments and optimize clinical outcomes by binding to Clever-1, an immunosuppressive receptor located on macrophages causing tumor growth and metastases.

Results from this study showed a 100% overall response rate in five frontline MDS patients and 80% in 20 relapsed/refractory patients. A median overall survival estimate of 13.4 months was reported in the relapsed/refractory population. During dose escalation, no dose limiting toxicities were reported. Ongoing safety follow-up indicates 13.7% of treatment-emergent adverse events are considered related to bexmarilimab.

Following an end-of-phase 2 meeting with the U.S. Food and Drug Administration (FDA), positive feedback was provided on the BEXMAB clinical trial. The meeting was held to align on the design of the planned registrational phase 2/3 trial evaluating bexmarilimab in combination with azacitidine for patients with treatment-naïve higher-risk MDS.

The trial will begin with a dose optimization run-in period comparing 1 mg/kg and 3 mg/kg regimens with placebo, all in combination with azacitidine. Once optimal dose is determined, the study will transition to a registrational stage including an interim analysis to support accelerated approval based on IWG 2023 response criteria in frontline patients.

The FDA confirmed that IWG 2023-defined Complete Response (CR) + CR equivalent (CReq) as an acceptable primary endpoint to support an application for accelerated approval in frontline patients. In line with this, CR + CReq and overall survival will be co-primary efficacy endpoints in the phase 2/3 trial. Accelerated approval will then be pursued based on interim results on the CR + CReq data. Composite complete remission will be the key secondary endpoint.

Chapters:
Introduction 00:00
High-Risk Myelodysplastic Syndromes 00:24
Bexmarilimab Overview 2:06
Clinical Studies 3:05

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Paula Rodriguez Otero, MD, PhD, Hematologist at the University of Navarra, discusses results from the LINKER-SMM1 trial in patients with high-risk smoldering multiple myeloma (HR-SMM).

HR-SMM is an asymptomatic clonal plasma cell disorder characterized by a high risk of progression to multiple myeloma. The typical age of diagnosis is 50 to 70 years. Due to its asymptomatic nature, diagnosis usually follows discovery of M protein in laboratory testing. Early intervention may have the potential to delay or prevent progression to active multiple myeloma.

Data from the LINKER-SMM1 clinical trial was recently presented at the International Myeloma Society 2025 meeting. The LINKER-SMM1 (NCT05955508) study is a phase 2, open-label trial evaluating the safety and efficacy of linvoseltamab in patients with HR-SMM. Linvoseltamab is a BCMAxCD3 bispecific antibody approved for triple-class exposed relapsed/refractory multiple myeloma after 4 or more prior lines of therapy.

Part 1 of the study looked at the safety of linvoseltamab in six patients. Primary endpoints included frequency of adverse events of special interest, and frequency and severity of treatment-emergent adverse events (TEAE). Part 2 of the study is ongoing with 24 patients enrolled as of May 28, 2025. Primary endpoints include complete response rate and MRD negativity at 12 and 24 months. Key secondary endpoints of both parts include overall response rate, MRD negativity rate, and duration of response.

In part 1, no safety concerns were identified. 92% of patients experienced 1 or more TEAE and 38% experienced a grade 3 or higher TEAE. Neutropenia was the only grade 3 or higher hematologic toxicity. Infections occurred in 79% of patients and consisted mostly of low-grade respiratory tract infections. However, treatment-related grade 3 infections were reported in 2 patients with Salmonella gastroenteritis and Staphylococcus epidermidis bacteremia, which were quickly resolved with antibiotics. Ig replacement was given to 95% of patients who received 1 or more cycles of therapy. CRS occurred in 42% but no ICANS were observed.

Following one or more cycles of linvoseltamab, overall response rate was 100%. Among part 1 patients with longer follow-up, 100% achieved ≥VGPR and 100% achieved MRD negativity at 10-6. All responses were ongoing at data cutoff.

Chapters:
Introduction 00:00
Treating High-Risk Smoldering Multiple Myeloma 00:13
Signs and Symptoms 2:46
LINKER-SSM1 Clinical Trial 3:39
Natural History of Progression 8:55

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