Joint stiffness

Immusoft gave a glimpse on Monday at how the first patient to ever receive an engineered B cell therapy is doing nine months after being dosed, suggesting that the treatment has been safe so far and is showing early signs that it improved his disease. The treatment is for mucopolysaccharidosis I, or MPS I, a genetic disease in which a key enzyme needed to break down sugars is missing. The adult patient in November received a low dose of Immusoft’s experimental treatment, ISP-001. He stayed on Sanofi’s Aldurazyme, an enzyme replacement therapy (ERT), for eight months and then was taken off ERT. Immusoft has said its ultimate goal is to replace ERT, which requires long weekly infusions, with higher doses of its engineered B cell therapy, which it hopes will act as a protein factory for the body to replace the missing enzyme. The company’s experimental treatment involves taking B cells from a patient and then programming them with non-viral gene delivery to make a key protein. The B cells are then returned to the patient in hopes that they will make that functional protein in the patient’s body. Notably, no preconditioning or immunosuppression was required for the B cell therapy. The first patient, who was treated at the University of Minnesota Medical Center, in the Phase 1 trial saw measures of complex sugars called GAGs in his urine fall in the normal range between three and eight months after treatment, which is not typically achieved on Aldurazyme alone. In an interview last week, Immusoft CEO Sean Ainsworth noted that none of the MPS I patients in Aldurazyme’s clinical trial who received the ERT reached normal urinary GAG levels. The patient also saw a 25% decrease in heparan sulfate as measured in his cerebrospinal fluid at six months. Companies and patient advocacy groups have said the FDA has agreed that heparan sulfate is an acceptable surrogate measure of disease activity for MPS. Beyond biomarker results, the patient also saw a 30% improvement in a 6-minute walk test and increased range of shoulder motion at six months. Joint stiffness is a symptom of MPS I. Ainsworth described the functional improvements as “unexpected,” noting the patient was given “the first and our lowest dose that we’ll be giving. And this was in an adult patient, so we didn’t think that there was much opportunity to reverse some of these manifestations.” There have been no adverse events reported to date by the patient, according to Immusoft. At nine months, one month after the ERT treatment had ended, the patient still saw an improvement on their six-minute walk test, though it was less than at six months. Meanwhile, the shoulder flexion improvement persisted. The company is planning to dose a second adult patient in the study and is opening a second site at UCSF, where it also plans to enroll children.

MONTREAL, Sept. 26, 2024 (GLOBE NEWSWIRE) -- From September 28 to October 1, the Shriners Hospitals for Children - Canada will host the 4th International Symposium on Arthrogryposis. Organized in collaboration with the other Montreal pediatric centers - CHU Sainte-Justine, Centre de réadaptation Marie Enfant and Montreal Children's Hospital - the symposium will take place at the Hôtel Omni Mont-Royal, 1050 Sherbrooke Street West. Pre-conference workshops will be held on Saturday, September 28 at the Shriners Hospitals for Children - Canada. Arthrogryposis is a group of rare diseases that occur in around 1 in 3,000 children. Arthrogryposis manifests itself as joint stiffness, present from birth and affecting all four limbs to varying degrees. It may be accompanied by other signs: skeletal, visceral or neurological. People with arthrogryposis live with a limited range of movement, often restricting their participation in daily activities. Arthrogryposis is one of a wide range of so-called fetal immobility syndromes, encompassing a multitude of neurological and muscular abnormalities whose inventory is not yet complete. Over the course of four days, experts from around the world will discuss ways of approaching and treating this pathology, as well as the latest research projects in progress. For Dr. Reggie Hamdy and Dr. Noémi Dahan-Oliel, co-chairs of the scientific and organizing committees, the need for this 4th international symposium is clear. Noémi Dahan-Oliel, clinical researcher and associate professor at McGill University, explains: “By promoting knowledge sharing and networking among an international community of experts and people living with this condition, we are on the lookout for scientific advances and discoveries that will enable optimal evidence-based care. One of our Quebec stars, Luca “Lazylegz” Patuelli, www.lucapatuelli.com, a member of the organizing committee for this 4th edition of the international symposium, will perform a dance show on Sunday, September 29 at the Omni Hotel's Salle Pierre de Coubertin during the cocktail reception at 5:45 pm. Luca embodies the “can-do attitude” of people living with a rare disease. He is proof that support for patients and families, as called for by Quebec's policy on rare diseases, is not only an inescapable necessity, but also a source of wealth.” “The Shriners Healthcare Network is at the forefront of clinical advancements, and its Genomics Institute seeks to better understand the genetic causes of rare diseases such as arthrogryposis. It's by working together with clinicians, researchers and people living with arthrogryposis that we can learn, innovate and move forward to meet the needs of this community,” says Reggie Hamdy, MD, MSc (Ortho) FRCSC, orthopaedic surgeon and director of the Arthrogryposis Clinic at the Shriners in Montréal. Several patients and families living with arthrogryposis will also be there speaking about the care they received and their life experiences. To view the symposium program and find out more about the guest speakers: https://event.fourwaves.com/fr/amcinternationalsymposium/pages The first international symposium on arthrogryposis was held in 2007 in Birmingham, UK, to discuss different aspects of care for people with arthrogryposis. These learnings set the tone for the second symposium, held in St Petersburg, Russia, in 2014. Clinical and research advances made in the field of arthrogryposis were shared at the 3rd symposium in Philadelphia, USA, in 2018. The hospital, in collaboration with other Montreal pediatric facilities, is proud to welcome the 4th International Arthrogryposis Symposium to Montreal! About Shriners Hospitals for Children – Canada Established in Montreal in 1925, Shriners Hospital for Children ─ Canada is the only Canadian facility within the extensive Shriners Hospitals network. A bilingual hospital, it offers ultra-specialized acute orthopedic care to children from Canada, the United States and around the world. The hospital's mission is to promote health and provide treatment and rehabilitation for infants, children and young adults with orthopedic and neuromuscular conditions such as scoliosis, osteogenesis imperfecta, clubfoot, hip dysplasia and cerebral palsy. The hospital is committed to excellence and innovation in clinical practice, research and education. Affiliated with McGill University, the hospital enables resident physicians and healthcare professionals to take advantage of its facilities on the Glen site to further their training and experience. In addition to offering a patient- and family-centered care environment, the hospital is present in communities across Canada through telemedicine, outreach clinics and satellite clinics. Information: Emmanuelle RondeauCommunicationsShriners Hospitals for Children – CanadaTel.: 514-282-6990; Cell.: 514-207-1057erondeau@shrinenet.org A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/7dc067b6-e47b-49a5-99fd-8507debbcdf2

Recent successful meeting with the FDA provides path to file for accelerated approval and subsequent conversion to full approval Plan to submit biologics license application (BLA) early in 2025 under the accelerated approval pathway New Phase 1/2 data will be presented this week at SSIEM 2024 demonstrating robust and durable biomarker responses and positive effects on clinical outcomes Sept. 03, 2024 -- Denali Therapeutics Inc. (Nasdaq: DNLI) today announced the outcome of a recent successful meeting with the Center for Drug Evaluation and Research (CDER) division of the U.S. Food and Drug Administration (FDA) providing a path to filing a biologics license application (BLA) for accelerated approval and subsequent conversion to full approval for tividenofusp alfa (DNL310) for the treatment of MPS II (Hunter syndrome). Agreement was reached that cerebrospinal fluid heparan sulfate (CSF HS) is reasonably likely to predict clinical benefit and can be used as a surrogate endpoint to support accelerated approval for tividenofusp alfa in MPS II. Based on discussions with CDER, Denali will include preclinical and clinical data on biomarkers (CSF HS and neurofilament light (NfL)) and safety in the BLA for tividenofusp alfa as a treatment of MPS II and intends to submit the BLA under the accelerated approval pathway in early 2025. “We thank CDER for a positive and collaborative discussion and their guidance on CSF HS as a surrogate biomarker, which we see as a significant step towards accelerating development of medicines for individuals and families living with MPS II,” said Carole Ho, MD, Chief Medical Officer of Denali. “This milestone reflects a collective effort across the patient community, academia and industry to communicate the science and advocate for faster paths to effective treatments addressing these devastating rare diseases. We are excited by the potential to deliver a new MPS treatment sooner using the accelerated approval pathway. We also look forward to plans for conversion to full approval following completion of the global Phase 2/3 COMPASS study, and we are grateful for the continued participation and commitment of patients, clinicians, and study teams involved in the tividenofusp alfa clinical studies.” “The Phase 1/2 data show that treatment with tividenofusp alfa produces robust and durable effects, with normalization of key disease biomarkers and improvement or stabilization in associated CNS and somatic clinical endpoints,” said Barbara Burton, MD, Professor of Pediatrics, Genetics, Genomics and Metabolism at Feinberg School of Medicine in Chicago, who will present the Phase 1/2 data at the SSIEM conference. “The totality of data support Denali's plans to file for accelerated approval of tividenofusp alfa with the potential to address a critical unmet need for CNS-penetrant therapies in MPS II.” Denali also announced new interim data from the Phase 1/2 study being presented at the Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM 2024) taking place September 3-6, 2024, in Porto, Portugal. The presentations include data from additional study participants (N=37) and longer duration of treatment with tividenofusp alfa (up to Week 129) as well as new analyses on biomarkers and clinical outcomes. Highlights are summarized as follows: CSF HS: 90% mean reduction in CSF HS from baseline at Week 24 with all participants having normal or near normal levels at Week 24. CSF HS reduction was sustained through Week 104. Urine GAGs: Proportion of participants with normal total urine glycosaminoglycans (GAGs) (colorimetric method) increased from 5% of participants at baseline to 77% at Week 24, and the effect was sustained through Week 129. Importantly, the majority of patients were on standard of care prior to switching to tividenofusp alfa, without a protocol defined washout period, suggesting additional urine GAG reduction with tividenofusp alfa treatment. Serum NfL: Significant and sustained reduction of serum NfL from baseline with all participants who had reached Week 129 having normal or near normal levels, suggesting a reduction of neuronal injury in participants with MPS II. More rapid NfL reductions were associated with younger age. Clinical Outcomes: Improvement or stabilization in adaptive behavior and cognitive scores, hearing, liver volume, and growth outcomes were observed. Safety: Tividenofusp alfa was generally well tolerated, with a safety profile that continues to support development as a treatment for MPS II. MPS II, also called Hunter syndrome, is a rare genetic disease that affects over 2,000 individuals, primarily males, world-wide, and leads to behavioral, cognitive, and physical symptoms ultimately resulting in shortened lifespan. MPS II is caused by mutations in the iduronate-2-sulfatase (IDS) gene, which leads to a deficiency of the IDS enzyme responsible for the breakdown of the glycosaminoglycans (GAGs) heparan and dermatan sulfate in lysosomes. Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth leading to short stature, and neurocognitive symptoms with impaired development. The disease is characterized by a buildup of GAGs in lysosomes — the part of the cell that breaks down materials including GAGs. The current standard of care enzyme replacement therapy partially treats the physical symptoms but does not cross the blood-brain barrier (BBB), and as a result, cognitive and behavioral symptoms experienced by the majority of patients with MPS II are not addressed. Therapies that address behavioral, cognitive, and physical manifestations of the disease are one of the greatest unmet needs for the MPS community. Tividenofusp alfa (DNL310) is a fusion protein composed of IDS fused to Denali’s proprietary Enzyme Transport Vehicle (ETV), which is engineered to cross the BBB via receptor-mediated transcytosis into the brain and to enable broad delivery of IDS into cells and tissues throughout the body with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS II. In March 2021, the U.S. Food and Drug Administration granted Fast Track designation to DNL310 for the treatment of patients with MPS II. In May 2022, the European Medicines Agency granted DNL310 Priority Medicines designation. DNL310 is an investigational product candidate and has not been approved by any Health Authority. Based on supportive clinical and preclinical data to date, Denali is enrolling the Phase 2/3 COMPASS study in North America, South America, Europe, and Australia. The Phase 2/3 COMPASS study is expected to enroll 54 participants with MPS II with and without neuronopathic disease. The participants are randomized 2:1 to receive either tividenofusp alfa (DNL310) or idursulfase, respectively. Cohort A includes children ages 2 to 6 with neuronopathic disease; Cohort B includes children ages 6 to 26 without neuronopathic disease. More information about the COMPASS study can be found here. The blood-brain barrier (BBB) is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. Historically, the BBB has posed significant challenges to drug development for central nervous system diseases by preventing most drugs from reaching the brain in therapeutically relevant concentrations. Denali’s Transport Vehicle (TV) platform is a proprietary technology designed to effectively deliver large therapeutic molecules such as antibodies, enzymes, proteins, and oligonucleotides across the BBB after intravenous administration. The TV technology is based on engineered Fc domains that bind to specific natural transport receptors, such as transferrin receptor and CD98 heavy chain amino acid transporter, which are expressed at the BBB and deliver the TV and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered with the TV technology demonstrate more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes without this technology. Oligonucleotides engineered with the TV technology demonstrate more than a 1,000-fold greater brain exposure in primates than systemically delivered oligonucleotides without this technology. Improved exposure and broad distribution in the brain may increase therapeutic efficacy by enabling widespread achievement of therapeutically relevant concentrations of product candidates. The TV platform has been clinically validated and three TV-enabled programs are currently in clinical development. Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier for neurodegenerative diseases and lysosomal storage diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the blood-brain barrier, and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com. The content above comes from the network. if any infringement, please contact us to modify.