Busulfan

LENMELDY™ is the first and only disease-modifying intravenous infusion proven to extend life expectancy in pre-symptomatic late infantile (PSLI) patients and mitigate the cognitive and/or physical impact of early-onset MLD Six accepted abstracts at ASGCT 2025 detail the therapeutic potential of HSC gene therapy to address severe multi-system diseases TOKYO, LONDON and BOSTON, May 13, 2025 (GLOBE NEWSWIRE) -- Orchard Therapeutics, a Kyowa Kirin company, today announced a publication on long-term safety and efficacy outcomes for Lenmeldy™ (atidarsagene autotemcel) in the treatment of early-onset metachromatic leukodystrophy (MLD). The manuscript, titled, “Long-term effects of atidarsagene autotemcel for metachromatic leukodystrophy” (F. Fumagalli, V. Calbi, A. Aiuti, et. al.) was published in the April 24 issue of NEJM. MLD is an ultra-rare, rapidly progressive, irreversible and ultimately fatal neurometabolic disease that affects approximately one in 100,000 live births. It is caused by an error in the gene responsible for encoding the enzyme arylsulfatase A (ARSA) leading to neurological damage and developmental regression. In the most severe form of MLD, babies develop normally but in late infancy start to rapidly lose the ability to walk, talk and interact with the world around them. These children eventually deteriorate into a vegetative state, which may require 24-hour intensive care, and the majority pass away within five years of symptom onset, creating an enormous emotional and financial burden on the family. Lenmeldy is the only approved therapy intended to correct the underlying cause of MLD for eligible patients in the United States (U.S.). It is known as Libmeldy® in Europe. The FDA approval of Lenmeldy is based on data from pediatric patients with early-onset MLD enrolled in two single-arm, open-label clinical studies or treated under European expanded access frameworks, who received a one-time administration of the hematopoietic stem cell (HSC) gene therapy and compared with natural history data from untreated patients. The NEJM publication details clinical outcomes of children treated in these studies. All treated patients were administered HSC gene therapy and subsequently monitored at Ospedale San Raffaele in Milan, Italy. The primary endpoint was severe motor impairment-free survival (sMFS), defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support (Gross Motor Function Classification-MLD [GMFC-MLD] Level ≥ 5) or death. With more than 12 years of follow-up in the earliest treated patients (median 6.76 years) and more than 250 patient years, treatment with Lenmeldy significantly extended overall survival and resulted in the preservation of motor function and cognitive skills in most late infantile MLD patients past ages at which untreated patients showed severe cognitive and motor impairments. Lenmeldy also resulted in the preservation of motor function and cognitive skills in some early juvenile MLD patients which is not expected when compared to untreated patients. Treatment with Lenmeldy was well-tolerated, with no treatment-related serious adverse events. Most adverse events were associated with busulfan conditioning or background disease. The most common non-laboratory adverse reactions (incidence ≥ 10%) were: febrile neutropenia (85%), stomatitis (77%), respiratory tract infections (54%), rash (33%), device related infections (31%), other viral infections (28%), pyrexia (21%), gastroenteritis (21%), and hepatomegaly (18%). The most common laboratory abnormalities were: elevated D-dimer (67%), neutropenia (28%), and elevated liver enzymes (23%). Please see below for additional details and Important Safety Information. “Lenmeldy represents a significant step forward in the treatment of MLD, a cruel and ultimately fatal disease for which there were previously no approved treatment options beyond supportive and end-of-life care,” said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard Therapeutics. “These compelling results, which encompass more than a cumulative 250 years of patient experience, continue to demonstrate the ability of Lenmeldy to preserve motor and cognitive function in eligible children with MLD particularly when treatment is administered prior to the onset of symptoms.” Dr. Gaspar continued, “These long-term results, coupled with the homogenous, predictable and precipitous decline and eventual death observed in the natural history cohort, underscores the urgent need to enable timely and accurate diagnosis and intervention through the proliferation of universal newborn screening for MLD.” Summary of Participation at ASGCT 2025 The company also announced six presentations (three oral and three posters) will be featured at the American Society of Gene and Cell Therapy (ASGCT) 28th Annual Meeting taking place May 13-17 in New Orleans. Featured data include several accepted abstracts and presentations detailing clinical, biochemical and other functional outcomes from across the company’s commercial- and clinical-stage neurometabolic portfolio in metachromatic leukodystrophy (MLD), the Hurler subtype of mucopolysaccharidosis type I (MPS-IH), and mucopolysaccharidosis type IIIA (MPS-IIIA), also known as Sanfilippo syndrome type A. Company researchers will also present data derived from its efforts to develop an automated manufacturing process for HSC gene therapy production and in developing an HSC gene therapy approach for the treatment of another lysosomal storage disorder. Finally, Leslie Meltzer, Ph.D., chief medical officer of Orchard Therapeutics, will give an invited talk on Friday, May 16 at 8:00 a.m. CDT, titled “Developing and delivering hematopoietic stem cell gene therapies to patients with rare neurometabolic diseases,” which will explore key insights into the development and delivery of one-time treatments for rare neurometabolic diseases and beyond. Details of the oral presentations are as follows (all times in CDT): Title: Lentiviral hematopoietic stem cell gene therapy (atidarsagene autotemcel) for late juvenile metachromatic leukodystrophy (MLD): Interim analysis of a Phase III trialDate/Time: Wednesday, May 14 at 2:45 p.m.Presenter: Valeria Calbi Title: Treatment effect of atidarsagene autotemcel (arsa-cel) in age-matched treated vs. untreated sibling pairs with early-onset metachromatic leukodystrophy (MLD)Date/Time: Friday, May 16 at 1:30 p.m. Presenter: Valeria Calbi Title: Extensive detoxification and favorable effects on systemic clinical outcomes after Hematopoietic Stem Cell Gene Therapy for Mucopolysaccharidosis Type I-Hurler (OTL-203)Date/Time: Friday, May 16 at 2:00 p.m.Presenter: Giulia Consiglieri Details of the poster presentations are as follows (all times in CDT): Title: Toward the development of an automated manufacturing process for hematopoietic stem cell gene therapiesDate/Time: Wednesday, May 14 from 5:30 to 7:00 p.m.Presenter: Vasileios Paraskevas #1302 Title: Anti-SGSH antibodies following hematopoietic stem cell (HSC) gene therapy in MPSIIIA patients neither impact engraftment of genetically modified HSC nor interfere with multi-compartment substrate reductionDate/Time: Thursday, May 15 from 5:30 to 7:00 p.m.Presenter: Brian Bigger#1513 Title: Correction of Glycogen Accumulation in Muscle, Heart and CNS in a Pre-Clinical Model of Hematopoietic Stem Cell Gene Therapy for Pompe DiseaseDate/Time: Thursday, May 15 from 5:30 to 7:00 p.m.Presenter: Piv Sagoo#1514 About MLDMLD is a rare and life-threatening inherited disease of the body’s metabolic system estimated to occur in approximately one in every 100,000 live births based on existing literature. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity, and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. In its late infantile form, mortality at five years from onset is estimated at 50 percent and 44 percent at 10 years for juvenile patients.i About Lenmeldy / LibmeldyLenmeldy™ (atidarsagene autotemcel), formerly known as OTL-200, is the only approved therapy in the U.S. for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early-symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD). For additional details about Lenmeldy, please refer to the full Prescribing Information. In Europe, Lenmeldy is known as Libmeldy®, where it has been approved by the European Commission (EC) and UK Medicines and Healthcare products Regulatory Agency (MHRA). For more information about Libmeldy, please see the Summary of Product Characteristics (SmPC) available on the EMA website. The program was originated by and developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. INDICATION LENMELDY™ (atidarsagene autotemcel) is an autologous hematopoietic stem cell-based gene therapy indicated for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ), or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD). IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Thrombosis and Thromboembolic Events: Treatment with LENMELDY may increase the risk of thrombosis and thromboembolic events. A child with PSEJ MLD died after experiencing a left hemisphere cerebral infarction secondary to a thrombotic event in a large blood vessel approximately 1 year after treatment with LENMELDY. Evaluate the risk factors for thrombosis prior to and after LENMELDY infusion according to best clinical practice. Encephalitis:Treatment with LENMELDY may increase the risk of encephalitis. A child with ESEJ developed a serious event of encephalitis after treatment with LENMELDY. The etiology of this event is unclear but attribution to LENMELDY cannot be ruled out. Treatment with LENMELDY may trigger a relapsing-remitting pattern of disease progression. No other events related to encephalitis have been reported during the clinical development of LENMELDY. Monitor children for signs or symptoms of encephalitis after LENMELDY treatment. Serious Infection:In the period between start of conditioning and within 1 year after LENMELDY treatment, severe Grade 3 infections occurred in 39% of all children (21% bacterial, 5% viral, 5% bacterial and viral or bacterial and fungal, and 8% unspecified). Grade 3 febrile neutropenia developed within 1 month after LENMELDY infusion in 82% of children. In the event of febrile neutropenia, monitor for signs and symptoms of infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. Monitor children for signs and symptoms of infection after myeloablative conditioning and LENMELDY infusion and treat appropriately. Administer prophylactic antimicrobials according to best clinical practice. Veno-Occlusive Disease: Three children (8%) treated in clinical trials of LENMELDY developed veno-occlusive disease (VOD) with one Grade 4 SAE and two Grade 3 AEs. None of these three events met Hy’s Law criteria. Monitor children for signs and symptoms of VOD including liver function tests in all children during the first month after LENMELDY infusion. Consider prophylaxis for VOD with anti-thrombotic agents based on risk factors for VOD and best clinical practice. Delayed Platelet Engraftment (DPE):DPE has been observed with LENMELDY treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in children with prolonged thrombocytopenia. In clinical trials of LENMELDY, 4 (10%) children had delayed platelet engraftment after day 60 (range day 67-109), with 3 children requiring platelet transfusions until engraftment occurred. Patients should be informed of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding until platelet engraftment and recovery are achieved. Neutrophil Engraftment Failure: There is a potential risk of neutrophil engraftment failure after treatment with LENMELDY. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a child treated with LENMELDY, provide rescue treatment with the unmanipulated back-up collection of CD34+ cells. Insertional Oncogenesis: There is a potential risk of LVV-mediated insertional oncogenesis after treatment with LENMELDY. Children treated with LENMELDY may develop hematologic malignancies and should be monitored life-long. Monitor for hematologic malignancies with a complete blood count (with differential) annually and integration site analysis as warranted for at least 15 years after treatment with LENMELDY. In the event that a malignancy occurs, contact Orchard Therapeutics at 1-888-878-0185 for reporting and to obtain instructions on collection of samples for testing. Hypersensitivity Reactions: The dimethyl sulfoxide (DMSO) in LENMELDY may cause hypersensitivity reactions, including anaphylaxis which is potentially life-threatening and requires immediate intervention. Hypersensitivity including anaphylaxis can occur in children with and without prior exposure to DSMO. Monitor for hypersensitivity reactions during infusion and after infusion. Anti-Retroviral Use: Children should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization, or for the expected duration of time needed for the elimination of the medications. Anti-retroviral medications may interfere with the manufacturing of LENMELDY. If a child requires antiretrovirals for HIV prophylaxis, initiation of LENMELDY treatment should be delayed until confirmation of a negative test for HIV. Interference With Serology Testing: Due to the likelihood of a false-positive test for HIV, children who have received LENMELDY should not be screened for HIV infection using a PCR-based assay. USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential Pregnancy TestingAs a precautionary measure, a negative serum pregnancy test must be confirmed prior to the start of mobilization, and reconfirmed prior to conditioning procedures, and before administration of LENMELDY in females of childbearing potential. Contraception Consult the Prescribing Information of the mobilization and conditioning agents for information on the need for effective contraception. Males capable of fathering a child and females of childbearing age should use an effective method of contraception from start of mobilization through at least 6 months after administration of LENMELDY. InfertilityThere are no data on the effects of LENMELDY on fertility. Data are available on the risk of infertility with myeloablative conditioning. In clinical trials of LENMELDY, seven children (50% of females) developed ovarian failure. Advise children of the option to cryopreserve semen or ova before treatment, if appropriate. For additional safety information, please see the full Prescribing Information. About Orchard TherapeuticsOrchard Therapeutics, a Kyowa Kirin company, is a global gene therapy leader focused on ending the devastation caused by genetic and other severe diseases by discovering, developing, and commercializing new treatments that tap into the curative potential of hematopoietic stem cell (HSC) gene therapy. In this approach, a patient’s own blood stem cells are genetically modified outside of the body and then reinserted, with the goal of correcting the underlying cause of disease with a single treatment. Founded in 2015, Orchard’s roots go back to some of the first research and clinical developments involving HSC gene therapy. Our team has played a central role in the evolution of this technology from a promising scientific idea to a potentially life-transforming reality. Today, Orchard is advancing a pipeline of HSC gene therapies designed to address serious diseases where the burden is immense for patients, families and society and current treatment options are limited or do not exist. For more information, please visit www.orchard-tx.com. About Kyowa KirinKyowa Kirin aims to discover and deliver novel medicines and treatments with life-changing value. As a Japan-based Global Specialty Pharmaceutical Company, we have invested in drug discovery and biotechnology innovation for more than 70 years and are currently working to engineer the next generation of antibodies and cell and gene therapies with the potential to help patients with high unmet medical needs, such as bone & mineral, intractable hematological diseases/hemato oncology, and rare diseases. A shared commitment to our values, to sustainable growth, and to making people smile unites us across the globe. You can learn more about the business of Kyowa Kirin at www.kyowakirin.com.______________________________iMahmood et al. Metachromatic Leukodystrophy: A Case of Triplets with the Late Infantile Variant and a Systematic Review of the Literature. Journal of Child Neurology 2010, DOI: http://doi.org.sutd.idm.oclc.org/10.1177/0883073809341669 Contact Benjamin Navon +1 857-248-9454 Benjamin.Navon@orchard-tx.com

iStock, PhonlamaiPhoto Beam Therapeutics and Verve Therapeutics have each built their lead candidates on a technique billed as a safer alternative to conventional CRISPR. Clinical results have so far been promising. Nine years ago this month, researchers led by Harvard University’s David Liu reported on a new gene editing technique, a variation on CRISPR/Cas9 that they dubbed base editing. Today, preliminary but encouraging results are trickling out from clinical trials on the first base editing therapies. Just last month, Beam Therapeutics announced that its candidate BEAM-302 can correct the disease-causing mutation in patients with alpha-1 antitrypsin deficiency. Weeks later, Verve Therapeutics released initial results from a Phase Ib trial showing that its VERVE-102 gene therapy reduced LDL cholesterol levels by half, on average, in four participants who received the highest dose. “I think the prospects and outlook [for base editing] look very positive right now,” Sami Corwin, an analyst at William Blair, told BioSpace . “We’ve seen it de-risked in three indications so far”—AATD, familial hypercholesterolemia and sickle cell disease (SCD). Beam owns the intellectual property behind base editing and, so far, has only licensed it to Verve, Beam President Giuseppe Ciaramella told BioSpace . But that may change: “Once you show success, I’m sure there are going to be some other companies that are going to be trying to use base editing to essentially do their own product,” he said. Base Editing Basics With CRISPR/Cas9 gene editing, researchers construct a guide RNA (gRNA) complementary to a targeted stretch of DNA. The gRNA is tethered to a Cas9 enzyme that snips a double-stranded break at the target, which is then repaired by the cell’s own machinery. It’s a process that carries risks, including that off-target breaks could be created and that breaks may not be properly repaired, creating unwanted mutations. “The problem is that [with] all of the nucleases, the only thing that they could do when they landed on the spot of DNA was making a double-stranded break, and . . . basically everything else is now left to the cell to sort out,” Ciaramella said. Double-stranded breaks “need to occur only under very controlled conditions when the cells are replicating because otherwise they can lead to all sorts of unpredictable editing outcomes.” The only CRISPR/Cas9-based therapy approved so far, Vertex and CRISPR Therapeutics’ Casgevy, relies on extracting bone marrow cells from a patient with SCD and editing them outside the body to disable a gene that suppresses production of fetal hemoglobin. The cells are then expanded and transplanted back into the patient, where they produce red blood cells with fetal hemoglobin as a stand-in for the adult hemoglobin that’s mutated in the disease. Casgevy is also approved for transfusion-dependent beta thalassemia. Base editing, like the original CRISPR/Cas9, uses a gRNA. However, it leverages a modified Cas9 that, rather than creating a double-strand break in the DNA, can chemically change an adenosine (A) base to a guanine (G) or a cytosine (C) to a thymine (T). Researchers can target either the coding DNA strand or its complementary partner for these edits, Ciaramella noted, which opens up more possibilities. “Essentially, we can achieve four edits with the two base editors that we’ve got.” Base editing is “actually much more versatile than maybe even people anticipated at the beginning,” when it was viewed mainly as a way to correct point mutations, Ciaramella added. For example, by making a change in the regulatory rather than the coding region of a gene, researchers can activate that gene. Beam: Running the Gamut After his group devised base editing, Liu and CRISPR pioneer Feng Zhang co-founded Beam specifically to develop therapeutics based on the technique. The company emerged from stealth in 2018 with $87 million in series A funding. The company has not confined itself to particular kinds of disorders or means of delivery. It has both in vivo and ex vivo programs for SCD and beta thalassemia alongside in vivo programs in alpha-1 antitrypsin deficiency (AATD) and glycogen storage disease 1a (GSD1a). Beam also has collaborations with Apellis and Pfizer, about which it’s revealed little. The candidate at the center of Beam’s March 10 announcement , BEAM-302, corrects a mutation that causes the body to produce a form of the AAT protein known as Z-AAT rather than the functional form, M-AAT. Z-AAT has deleterious effects on both the lungs and liver. BEAM-302 delivers base editing machinery to the liver, where AAT is made, via lipid nanoparticles. At sites in Australia, New Zealand, the Netherlands and the U.K., the company tested single intravenous doses of 15 mg, 30 mg and 60 mg in three-patient cohorts and found dose-dependent, durable increases in total AAT and decreases in Z-AAT, along with only minor adverse events. Total circulating AAT levels were high enough in the highest-dose group that those patients can be considered to no longer have progressive disease, Ciaramella said. He added, however, that these were only interim results and that the company is testing higher doses and considering redosing some patients. The AATD data “confirmed that the sensitivity and efficacy of the base editing technology was there,” Corwin said. Since the treatment was well-tolerated even at higher doses, the readout also suggested that an inflammatory response to another base editing candidate reported earlier by Verve was due to the lipid nanoparticle vehicle rather than the base editing machinery itself, she added. Other analysts also took note. Jefferies’ Michael Yee said in a note to investors that “safety has been a major area of focus in the context of issues from other LNP products for gene editing,” but that “BEAM safety looks clean.” He added that BEAM-302 “looks to have important benefits that differentiate from RNA editing and plasma-derived AAT therapy. . . . [W]e are seeing ‘correction’ of the disease with a one-time therapy.” With another program, Beam is seeking to set itself apart in the sickle cell disease space. Both bone marrow transplants and Casgevy treatment require patients to undergo a course of the chemotherapy drug busulfan to open up space in the marrow for the new blood-making cells that will be introduced. The treatment has side effects, including the possibility of impaired fertility. Beam’s ex vivo SCD candidate, BEAM-101, edits cells so that not only is fetal hemoglobin production switched on, but a receptor is tweaked to confer resistance to an antibody Beam devised. Rather than busulfan, patients are treated with the antibody, which starves unedited bone marrow cells of a growth factor needed to proliferate. “We can confer advantages of survival to the edited cells over unedited cells simply by changing a single amino acid in this receptor,” Ciaramella said. Beam presented positive safety and efficacy data on the first seven patients treated with BEAM-101 in a U.S.-based study at the American Society of Hematology meeting in December. Verve: A Focus on the Heart Boston-based Verve’s origin story begins with a competition entry that wasn’t selected, said CEO and co-founder Sek Kathiresan. The 2016 contest, run by the American Heart Association, promised $75 million in funding for an idea to tackle coronary heart disease. Kathiresan, then a professor at Harvard Medical School and director of Massachusetts General Hospital’s Center for Genomic Medicine, said he took inspiration from natural mutations that keep cholesterol levels low and thus protect people carrying the mutations from developing heart disease. Kathiresan wanted to develop a therapy that mimicked natural protective mutations. “The proposal was really: well, we understand what causes disease, which is cholesterol. We know a key way to stop this disease, which is to get cholesterol down and keep it down for a long time,” he told BioSpace . When the application was turned down, he forged ahead anyway, gathering the investors and initial team needed to found Verve in 2018. The company tested both base editing and traditional CRISPR/Cas9 on target genes in preclinical research, and “what ultimately led us to choose base editing was the possibility of it being a fair bit safer because it did not cut DNA in both strands, but rather just tried to make the single spelling change A to G at one spot,” he said. The editing was also precise: “we’re not really seeing any off targets elsewhere in the genome.” But for another of its programs, Verve settled on a different gene editor because it found base editing wasn’t the most effective way forward. The company now has three base editors in clinical trials, although the trial of VERVE-101 was paused last April after one patient developed grade 3 drug-induced thrombocytopenia within days of dosing. Verve, like Corwin, has since attributed those abnormalities to the lipid nanoparticle vector. Verve said at the time that it would instead prioritize VERVE-102, which like VERVE-101 treats heterozygous familial hypercholesterolemia, a genetic propensity to high cholesterol. VERVE-102 uses a different lipid nanoparticle from VERVE-101 that targets the PCSK9 gene for inactivation in liver cells. Last month, Verve announced IND clearance for VERVE-102 based on initial clinical data from outside the U.S. showing the therapy was well-tolerated. In its April 14 press release , the company reported a dose-dependent response and no serious adverse events in a Phase Ib trial, with a maximum LDL cholesterol reduction of 69% in the highest-dose cohort. Verve is now testing a still-higher dose and plans to begin a Phase II trial in the second half of this year, per its announcement. Meanwhile, VERVE-201, which targets the ANGPTL3 gene in liver cells, is in trials for the homozygous version of the condition as well as for patients whose hypercholesterolemia is not responding to other therapies. The first patient was dosed with VERVE-201 in a Phase Ib trial in Canada and the U.K. in November 2024. Getting this far has required breaking new ground in a few ways, Kathiresan said, from devising the mRNA and gRNA that would go into treatments to interfacing with the FDA. “We were actually the first to go in front of the U.S. FDA and propose in vivo gene editing in humans,” he notes, as other companies in the space have so far run their early trials in other countries, just as Verve did for VERVE-102. Gene editing and other gene therapies are usually associated with rare disease, often those with no other effective treatments. High cholesterol is both common and treatable, but Kathiresan argued gene editing could nonetheless fill an important unmet need. “Theoretically, current medicines can lower LDL at a single time point [by] 40, 50, 60%. . . . But the challenge is discontinuation. A year out after starting any cardiovascular medication, a third to 50% of people have discontinued,” he said. In contrast, with base editing, “you basically lower LDL and then keep it low for your whole life. And that can really have a dramatic impact on your risk for heart attack.” Ultimately, though, Kathiresan characterized base editing not as a silver bullet but as one tool companies can consider. “I think base editing will have a place. . . . But there will be other technologies as well that I think may be even better suited for a given target,” he said. “So I think right now the focus is really on the targets and the disease indications, and then, at least for us, finding the right gene editing tool for that target.”