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Lysosomal Disorders

Oncology

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Authors

Alison R. Sehgal, MD, assistant professor of medicine, hematologist/medical oncologist, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, discusses the clinical implications of CAR T-cell therapy in diffuse large B-cell lymphoma (DLBCL).

Dr. Sehgal on the Clinical Implications of CAR T-Cell Therapy in DLBCL

Alison R. Sehgal, MD, assistant professor of medicine, hematologist/medical oncologist, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, discusses ways to manage cytokine release syndrome (CRS) and neurotoxicity associated with CAR T-cell therapy.

Dr. Sehgal on Managing CRS and Neurotoxicity From CAR T-Cell Therapy

Patient use of the 2 FDA-approved gene therapy products for sickle cell disease (SCD), Vertex Pharmaceuticals' and CRISPR Therapeutics’ 

 (exa-cel; marketed as Casgevy) and bluebird bio’s 

 (lovo-cel; marketed as Lyfgenia), in the commercial setting has remained low.

Despite the approval of both gene therapy products by the FDA occurring simultaneously on December 8, 2023, only 4 patients have begun treatment with lovo-cel in the commercial setting, while 20 patients are reported to have begun treatment with exa-cel. Alongside the number for lovo-cel, bluebird also pointed out that this year 4 patients have started on elivaldogene autotemcel (Lenti-D, Skysona), its marketed gene therapy for cerebral adrenoleukodystrophy, and 19 patients have started on betibeglogene autotemcel (beti-cel, Zynteglo), its marketed gene therapy for transfusion dependent thalassemia (TDT). As such, bluebird bio has reported 23 total cell collections for SCD/TDT gene therapies lovo-cel and beti-cel. The company expects that patient uptake of the 3 aforementioned therapies will continue to increase, with 85 patient starts expected across the therapies by the end of the year.

“We are seeing clear evidence that our commercial launch is accelerating, with over 20 cell collections completed in SCD and TDT to date in 2024, and more than 40 additional patients already scheduled to initiate the treatment journey for a bluebird gene therapy by the end of this year,” Andrew Obenshain, MBA, the chief executive officer of bluebird bio, said in a statement.

 “We are further encouraged by the commitment to provide patient access across both commercial and government payers, most recently conveyed through multiple positive Medicaid decisions and the growing number of published coverage policies for Lyfgenia, and we expect approximately 85 patient starts across our portfolio this year.”

Notably, unlike lovo-cel, exa-cel is indicated for both SCD and TDT. Since Vertex has not clarified the breakdown of patients treated with exa-cel for each disease, direct comparison is difficult. The approval in TDT came slightly later, with 

“Vertex delivered another strong quarter of revenue growth coupled with outstanding execution across the business, and we are increasing our full year product revenue guidance,” Reshma Kewalramani, MD, the chief executive officer and president of Vertex, said in an August 1, 2024, statement.

 “Our focus for the second half of the year remains on commercial execution in cystic fibrosis and the global launch of Casgevy, readying for the upcoming potential launches of the vanzacaftor triple in cystic fibrosis and suzetrigine in acute pain, while rapidly advancing a robust pipeline that is poised to deliver value for patients and shareholders for the long term.”

Beyond gene therapy for SCD and TDT, uptake of 

hemophilia gene therapies has also been slow

. Although BioMarin’s valoctocogene roxaparvovec (val-rox, marketed as Roctavian) was approved in June 2023, the first patient outside of clinical trials 

 until December 2023, at the Center for Inherited Bleeding Disorders (CIBD) in California.

 Just this month, BioMarin announced that 

 with regard to val-rox, with the company now mainly focusing on distributing the gene therapy in the United States, Germany, and Italy, the 3 countries in which it has been approved for use by relevant regulatory authorities and is reimbursed.

 UniQure and CSL Behring’s hemophilia B gene therapy, etranacogene dezaparvovec (marketed as Hemgenix), which was 

, has also been slow to be embraced by patients.

“We haven't seen a lot of patients dosed yet,” Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, told 

 regarding Hemegenix earlier in 2024. “And I don't think that’s related to either the enthusiasm of the clinicians or the patients, but really just the mechanics of how to deliver this in the clinical space, as opposed to the research trials... We've seen that a lot of the hemophilia treatment center sites have got their components together, their infrastructure and personnel so that they can actually start delivering this in the commercial setting. And so, I'm really looking forward to seeing this making a difference in patients' lives in a real world setting.”

REFERENCES
1. bluebird bio reports second quarter 2024 results and highlights operational progress and 2024 guidance. News release. bluebird bio, Inc. August 14, 2024. Accessed August 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-second-quarter-2024-results-and-highlights
2. Stock dive for bluebird as sickle cell gene therapy lags behind Vertex rival. News article. Anna Bratulic. FirstWord Pharma. August 14, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5885598
3. Vertex announces US FDA approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Incorporated. January 16, 2024. Accessed August 15, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
4. Vertex reports second quarter 2024 financial results. News release. Vertex Pharmaceuticals Incorporated. August 1, 2024. Accessed August 15, 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-second-quarter-2024-financial-results
5. Center for Inherited Blood Disorders Administers Country's First Gene Therapy Infusion to Treat Hemophilia A. News release. Center for Inherited Blood Disorders. January 11, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5817834?from=article
6. BioMarin Announces Updated Strategy for ROCTAVIAN® to Focus on U.S., Germany and Ital. News release. BioMarin Pharmaceutical Inc. August 5, 2024. Accessed August 15, 2024. https://investors.biomarin.com/news/news-details/2024/BioMarin-Announces-Updated-Strategy-for-ROCTAVIAN-to-Focus-on-U.S.-Germany-and-Italy/default.aspx
7. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. Accessed August 15, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

bluebird bio has reported 23 total cell collections for SCD and TDT gene therapies lovo-cel and beti-cel and Vertex Pharmaceuticals has reported approximately 20 cell collections for SCD/TDT gene therapy exa-cel.

Topic

Uptake of Nononcology Gene Therapy Remains Slow in Hematology

(arsa-cel, OTL-200; Orchard Therapeutics) is a gene-edited cell therapy designed to restore arylsulfatase A (ARSA) enzyme activity in children with presymptomatic (PS) late infantile (LI), PS early juvenile (EJ), or early symptomatic (ES) early juvenile (EJ) metachromatic leukodystrophy (MLD).

 arsa-cel under the name Lenmeldy to become the first gene therapy for children with MLD to be approved in the United States, following its approval in the European Union, UK, Iceland, Switzerland, Liechtenstein and Norway under the name Libmeldy.1 Orchard Therapeutics previously announced that the FDA had accepted the biologics license application with 

The FDA’s decision was based on data from patients treated with arsa-cel across 2 clinical trials (NCT01560182; NCT03392987) and additional patients treated in expanded access frameworks. These patients had follow-up times ranging from 0.64 years to 12.19 years (median, 6.76).

“Metachromatic leukodystrophy, is a really important unmet need in the pediatric community. So, this is a disease that's rare, it affects about one in 40,000 children. And up until recently, we have had no curative treatment option for this,” Madeleine Powys, MBBS, Staff Specialist, Blood Transplant and Cell Therapies, The Children's Hospital at Westmead, told 

. "Autologous hematopoietic stem cell gene therapy has offered really promising new hope for these patients.”

Madeleine Powys, MBBS, on Lessons Learned With Libmeldy

Arsa-cel is currently being evaluated in 6 participants enrolled in a phase 3 clinical trial (NCT04283227). The trial enrolled participants with documented biochemical and molecular diagnosis of MLD, including low ARSA activity and identification of 2 disease-causing ARSA alleles, with novel mutations analyzed and excluded as common polymorphisms, alongside specific genotype criteria. Symptomatic individuals must have onset between 7 and 17 years of age, or pre-symptomatic participants must be less than 17 years at treatment initiation and have a sibling with late-juvenile MLD variant, along with normal cognitive and motor function, with seizures or disease signs revealed by instrumental evaluations not being exclusionary if present alone, and compliance with contraceptive use requirements if applicable, with signed informed consent or assent provided by the participant or guardian.

The exclusion criteria for the study include documented HIV infection, malignant neoplasia except localized skin cancer or hereditary cancer syndrome unless successfully treated with no recurrence, myelodysplasia, acute myeloid leukemia, or serious hematological disorders, current enrollment in other interventional trials, prior allogeneic HSPC gene therapy or gene therapy, symptomatic herpes zoster unresponsive to treatment, active tuberculosis unless on antibiotic prophylaxis, acute or chronic stable Hepatitis B or positive Hepatitis C RNA test result unless specific conditions are met, end-organ dysfunction, severe infection not responsive to treatment, or other severe diseases deemed inappropriate for the study by the investigator. Additionally, testing for other transmissible infectious agents may be considered, and participants with elevated liver enzymes or bilirubin may be included after discussion and agreement with the medical monitor.

The study’s primary measures involve assessing the OTpbmsL-200 Arylsulfatase A (ARSA) activity levels in cerebrospinal fluid (CSF) and the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter brain regions, both evaluated at 24 months post-treatment, with changes from baseline being monitored.

Secondary measures involve evaluating changes in ARSA activity levels in CSF and neuronal metabolite ratio in white matter brain regions, assessing ARSA levels in peripheral blood mononuclear cells (PBMCs) and specific subtypes, comparing neuronal metabolite ratios to baseline, siblings, or untreated controls, determining engraftment through lentiviral positivity in bone marrow progenitors and vector copy number in BM cells and PBMCs, assessing severity scale for brain MRI, neurocognitive function, full neurological clinical examination, gross motor function classification, nerve conduction velocity, Vineland Adaptive Behavior Scale, and monitoring conditioning regimen and non-conditioning-related adverse events up to 8 years post gene therapy, along with hematological reconstitution, infusion-related reactions, immune response, abnormal clonal proliferation, replication-competent lentivirus, and integration site analysis findings over time.

, held February 4-9, in San Diego, California, by Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy. The data were from 5 patients with LJ MLD that had follow-up ranging from 3.2 to 21.3 months (median, 17.3). At the time of treatment, 3 patients had PS MLD and 2 had ES MLD. The group included a 2.7-year-old girl (PS), a 9.9-year-old boy (ES), a 15.2-year-old boy (PS), a 6.6-year-old girl (PS), and 10.9-year-old boy (ES) as of the December 2023 cutoff date.

"This represents of course, the proof of principle that gene therapy with ex- vivo lentiviral gene therapy into stem cells can correct a lysosomal storage disorder (LSD)... and could be applicable to other LSDS. So we're working on new diseases to bring this approach of enzyme correction also to other LSDs," investigator Alessandro Aiuti, MD, PhD, deputy director, clinical research, and head, Clinical Research Unit, San Raffaele Telethon Institute for gene therapy, and Group leader, Pathogenesis and therapy, primary immunodeficiencies unit, and full professor, Università Vita Salute San Raffaele, and chief of clinic, Pediatric Immunohematology Unit, San Raffaele, told 

Data from these participants showed that they all had normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings. Time to neutrophil engraftment ranged from 26 to 42 days (median, 33) posttreatment and time to platelet engraftment ranged from 25 to 46 days (median, 26) posttreatment. ARSA activity reached supranormal levels in the PBMCs and in CD15+ cells and increased to normal levels in the CSF in 3 patients for whom central nervous system pharmacodynamic efficacy measures were available.At 90 days after administration of arsa-cel transduced bone marrow progenitors made up between 23.81% to 81.25% of bone marrow progenitors. At this time point, the PBMCs showed a median vector copy number (VCN) of 0.49 copies/cell and the CD15+ cells showed a median VCN of 0.82 copies/cell.

In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel. One nonserious AE deemed potentially related to the therapy, a case of erythematous rash, occurred in 1 patient. No SAEs deemed potentially related to the Busulfan conditioning regimen occurred; although cases of febrile neutropenia, cytopenia, and stomatitis were deemed to have potential relation to the regimen. An SAE of upper respiratory tract infection occurred in 1 patient. One patient with prolonged thrombocytopenia who had previously experienced treatment-failure with allogeneic transplant in the form of autologous reconstitution was administered thrombopoietin receptor agonist therapy for 5 months. No multilineage engraftment of transduced cells or malignancy occurred and there was no indication of clonal expansion or replication competent lentivirus.

1. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph
2. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed September 18, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
3. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsageneautotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #92
4. Gallo V, Calbi V, De Mattia F, et al. Lentiviral hematopoietic stem cell gene therapy (atidarsageneautotemcel) for late juvenile metachromatic leukodystrophy (MLD). Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #96

The gene-edited cell therapy has been approved as Lenmeldy by the FDA. 

Phase 3 Trial Seeks to Continue Supporting Arsa-Cel Gene Therapy for MLD 

This is the second part of an interview with David Porter, MD. For the first part, 

The director of cell therapy and transplant at Penn Medicine also summed up his main message regarding the current state of the field in general.

David Porter, MD, on Progress With Cross-Disciplinary Collaboration in Cell Therapy for Autoimmune Disease

“I will say it's been tremendously rewarding at my institution—at University of Pennsylvania—that we've been able to put together a cross disciplinary group with expertise in all these areas who have worked beautifully together. I think that's going to be critical to the success of this field.”

As chimeric antigen receptor T-cell (CAR-T) therapy has made headway into the realm of clinical trials for autoimmune disease, many doctors and other stakeholders in the field are beginning to think about the practical considerations needed for effectively implementing these new therapies. Indeed, even in early clinical trials, a new need for cross-disciplinary collaboration has become clear. As it currently stands, most doctors and other healthcare professionals who have experience working with CAR-T work in oncology, specifically with hematologic malignancies, where CAR-T was first explored and the only discipline in which CAR-T is now a staple of standard of care treatment. These practitioners are experts on administration of CAR-T and management of the unique risks for toxicities that come with the advanced therapeutic. On the other hand, doctors and other healthcare professionals who have expertise in treating autoimmune disease, tend to have comparatively little experience in dealing with CAR-T. As such, when it comes to the clinical application of CAR-T in autoimmune disease, the need for collaboration between these 2 groups—CAR-T experts and disease area experts—has become apparent.

As part of a larger discussion on the learnings from 2024 in cell therapy for autoimmune disease, 

 asked David Porter, MD, the director of cell therapy and transplant at Penn Medicine, about the progress that has been made in fostering collaboration in the field. Porter spoke about the substantial collaboration that has been facilitated at his own institution, and noted that 2024 helped show that such collaboration is possible. Porter also summed up his main message regarding the current state of the field in general, and emphasized that it is an exciting time, but that a lot still remains to be learned regarding cell therapy in autoimmune disease.

Videos

Joseph Fraietta, PhD, previews his new podcast, ImmunoLogic

ImmunoLogic Episode 0

an assistant professor of microbiology and the director of the Fraietta Lab at the University of Pennsylvania! Our hope is that this show will become a critical forum for clinicians, translational researchers, and biotech professionals to explore the evolving landscape of immunotherapy. We're seeking to bridge cutting-edge research with practical applications and delve into how immune-based therapies transition from innovative discoveries to transformative patient care solutions.

In this short preview episode, Fraietta outlines the podcast’s mission to scrutinize the critical milestones shaping immunotherapy today and discuss how episodes will analyze the journey from bench to bedside—focusing on the real-world implementation of clinical data and the impact of regulatory achievements on patient outcomes. Topics will include discussions on chimeric antigen receptor (CAR) T-cell therapies, tumor-infiltrating lymphocyte (TIL)-based approaches, antibody-driven treatments, and the latest advances in gene editing technologies such as CRISPR, with a goal of expanding the conversation outside of the field of oncology.

 will be tailored for an audience fluent in the language of medicine and biotechnology, offering data-driven insights while maintaining accessibility. With its first full episode launching in early 2025, this podcast promises to be an essential resource for those driving the future of immunotherapy.

Interested in co-hosting an episode or being a guest? Have feedback to share? 

If you'd like to get in touch to talk about the show, contact our editorial director, Matt Hoffman: 

Hosted by Joseph Fraietta, PhD, ImmunoLogic will be tailored for an audience fluent in the language of medicine and biotechnology, offering data-driven insights while maintaining accessibility.

CGTLive® Presents: ImmunoLogic, A Video Podcast With Joseph Fraietta, PhD

Genethon and Hansa Biopharma have initiated a phase 2 clinical trial (GNT-018-IDES; NCT06518005) evaluating Hansa’s immunoglobulin G (IgG) antibody cleaving enzyme therapy imlifidase (marketed in Europe under the name Idefirix) as a pretreatment for Genethon’s GNT-0003, an investigational adeno-associated virus serotype 8 (AAV8) vector-based gene therapy intended to treat severe Crigler–Najjar syndrome.

The single-arm GNT-018-IDES study, which will seek to enroll 3 adult patients with preformed antiAAV8 antibodies and Crigler-Najjar syndrome who need at least 6 hours per day of phototherapy, will include a 3 month observational period after screening. After the observational period, patients will be treated with imlifidase and subsequently receive GNT-0003. The companies anticipate reporting initial results from the study at some point next year.

Imlifidase is intended to allow for the treatment with AAV8 vector-based gene therapy of patients who would not normally be eligible for such therapies because of preexisting antibodies. It functions by cleaving IgG-antibodies in order to inhibit their activity. Imlifidase is currently available in Europe under a conditional marketing approval for desensitization treatment of highly sensitized patients who received adult kidney transplants and who have a positive crossmatch against an available deceased donor.

“We know that antiAAV antibodies prevent up to 1 in 3 people from benefitting from gene therapies using AAV-vectors,” Søren Tulstrup, MSc, the president and CEO of Hansa Biopharma, said in a statement.

 “That’s why our collaboration with Genethon and the initiation of the phase 2 clinical trial in Crigler-Najjar syndrome is so important. This collaboration with Genethon is the second of our 3 partnerships with leading gene therapy companies to have reached the clinical stage, marking an important milestone in our efforts to enable a much larger group of patients to benefit from potentially lifesaving gene therapies.”

Outside of GNT-018-IDES, GNT-0003 is also being evaluated as a monotherapy in a pivotal phase 1/2 clinical trial (NCT03466463). The gene therapy 

received PRIority MEdicines (PRIME) designation

 from the European Medicines Agency in March 2023.

"This new clinical trial reflects Genethon’s commitment in pursuing innovative strategies to ensure and broaden access to gene therapies for patients suffering from rare diseases,” Frederic Revah, PhD, the chief executive officer of Genethon, added to the statement.

 “Patients with preexisting neutralizing antibodies against AAV vectors cannot today benefit from gene therapy. The initiation of this clinical trial and the collaboration with Hansa Biopharma is a crucial step for Genethon and highlights several years of pioneering research to understand and control the immune response to AAV in order to make gene therapy more effective and to increase the number of patients able to access it."

Crigler-Najjar syndrome, an autosomal recessive inherited disorder, is caused by mutations in the 

 gene, which lead to decreased or absent UDP-glucuronosyltransferase enzyme levels.

 The lack of this enzyme leads to the build-up of unconjugated bilirubin. GNT-003 is delivered via intravenous injection and is intended to provide normal copies of 

Results from an earlier portion of the monotherapy trial for GNT-0003 

 The data showed that patients with the rare liver disease who received the trial’s higher dose (n = 3; 5×10

 vg/kg) experienced a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration.

“Although our study is small, among the patients who received the dose of 5×10

 vg/kg, GNT-0003 restored UGT1A1 activity to levels that permitted suspension of phototherapy, and the efficacy persisted at 18 months after the treatment,” study author Lorenzo D’Antiga, MD, of the Department of Pediatric Hepatology, Gastroenterology, and Transplantation at Hospital Papa Giovanni XXIII, in Bergamo, Italy, and colleagues wrote.

 “A test of replication in a larger, well-characterized cohort of patients will be important.”

REFERENCES
1. Genethon and Hansa Biopharma announce initiation of a Phase 2 trial of imlifidase as a pre-treatment to GNT-0003 in severe Crigler-Najjar syndrome. News release. Hansa Biopharma. December 3, 2024. Accessed December 3, 2024. https://www.hansabiopharma.com/media/press-releases/2024/genethon-and-hansa-biopharma-announce-initiation-of-a-phase-2-trial-of-imlifidase-as-a-pre-treatment-to-gnt-0003-in-severe-crigler-najjar-syndrome/
2. Genethongiven PRIME status by EMA for gene therapy to treat Crigler-Najjar syndrome, a rare liver disease. News release. Genethon. March 6, 2023. Accessed December 3, 2024. https://www.genethon.com/app/uploads/2023/03/PRIME-Status_EMA_Gene_therapy_Crigler_N_23_03_06-1.pdf
3. Bhandari J, Thada PK, Yadav D. Crigler Najjar Syndrome. National Library of Medicine. Website Accessed January 10, 2023. https://www.ncbi.nlm.nih.gov/books/NBK562171/
4. D’Antinga L, Beuers U, Ronzitti G, et al. Gene Therapy in Patients with the Crigler–Najjar Syndrome. 

. 2023; 389:620-631. doi:10.1056/NEJMoa2214084

The phase 2 trial will assess Hansa’s imlifidase as a pretreatment for Genethon’s GNT-0003.

Genethon and Hansa Biopharma Launch Trial for Gene Therapy and Antibody Cleaving Enzyme Therapy Combination Treatment in Crigler-Najjar Syndrome

For all of 2024, our team was following the clinical development of targeted and novel engineered approaches to the treatment of patients with various medical disorders. These efforts included holding in-depth conversations with experts in the clinical care of these individuals, as well as in cell and gene therapy development, culminating in our coverage of each step of progress that the most exciting cellular and genetic treatments have made along the pipeline.

Part of those conversations resulted in our long-form approaches to reporting on the latest cell and gene news in the form of feature stories. When you spend all year bringing the latest information to the website's front page, sometimes there's a longer story to tell. 

Here, we'll offer previews of some of the most-read features and long-form content from 

'scoverage this year. Click the buttons to read further into these stories.

Real-World Experience With Duchenne Muscular Dystrophy Gene Therapy

Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (marketed as Elevidys), an adeno-associated virus (AAV) vector-based gene therapy for patients with Duchenne muscular dystrophy (DMD), was originally granted FDA approval under an accelerated approval pathway for a limited indication on June 22, 2023: ambulatory patients aged 4 to 5 years with DMD and a confirmed mutation in the DMD gene, excluding patients with any deletion in exon 8 and/or exon 9. Later, on June 20, 2024, the FDA approved the gene therapy for use in a broader indication: ambulatory patients (via traditional approval) and nonambulatory patients (via accelerated approval) with a confirmed mutation in the 

 gene who are 4 years of age or older and who do not have any deletion in exon 8 or exon 9 in the gene.

A Slow Embrace: Hemophilia's Gradual Adoption of Gene Therapy

The treatment landscape for patients with hemophilia has been enriched with one-time gene therapies, as of the November 2022 United States (US) approval of etranacogene dezaparvovec and the June 2023 US approval of valoctocogene roxaparvovec, both adeno associated virus (AAV) vector gene therapies.

UniQure and CSL Behring’s etranacogene dezaparvovec, marketed as Hemgenix, is approved for treating adults with hemophilia B who currently use Factor IX (FIX) prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes. BioMarin’s valoctocogene roxaparvovec, marketed as Roctavian, is approved for the treatment of adults with severe hemophilia A defined as congenital factor VIII (FVIII) deficiency with FVIII activity of less than 1 IU/dL who do not have antibodies to adeno-associated virus serotype 5 (AAV5) according to an FDA-approved test.

Navigating a Novel Therapy Frontier: Gene Therapy's Stunted Impact on Leukodystrophies

Leukodystrophies are a group of inherited neurological disorders in which genetic mutations affect the myelin sheath, and are categorized as rare diseases, with a prevalence of around 1 in 7000 live births. Researchers have identified more than 50 types of leukodystrophies, with some common types including adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Krabbe disease or globoid cell leukodystrophy, and Canavan disease.

Despite their rarity, leukodystrophies are a prime target for gene therapy as most affected patients have a single gene mutation responsible for the disease phenotype. Substantial progress has been made in the field, with 2 gene therapies approved for leukodystrophies in the United States (US) in 2022 and 2024: bluebird bio’s elivaldogene autotemcel (eli-cel/Skysona) for cerebral ALD and Orchard Therapeutics’ atidarsagene autotemcel (arsa-cel/Lenmeldy) for early-onset MLD.

Choosing the Right Treatment Path for Sickle Cell Disease

The molecular basis of sickle cell disease (SCD), an inherited blood disorder characterized by red blood cells (RBCs) that carry mostly an abnormal form of hemoglobin that sometimes results in sickle-shaped RBCs, has been well-understood since at least the 1950s.

 Despite this knowledge of its pathophysiology, treatment options for SCD were quite limited for many decades afterward. Up until about 10 years ago, the main treatment option for SCD was the small-molecule drug hydroxyurea.

Now, the landscape of care for SCD is rapidly changing. On a single day in 2023—December 8—the field of hematology was shaken by the FDA’s simultaneous approval of 2 gene therapy products for the treatment of SCD: Vertex Pharmaceuticals' and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; marketed as Casgevy) and bluebird bio’s lovotibeglogene autotemcel (lovo-cel; marketed as Lyfgenia).

Cell Therapies Hope to Be Next Frontier for Alzheimer Disease

Alzheimer disease (AD) is a growing problem, affecting nearly 7 million people in the United States. In 2021, AD was the fifth-leading cause of death among people aged 65 years and older. Prior to 2023, the field of research for AD had stood relatively stagnant for 10 years until the FDA approved the controversial anti-amyloid therapy aducanumab (Aduhelm).

Take a look what stood out as pillars of progress and success from all of CGTLive's most popular feature stories in 2024.

Alison R. Sehgal, MD

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