Glybera (alipogene tiparvovec) / uniQure, Chiesi, Xenon - LARVOL DELTA

AAV KP1 Efficiently Transduces Human Cell Lines In Vitro and Mouse Liver but Not Non-Human Primate Liver After Intravenous Injection (ASGCT 2024) - "To date, seven AAV gene therapy drugs have been approved including Glybera (2012), Luxturna (2017), Zolgensma (2019), Upstaza (2022), Roctavian (2022), Hemgenix (2022), and ELEVIDYS (2023)...Our observation is consistent with other reported studies in rhesus and cynomolgus monkeys (Pekrun et al., 2022; Catalyst Biosciences, 2020). The underlying cause of low transduction in NHP liver remains to be understood and whether KP1 can efficiently transduce human hepatocytes in human patients remains unknown."

Preclinical • Gastrointestinal Cancer • Gene Therapies • Hepatocellular Cancer • Liver Cancer • Solid Tumor

Viral Vectors in Gene Replacement Therapy. (PubMed, Biochemistry (Mosc)) - "Special attention is given to successful preclinical and clinical studies that have led to the approval of gene therapies: six AAV-based (Glybera® for lipoprotein lipase deficiency, Luxturna® for retinal dystrophy, Zolgensma® for spinal muscular atrophy, Upstaza® for AADC, Roctavian® for hemophilia A, and Hemgenix® for hemophilia B) and three LV-based (Libmeldy® for infantile metachromatic leukodystrophy, Zynteglo® for β-thalassemia, and Skysona® for ALD). The review also discusses the problems that arise in the development of gene therapy treatments, which, nevertheless, do not overshadow the successes of already developed gene therapies and the hope these treatments give to long-suffering patients and their families."

Journal • Review • Viral vector • Beta-Thalassemia • CNS Disorders • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Inherited Retinal Dystrophy • Metabolic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Ophthalmology • Rare Diseases • LPL

GENIALL: Glybera Registry, Lipoprotein Lipase Deficient (LPLD) Patients (clinicaltrials.gov) - P=N/A | N=16 | Completed | Sponsor: UniQure Biopharma B.V.

Trial completion date • Trial primary completion date • Dyslipidemia • Metabolic Disorders

GENIALL: Glybera Registry, Lipoprotein Lipase Deficient (LPLD) Patients (clinicaltrials.gov) - P=N/A | N=16 | Completed | Sponsor: UniQure Biopharma B.V. | Active, not recruiting ➔ Completed

Trial completion • Dyslipidemia • Metabolic Disorders

Preclinical Development and Characterization of Novel Adeno-Associated Viral Vectors for the Treatment of Lipoprotein Lipase Deficiency. (PubMed, Hum Gene Ther) - "Glybera was one of the first adeno-associated virus (AAV) gene replacement therapy to receive European Medicines Agency regulatory approval for the treatment of LPLD...These results highlight the feasibility of developing a superior AAV vector for the treatment of LPLD and provide critical insight for initiating studies in larger animal models. The identification of an AAV gene therapy vector that is more efficacious at lower doses, when paired with recent advances in production and manufacturing technologies, will ultimately translate to increased safety and accessibility for patients."

Journal • Preclinical • Viral vector • Gene Therapies • LPL

Re-Development of Glybera: A Novel Adeno-Associated Virus Gene Therapy for the Treatment of Lipoprotein Lipase Deficiency (ASGCT 2023) - "Our results collectively suggest that it is feasible to develop a superior AAV-based gene therapy product for the treatment of LPLD. The identification of a novel AAV formulation that is superior to Glybera at lower doses, when paired with recent advances in AAV manufacturing processes and scale-up, will translate to deliver a potent drug with increased safety and efficacy, at a lower manufacturing cost."

Gene therapy • Dyslipidemia • Gene Therapies • Hypertriglyceridemia • Pancreatitis • LPL

Genetic engineering of baculovirus-insect cell system to improve protein production. (PubMed, Front Bioeng Biotechnol) - "To date, eleven BEVS-derived products have been approved for use, including four human vaccines [Cervarix against cervical cancer caused by human papillomavirus (HPV), Flublok and Flublok Quadrivalent against seasonal influenza, Nuvaxovid/Covovax against COVID-19], two human therapeutics [Provenge against prostate cancer and Glybera against hereditary lipoprotein lipase deficiency (LPLD)] and five veterinary vaccines (Porcilis Pesti, BAYOVAC CSF E2, Circumvent PCV, Ingelvac CircoFLEX and Porcilis PCV). As the demand for biotechnology increases, there has been a concomitant effort into optimizing yield, stability and protein glycosylation through genetic engineering and the manipulation of baculovirus vector and host cells. In this review, we summarize the strategies and technological advances of BEVS in recent years and explore how this will be used to inform the further development and application of this system."

Journal • Review • Cervical Cancer • Gene Therapies • Genito-urinary Cancer • Infectious Disease • Influenza • Novel Coronavirus Disease • Oncology • Prostate Cancer • Respiratory Diseases • Solid Tumor • LPL

Liver Gene Therapy. (PubMed, Hum Gene Ther) - "Glybera was the first liver targeted gene therapy to be approved for patients with lipoprotein lipsase deficiency...Roctavian, the first gene therapy for treatment for hemophilia A, has received a favourable opinion from the European Medicines agency (EMA). Another, Etranacogene dezaparvovec (AMT-061) for hemophilia B is also in the final stages of approval. A number of other liver targeted gene therapy products are at an advanced stage of development, thus heralding a new era of potentially curative molecular medicine. This review explores the recent clinical advances in liver targeted gene therapy as well as the challenges that need to be overcome for the widespread adoption of this new treatment paradigm."

Journal • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Hepatology • Metabolic Disorders • Rare Diseases • Transplantation

An overview of health technology assessments of gene therapies with the focus on cost-effectiveness models. (PubMed, J Mark Access Health Policy) - "We identified economic models of gene therapies from six countries (NICE, IQWiG, SMC, HAS, CADTH, ICER) and focused on nine agents (Glybera, Imlygic, Strimvelis, Yescarta, Kymriah, Luxturna, Zynteglo, Zolgensma, Tecartus)...Although challenges were resolved by adjustments to the currently used value assessment framework, new methodological approaches would be useful. In addition, to improve the methods and quality of an evaluation, further research would be valuable."

HEOR • Journal • Review • Gene Therapies • Genetic Disorders

"A fact earlier demonstrated by Glybera (remember Glybera?) and Strimvelis." (@JacobPlieth)

Evolving AAV-delivered therapeutics towards ultimate cures. (PubMed, J Mol Med (Berl)) - "Since the first AAV-derived therapeutics Glybera was approved by the European Medicines Agency (EMA) in 2012, there is an increasing number of AAV-based gene augmentation therapies that have been developed and tested for treating incurable genetic diseases. In the subsequent years, the United States Food and Drug Administration (FDA) approved two additional AAV gene therapy products, Luxturna and Zolgensma, to be launched into the market...Here, we describe the clinical updates of AAV gene therapies and the latest development using AAV to deliver the CRISPR components as gene editing therapeutics. We also discuss the major challenges and safety concerns associated with AAV delivery and CRISPR therapeutics, and highlight the recent achievement and toxicity issues reported from clinical applications."

Journal • Review • Gene Therapies

[VIRTUAL] The Comparison of GENE Therapies Approvals in Europe and ASIA (ISPOR-EU 2020) - "METHODS : The official websites of European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, Ministry of Food and Drug Safety (MFDS) in South Korea, and National Medical Products Administration (NMPA) in China, were searched to identify the gene therapies granted marketing authorization until February 2020.RESULTS : A total of 7 GTs were approved in Europe, among which Glybera® was withdrawn since October 2017. Kymriah® was designated as orphan drug by South Korea in March 2019 to accelerate its approval. CONCLUSIONS : Europe is ahead of Asian countries with more GTs approved, while Asian countries are exploring proactive strategies to foster innovative GTs market access."

Gene Therapies

Recombinant Adeno-Associated Virus Gene Therapy in Light of Luxturna (and Zolgensma and Glybera): Where Are We, and How Did We Get Here? (PubMed, Annu Rev Virol) - "Expected final online publication date for the Annual Review of Virology Volume 6 is September 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates."

Journal • Rare Diseases

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy. (PubMed, Korean Circ J) - "...Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters...Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in..."

Journal • Review • Atherosclerosis • Biosimilar • Cardiovascular • Dyslipidemia

Dyslipidaemia: what's around the corner? (PubMed) - "Specialised therapies are in development for treatment of orphan disoders such as homozygous familial hypercholesterolaemia (lomitapide) or familial chylomicroaemia (alipogene tiparvovec). These novel lipid-lowering agents are likely to find uses in treating patients at the highest cardiovascular risk."

Journal • Acute Coronary Syndrome • Atherosclerosis • Biosimilar • Dyslipidemia • Fibrosis • Immunology • Inflammation

Duration of effect of alipogene tiparvovec treatment, which was administered in other studies (clinicaltrials.gov) - P=NA, N=19; Enrolling by invitation -> Suspended

Trial suspended • Dyslipidemia

Amsterdam Molecular Therapeutics announces negative equity position (AMT Biopharma) - Amsterdam Molecular Therapeutics announced that the Company has a negative equity position, as a result of ongoing loss-making operations

Corporate update • Dyslipidemia

Will the floodgates open for gene therapy? (Nat Biotechnol) - Towards the end of Jul, 2012 the EMA's CHMP recommended the approval in the EU of a treatment called Glybera (alipogene tiparvovec) from the uniQure Biopharma; Unless matters get untypically administratively complicated, it should be only a matter of days before the EC endorses this recommendation, making the approval official

Anticipated EU regulatory • Dyslipidemia

MARKET ACCESS OF ADVANCED THERAPY MEDICINAL PRODUCT (ATMP) IN EUROPE: LESSONS LEARNT AND KEY CONSIDERATIONS FOR FUTURE SUCCESS (ISPOR-EU 2017) - "...The first four ATMPs, ChondroCelect, Glybera, Provenge and MACI, have already withdrawn from market due to commercial reasons...The clinical benefits of Holoclar, Imlygic and Strimvelis have been recognised and reimbursement granted in at least one country in Europe...ATMPs approved by the EMA in the last two years have been more successful at gaining reimbursement in Europe. Success is driven by a combination of demonstrating clinical benefits and addressing payer clinical/financial concerns, as well as maturity in environment/infrastructure."

Clinical • Biosimilar

Biochemical Analysis of the LPL Truncation Variant, LPLS447X Reveals Increased Lipoprotein Uptake. (PubMed) - Biochemistry - "LPLS447X is used in Alipogene tiparvovec, the gene therapy product for individuals with familial LPL deficiency. Finally, we analyzed LPL-mediated uptake of fluorescently labeled lipoprotein particles and found that LPLS447X enhanced lipoprotein uptake to a greater degree than LPL. An LPL structural model suggests that the LPLS447X truncation exposes residues implicated in LPL binding to uptake receptors."

Journal • Review • Biosimilar

GENE THERAPY IN LIPOPROTEIN LIPASE DEFICIENCY (LPLD): CASE REPORT ON THE FIRST PATIENT TREATED WITH ALIPOGENE TIPARVOVEC UNDER DAILY PRACTICE CONDITIONS. (PubMed, Hum Gene Ther) - "In March 2017, the patient suffered from a PA due to diet violation. Within the first 12 months post treatment overall Quality of Life improved and no change in humoral or cellular immune response against LPL or AAV1 was observed."

Clinical • Journal • Biosimilar • Cardiovascular • CNS Disorders • Dyslipidemia • Immunology • Metabolic Disorders • Pain • Pancreatitis

European regulator defends tough stance on approving gene and cell therapies (Br Med J) - Given that Glybera has no safety concerns, that on present evidence it appears likely to be of clinical value & that failure of its approval by the European Commission, the final arbiter, would be a major setback for gene therapy as a whole, an alternative attitude to the one taken by the CHMP would have been to give Glybera a chance to prove its efficacy under the carefully controlled conditions of the post-registration programme offered by the company

Review • Dyslipidemia

Xenon outlines key milestones for 2016 (GlobeNewswire) - "Xenon is eligible to receive a royalty on commercial sales of Glybera®, which is licensed to uniQure Biopharma...The first patient treated with Glybera as a commercially-available gene therapy was announced by uniQure in November 2015 and enabled by its commercialization partner in the EU, Chiesi Farmaceutici S.p.A."

Anticipated commercial • Atherosclerosis • Dyslipidemia • Gene Therapies

Alipogene Tiparvovec: A Review of Its Use in Adults with Familial Lipoprotein Lipase Deficiency. (PubMed) - "Alipogene tiparvovec was generally well tolerated, with most adverse events being localized, transient, mild to moderate injection-site reactions. This article reviews the pharmacology of alipogene tiparvovec and its efficacy and safety in adults with LPLD."

Journal • Atherosclerosis • Biosimilar • Oncology • Pain

"Approved or near approval gene therapy list, with my edit. This list ignores approved antisense, oligos, and vaccines." - @antonioregalado

Anticipated regulatory • Pipeline update • Gene Therapies • Inherited Retinal Dystrophy • Ophthalmology