NPC2

iStockphoto/ Olivier Le Moal ITF, IntraBio and Orchard are among the companies that have won FDA nods in the past year for Duchenne muscular dystrophy, Niemann-Pick disease type C, metachromatic leukodystrophy and more. Rare Disease Day, which falls at the end of February each year, is an opportunity to take stock of advances in this space, as well as the many remaining gaps in care and treatment. Defined as diseases that affect fewer than 200,000 people in the U.S., rare diseases collectively afflict about 350 million people worldwide, according to the National Organization for Rare Disorders . An estimated 7,000 of these conditions have been identified, and more than 90% of them have no FDA-approved treatment. Yet progress toward developing such treatments continues, particularly among smaller companies. Here are five rare diseases that have seen drug approvals since last year’s Rare Disease Day. Duchenne Muscular Dystrophy Duchenne muscular dystrophy (DMD) is a relatively common rare disease, affecting about one out of every 3,600 baby boys. This X-linked genetic disease affects the dystrophin protein, a component of muscle, and causes progressive weakening of skeletal and heart muscle. Families affected by DMD saw a spate of treatment approvals in 2023 and 2024, including Sarepta Therapeutics’ Elevidys and Catalyst Pharmaceuticals’ Agamree. The most recent was Duvyzat (givinostat), a small molecule therapy marketed by ITF Therapeutics. It targets histone deacetylases, enzymes that modulate gene and protein expression in the muscle. “Deregulation of HDACs is a major consequence of the lack of dystrophin associated with DMD,” Matt Trudeau, head of ITF, told BioSpace in an email ahead of the FDA decision in March 2024. “We believe givinostat’s mode of action has the potential to inhibit HDAC pathological overactivity and thereby impact the cascade of events leading to muscle damage which, in turn, may counteract disease pathology and slow muscle deterioration.” In the Phase III Epidys trial , givinostat met the primary endpoint of a change in the four-stair climb assessment from baseline to 72 weeks. Italfarmaco, the parent company of ITF which developed the drug, also reported that it showed “favorable outcomes” in key secondary measures, including on the North Star Ambulatory Assessment (NSAA), a scale that measures motor function skills. On the NSAA, patients treated with the new drug saw less worsening compared to placebo after 18 months. Givinostat was generally well tolerated, with no treatment-related severe or serious adverse events. Metachromatic Leukodystrophy Metachromatic leukodystrophy (MLD) is a metabolic disease that affects one in every 100,000 live births. It is caused by a mutation in the arylsulfatase-A ( ARSA ) gene, which codes for an enzyme that breaks down sulfatides, and is characterized by a pathological build-up of sulfatides in the brain, liver, kidneys, spleen and other body parts. Over time this buildup can lead to organ damage and neurological issues, and patients often experience motor, behavioral and cognitive problems, as well as seizures. Most patients die within five years of disease onset. The FDA approved the first therapy for early juvenile or early symptomatic forms of the disease, Lenmeldy (atidarsagene autotemcel), in March 2024. The gene therapy, marketed by Orchard Therapeutics, uses a patient’s own stem cells to deliver a functioning copy of the ARSA gene. Lenmeldy was also approved by the European Union in December 2020 , where it is marketed as Libmeldy. The FDA’s approval of Lenmeldy is backed by data from two single-arm, open-label trials enrolling a total of 37 pediatric MLD patients. Over a median follow-up of 6.76 years, Lenmeldy led to significantly better overall survival compared with natural history data. The gene therapy also preserved motor and cognitive function in late-infantile MLD patients. Lenmeldy’s most common adverse events were febrile neutropenia, stomatitis, respiratory tract infections and rashes. WHIM Syndrome Fewer than 1,000 people in the U.S. have been diagnosed with WHIM syndrome, according to the NIH. The condition’s name is an acronym of the four characteristics of the disease: warts, hypogammaglobulinemia (low antibody levels), infections and myelokathexis (a white blood cell disorder). The syndrome is caused by mutations in the chemokine receptor ( CXCR4 ) gene that increase the activity level of the resulting protein. In April 2024, the FDA approved X4 Pharmaceuticals’ Xolremdi (mavorixafor) as the first targeted treatment for WHIM. Xolremdi is an oral CXCR4 antagonist that draws white blood cells from the bone marrow into the blood to improve immune deficiencies. It is approved for patients 12 and older. Phase III results from the 4WHIM trial of Xolremdi showed a 60% reduction in annualized infection rate compared to placebo; trial participants had less than one infection per year compared with 4.5 for the placebo group. Teresa Tarrant, an associate professor at Duke University’s School of Medicine and lead investigator of the 4WHIM trial, told BioSpace last year that previous treatments for the disease were only supportive. “I think that for a lot of patients, the idea that there is a targeted therapy . . . something that is directly correcting the underlying problem for the individual, I think that gives them a lot of hope, a lot of optimism,” Tarrant said. “I think WHIM is going to be a poster child for rare diseases and the ability where we’re at now in modern medicine to design therapies to treat underlying genetic disorders.” Niemann-Pick Disease Type C Afflicting approximately one in every 150,000 people , Niemann-Pick disease type C (NPC) is an ultrarare lysosomal storage disease that progressively impairs patients’ physical and cognitive function. It is caused by mutations in the NPC1 and NPC2 genes that hinder the body’s ability to clear cholesterol and other lipids from inside cells, leading to their pathologic build-up in the brain and other crucial organs. NPC affects patients’ speech, motor and swallowing functions. According to the FDA , patients with NPC typically live only up to around 13 years of age. September 2024 saw not one, but two approvals of therapies for NPC. The first, Zevra Therapeutics’ Miplyffa (arimoclomol), is an oral drug approved for patients 2 years and older that is intended to be used alongside miglustat , a small molecule approved to treat the neurological manifestations of NPC. According to the company , Miplyffa activates transcriptional factors, resulting in the upregulation of coordinated lysosomal expression and regulation (CLEAR) genes. In a clinical trial, Zevra found that Miplyffa plus miglustat stopped disease progression during 12 months of treatment, decreasing patients’ scores on an assessment of NPC symptom severity. Meanwhile, patients treated with miglustat alone experienced a progression in symptoms. The second approval was for IntraBio’s Aqneursa (levacetylleucine) in adults and children weighing at least 15 kg. According to the company, it is not clear what Aqneursa’s target is, but it may activate cerebral glucose metabolism in the cerebellum and thus boost cerebellar activity. A randomized, double-blinded and placebo-controlled crossover study found that during the 12-week period that patients were treated with Aqneursa, they showed better functional performance as measured by a score that assesses their gait, sitting, stance and speech. The drug was well-tolerated, with common side effects including vomiting, abdominal pain, difficulty swallowing and upper respiratory tract infections. The drug’s label includes a warning for embryo-fetal harm if used during pregnancy. The back-to-back NPC approvals highlighted the FDA’s commitment to supporting the development of innovative therapies for rare diseases, Janet Maynard, director of the agency’s Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, said in a statement . Cerebrotendinous Xanthomatosis Cerebrotendinous xanthomatosis (CTX) is a very rare metabolic disease, affecting just one in a million people globally . It is characterized by the inability to break down certain types of cholesterol and other lipids, leading to their toxic accumulation throughout the body, particularly in the brain and connective tissues. Patients with CTX suffer from neurological abnormalities in early adulthood, including seizures and problems with movement and speech. Just last week, CTX got its first approved drug with the FDA’s greenlight of Mirum Pharmaceuticals’ oral therapy Ctexli (chenodiol). CTX is caused by mutations in the CYP27A1 gene, which codes for an enzyme that breaks down cholesterol into bile acids, and Ctexli replenishes the body’s levels of bile acids. This reduces the build-up of the toxic metabolites that cause the disease. Mirum’s application for approval of the drug included data from the Phase III RESTORE study, a June 2024 readout of which showed the drug could lower bile alcohols “with high statistical significance,” the biotech said at the time. Ctexli’s benefit was 20-fold greater in magnitude than that of placebo. The most common adverse events associated with Ctexli include hypertension, muscle weakness and diarrhea, and its label includes precautions about potential liver toxicity.

GAINESVILLE, Fla.--( BUSINESS WIRE )-- Cyclo Therapeutics, Inc. (Nasdaq: CYTH) (“Cyclo Therapeutics” or the “Company”), a clinical stage biotechnology company dedicated to developing life-changing medicines through science and innovation for patients and families living with rare and challenging diseases, today announced the presentation of data from its ongoing Pivotal Phase 3 global study (TransportNPC™) evaluating Trappsol ® Cyclo™ for Niemann-Pick Disease Type C1 (“NPC1”) at the 21 st Annual WORLD Symposium ™ in San Diego, CA. The TransportNPC™ study is the most comprehensive, controlled pivotal study regarding patient size, global footprint, duration and clinical outcomes of an investigational therapy for NPC1. The study completed enrollment in May 2024. Additionally, the Company enrolled ten (10) patients in its single-arm sub-study per their adopted Pediatric Investigational Plan (PIP) treating newborns to 3 years of age. Two patients terminated the sub-study after 48 weeks (caregiver decision). The sub-study is evaluating Trappsol ® Cyclo™ in the youngest age subsets as it targets also the visceral aspects of the disease and may achieve its most optimal results when administered early in the disease course, thus having the potential of a preventative effect in overall symptom development. The sub-study is being conducted in countries outside of the United States per the Company’s adopted PIP. As part of the Annual WORLD Symposium™ , Ronen Spiegel, MD, Clinical Associate Professor, Director of Pediatric B Department, and Director Center of Rare Disease, at Emek Medical Center gave an oral presentation titled, “ Trappsol ® Cyclo™: Open Label Treatment in the TransportNPC™ Sub-Study in Patients Under the Age of 3 Diagnosed with Niemann-Pick Disease Type C1.” Key Data Highlights Clearance of lipids centrally and systemically were consistently demonstrated in a completed 14-week Phase 1 study in adult patients with NPC; At baseline, sub-study patients had a mixture of very mild to severe disease based on the Clinical Global Impression – Severity (CGI-S) scale. Clinical improvements seem to be best in patients with clinically mild to moderate disease; 7 of 8 patients who have reached 24 weeks and 6 of 7 who have reached 48 weeks show stabilization or improvement in CGI-C; Adverse Effect (AE) profile is in line with prior findings from earlier studies, and from a double-blind Phase 3 study running in parallel irrespective of age and disease severity; As of December 2024, AEs are limited (107), majority are mild (77%) or moderate (22%) and 1 AE is severe; with only 1 (mild grade) considered possibly related to or possibly related to study drug; and Of all 107 AEs, 19 were reported as SAEs. No SAEs were considered as related to or possibly related to study drug. Dr. Spiegel commented, “The preliminary findings from the TransportNPC™ sub-study are encouraging and further underscore the potential of Trappsol ® Cyclo™ to address the significant unmet medical need in the treatment of NPC. Slowing down disease progression through cholesterol mobilization is an important consideration for patients with established disease, who can expect to experience neurodegeneration without treatment. We look forward to gathering additional data from this ongoing study and establishing the effect of Trappsol ® Cyclo™ on progress of NPC.” “We continue to be encouraged by the data demonstrated by Trappsol ® Cyclo™ in the treatment of NPC. The growing body of data from our TransportNPC™ study and sub-study continue to demonstrate the potential of Trappsol ® Cyclo™ to address a devastating disease with significant unmet need. We look forward to our interim data readout from the TransportNPC™ study, which is expected in H1 2025 and ultimately providing a much needed treatment option for patients,” commented N. Scott Fine, Chief Executive Officer of Cyclo Therapeutics. The Company’s ongoing TransportNPC™ study is a randomized, double-blind, placebo-controlled, parallel group, multicenter study designed to evaluate the safety, tolerability, and efficacy of 2,000 mg/kg doses of Trappsol ® Cyclo™ administered intravenously and standard of care (SOC), compared to placebo administered intravenously and SOC alone, in patients with NPC1, a rare, genetic disease causing cholesterol accumulation in cells, leading to dysfunction primarily of the liver, lung, spleen and brain and premature death. The study duration is a 96-week study, with a 48-week comparative interim analysis. Should the 48-week interim data meet statistical significance, the Company, in alignment with the FDA and EMA, intends to submit marketing applications for approval to market Trappsol ® Cyclo™ based on the 48-week interim data. In addition to the oral presentation given by Dr. Spiegel, the Company had two posters presented by Dr. Caroline Hastings, Pediatric hematologist oncologist, Director of Neuro-oncology, and Professor of Pediatrics at UCSF Benioff Children’s Hospital Oakland titled, “ Trappsol ® Cyclo™ (HPβCD) for the Long-Term Treatment of Niemann-Pick Type C1: Efficacy and Safety Data from 4 Clinical Studies and the Ongoing Expanded Access Program,” and “ Trappsol ® Cyclo™ and NPC: Efficacy Shown Across Individual 5D Domains and Utilization of Future Assessment Tools to Demonstrate Clinically Relevant Outcomes.” Dr. Spiegel also presented the poster titled, “ Trappsol ® Cyclo™: Open Label Treatment in the TransportNPC™ Sub-Study in Patients Under the Age of 3 Diagnosed with Niemann-Pick Disease Type C1 .” The presented posters are available on the Company’s website here . For more information about the Company’s TransportNPC™ pivotal Phase 3 study, visit www.ClinicalTrials.gov and reference identifier NCT04860960 . Cyclo Therapeutics received Orphan Drug Designation for Trappsol ® Cyclo™ to treat NPC1 in both the U.S. and EU and Fast Track and Rare Pediatric Disease Designations in the U.S. The Rare Pediatric Disease Designation is one of the chief requirements for sponsors to receive a Priority Review Voucher in the U.S. upon marketing authorization. About WORLD Symposium™ WORLD Symposium™ is an annual research conference dedicated to lysosomal diseases. WORLD is an acronym that stands for We’re Organizing Research on Lysosomal Diseases. Since its inception as a small group of passionate researchers in 2002, WORLD Symposium™ has grown to an international research conference that attracts over 2,000 participants from more than 50 countries around the globe. For more information, please visit: worldsymposia.org . About Niemann-Pick Disease Type C1 (NPC) NPC is a rare genetic disease affecting 1 in 100,000 live births globally. Approximately 95% of individuals with NPC have mutations in the NPC1 gene and 5% have mutations in the NPC2 gene. NPC affects nearly every cell in the body due to a deficiency in either the NPC1 or NPC2 protein, which are required for the transport and processing of cholesterol within the cell. As cholesterol accumulates within cells, NPC causes symptoms that affect the brain, liver, spleen, lungs, and other organs and often leads to premature death. About Cyclo Therapeutics Cyclo Therapeutics, Inc. is a clinical-stage biotechnology company dedicated to developing life-changing medicines through science and innovation for patients and families living with rare and challenging diseases. The Company’s Trappsol ® Cyclo™, an orphan drug designated product in the United States and Europe, is the subject of four formal clinical trials for Niemann-Pick Disease Type C1, a rare and fatal genetic disease, ( NCT02939547 , NCT02912793 , NCT03893071 and NCT04860960 ). The Company is conducting a Phase 2b clinical trial using Trappsol ® Cyclo™ intravenously in early Alzheimer’s disease ( NCT05607615 ) based on encouraging data from an Expanded Access program for Alzheimer’s disease ( NCT03624842 ). Additional indications for the active ingredient in Trappsol ® Cyclo™ are in development. For additional information, visit the Company’s website: www.cyclotherapeutics.com . On August 21, 2024, Cyclo Therapeutics entered into an Agreement and Plan of Merger (as amended, the “Merger Agreement”), by and among the Company; Rafael Holdings, Inc., a Delaware corporation (“Rafael”); Tandem Therapeutics, Inc., a Nevada corporation and a wholly-owned subsidiary of Rafael (“First Merger Sub”); and Tandem Therapeutics, LLC, a Nevada limited liability company and a wholly-owned subsidiary of Rafael (“Second Merger Sub”), pursuant to which: (i) First Merger Sub will merge with and into the Company, with the Company being the surviving entity (the “First Merger”), and (ii) immediately following the First Merger, the Company will merge with and into Second Merger Sub, with Second Merger Sub being the surviving entity of the subsequent merger (the “Second Merger” and together with the First Merger, the “Merger”). The Merger is subject to the satisfaction or waiver of several conditions set forth in the Merger Agreement and the approval of the Company’s and Rafael’s respective stockholders. Rafael is the holder of approximately 39.5% of the Company’s outstanding common stock, par value $0.0001 per share (the “Common Stock”). Safe Harbor Statement This press release contains “forward-looking statements” about the company’s current expectations about future results, performance, prospects and opportunities. Statements that are not historical facts, such as “anticipates,” “believes” and “expects” or similar expressions, are forward-looking statements. These statements are subject to a number of risks, uncertainties and other factors that could cause actual results in future periods to differ materially from what is expressed in, or implied by, these statements. The factors which may influence the company’s future performance include the company’s ability to complete the merger transaction with Rafael Holdings Inc., success in achieving regulatory approval for clinical protocols, enrollment of adequate numbers of patients in clinical trials, unforeseen difficulties in showing efficacy of the company’s biopharmaceutical products, success in attracting additional customers and profitable contracts, and regulatory risks associated with producing pharmaceutical grade and food products. These and other risk factors are described from time to time in the company’s filings with the Securities and Exchange Commission, including, but not limited to, the company’s reports on Forms 10-K and 10-Q. Unless required by law, the company assumes no obligation to update or revise any forward-looking statements as a result of new information or future events.

Leiden, Netherlands, 09 January 2025 – Azafaros, a company focused on developing treatments for the unmet needs of patients with rare lysosomal storage disorders, today announced that it will present at J.P. Morgan’s 43rd Annual Healthcare Conference on Thursday, January 16, 2025. The company’s presentation will begin at 8:30 a.m. PT/11:30 am (Eastern Time). The presentation will focus on the company’s lead product, nizubaglustat, a potential treatment for rare lysosomal storage disorders with neurological involvement including GM1/GM2 gangliosidoses and Niemann Pick type C (NPC). Positive topline data reported earlier this year from the company’s successful Phase 2 study investigating nizubaglustat in GM2 and NPC patients demonstrated that the compound had a positive safety profile. Preliminary improvements or stabilization of clinical endpoints were observed in the majority of patients, highlighting encouraging early efficacy trends for the compound. Azafaros is preparing to initiate Phase 3 studies with nizubaglustat in GM1/GM2 gangliosidoses and NPC in Q2, 2025. About nizubaglustat Nizubaglustat is a small molecule, orally available and brain penetrant azasugar with a unique dual mode of action, developed as a potential treatment for rare lysosomal storage disorders with neurological involvement, including GM1 and GM2 gangliosidoses and Niemann-Pick disease type C (NPC). Nizubaglustat has received the following designations and support: United States Food and Drug Administration (FDA) Rare Pediatric Disease Designations (RPDD) for the treatment of GM1 and GM2 gangliosidoses and NPC. Orphan Drug Designations (ODD) for GM1 and GM2 gangliosidosis (Sandhoff and Tay-Sachs Diseases) and NPC. Fast Track Designation and IND clearance for GM1/GM2 gangliosidoses and NPC European Medicines Agency (EMA) Orphan Medicinal Product Designation (OMPD) for the treatment of for GM1 and GM2 gangliosidosis GM2 Gangliosidosis. UK Medicines and Healthcare Products Regulatory Agency (MHRA) Innovation Passport for the treatment of GM1 and GM2 gangliosidoses. About GM1 and GM2 gangliosidoses GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are lysosomal storage disorders caused by the accumulation of GM1 or GM2 gangliosides respectively, in the central nervous system (CNS), resulting in progressive and severe neurological impairment and premature death. These diseases mostly affect infants and children, and no disease-modifying treatments are currently available. About Niemann-Pick disease type C (NPC) Niemann-Pick disease type C is a progressive, life-limiting neurological lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene and aberrant endosomal-lysosomal trafficking, leading to the accumulation of various lipids, including gangliosides in the CNS. The onset of disease can happen throughout the lifespan of an affected individual, from prenatal life through adulthood. About Azafaros Azafaros is a clinical-stage company founded in 2018 with a deep understanding of rare genetic disease mechanisms using compound discoveries made by scientists at Leiden University and Amsterdam UMC and is led by a team of highly experienced industry experts. Azafaros aims to build a pipeline of disease-modifying therapeutics to offer new treatment options to patients and their families. By applying its knowledge, network and courage, the Azafaros team challenges traditional development pathways to rapidly bring new drugs to the rare disease patients who need them. Azafaros is supported by a syndicate of leading Dutch and Swiss investors including Forbion, BioGeneration Ventures (BGV), BioMedPartners, Asahi Kasei Pharma Ventures, and Schroders Capital. For further information: Azafaros B.V. Email: info@azafaros.com www.azafaros.com