Adagen (pegademase bovine) / Leadiant Biosci - LARVOL DELTA

Multi-Year Registry Study of Elapegademase Treatment in Patients With Adenosine Deaminase Severe Combined Immunodeficiency (ADA-SCID) Requiring Enzyme Replacement Therapy. (PubMed, J Clin Immunol) - P | "Effectiveness of elapegademase was maintained up to 4 years of use and with no new safety concerns."

Journal • Genetic Disorders • Immunology • Infectious Disease • Primary Immunodeficiency

Patient with Adenosine Deaminase Severe Combined Immunodeficiency (ADA-SCID) and Glutaric Aciduria Type 1 (GA1) Successfully treated with delayed Hematopoietic Stem Cell Transplant (HSCT) (CIS 2024) - "At 4-weeks he started pegademase(Adagen)with partial recovery of B and NK cells, however, d-AXP levelsremained elevated (Figure 1a)...His conditioning includedCampath, Fludarabine and Busulfan (AUC 50)...Patient experienced adenovirus reactivation thatresponded to Cidofovir and an infusion of adenovirus specific-cytotoxic Tcells with complete resolution. No significant organ toxicity or metaboliccrisis. He is 2.5y out of HCT, has stable mixed donor chimerism and hasachieved T and B cell immune reconstitution."

Clinical • Bone Marrow Transplantation • Cardiovascular • CNS Disorders • Gene Therapies • Genetic Disorders • Immunology • Infectious Disease • Metabolic Disorders • Primary Immunodeficiency • Transplantation • CD34

Increased dosage of elapegademase-lvlr improved metabolic andimmunologic function in a patient with late-onset adenosine deaminase deficiency and neutralizing anti-drug antibodies (CIS 2024) - "At 260 weeks, at adose of 0.37 mg/kg/week divided thrice weekly, plasma ADA activity was52.47 umol/h/ml and RBC %dAXP was 0.5%.Anti-drug antibodies in patients treated with PEG-ADA are usually nonneutralizing; in this case neutralizing antibodies were identified as theefficacy of ERT diminished. Through significant increases in elapegademase-lvlr dose and frequency, therapeutic efficacy was restored withoutimmunosuppressive agents."

Clinical • Dermatology • Genetic Disorders • Immunology • Primary Immunodeficiency

Multi-Year Registry Study of Elapegademase-lvlr Treatment in Patientswith Adenosine Deaminase Severe Combined Immunodeficiency (ADASCID) Requiring Enzyme Replacement Therapy (ERT) (CIS 2024) - "However, due to concerns with thesafety and stability, Adagen® was replaced in 2018 by Revcovi® (elapegademase-lvlr), a PEGylated recombinant ADA. In this registry study, effectiveness of elapegademase-lvlr wasmaintained for up to 4 years of use."

Clinical • Bone Marrow Transplantation • Genetic Disorders • Immunology • Infectious Disease • Primary Immunodeficiency • Transplantation

Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency. (PubMed, J Clin Immunol) - "Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data."

Journal • Bone Marrow Transplantation • Cardiovascular • Gene Therapies • Genetic Disorders • Hematological Disorders • Immunology • Primary Immunodeficiency • Thrombocytosis • Transplantation

Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy. (PubMed, Sci Adv) - "Depletion of adenosine in the TME by the repurposed drug PEGylated adenosine deaminase (PEG-ADA) increases CD8 T cell activity and enhances response to ICI therapy. Use of PEG-ADA can therefore be a therapeutic option to overcome resistance to ICIs in cancer patients."

IO biomarker • Journal • Breast Cancer • Immune Modulation • Melanoma • Oncology • Solid Tumor • CD8 • NT5E • STAT3

Enzymatic depletion of adenosine to overcome resistance to immune checkpoint inhibitors in non-small cell lung cancer (P583) (IMMUNOLOGY 2023) - "Our results showed that in tumor microenvironment (TME), tumor cells derived PGE2; a prostaglandin that directly induces CD73 (an ecto-nucleotidase that converts AMP to immunosuppressive adenosine) expression in M-MDSCs; consequently, CD73 expressing M-MDSCs suppress T cells via adenosine thus confer resistance to ICIs. In addition, we have shown that the depletion of adenosine via PEGylated Adenosine Deaminase (PEG-ADA) can reinvigorate CD8+ T cells, ultimately enhance the anti-tumor immunity."

Checkpoint inhibition • IO biomarker • Immune Modulation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • NT5E

Long-term immune reconstitution in ADA-deficient patients treated with elapegademase: a real-world experience. (PubMed, J Allergy Clin Immunol Pract) - "REVCOVI® is effective for the management of ADA-SCID."

Journal • Real-world • Real-world evidence • Genetic Disorders • Immunology • Primary Immunodeficiency • CD19 • CD4

Lentiviral Gene Therapy with Autologous Hematopoietic Stem and Progenitor Cells (HSPCs) for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (ADA-SCID): Results in an Expanded Cohort (ASH 2019) - P1/2; "Single dose busulfan (4 mg/kg) was administered prior to infusion of OTL-101...One of 30 OTL-101 subjects (3%) did not engraft and was restarted on ERT; the subject was withdrawn from the study at 5.9 mo and subsequently received a rescue HSCT, whereas 42% of HSCT patients required rescue HSCT, PEG-ADA ERT or died... Based on sustained gene correction and restoration of immune function in all subjects who engrafted, treatment of ADA-SCID with OTL-101 has a favorable benefit-risk profile. Key correlates of engraftment were consistent across the expanded cohort. Importantly, higher rates of OS and EvFS compared with HSCT (with or without an MRD) were observed."

CD34

Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID (clinicaltrials.gov) - P1/2 | N=13 | Completed | Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust | Active, not recruiting ➔ Completed

Preclinical • Trial completion • Viral vector • Genetic Disorders • Immunology • Primary Immunodeficiency

Polymer-drug conjugates: Design principles, emerging synthetic strategies and clinical overview. (PubMed, Int J Pharm) - "Adagen, an enzyme replacement treatment for adenosine deaminase deficiency, was the first protein-polymer conjugate to be approved in early 1990s...The potential synthetic strategies to formulate PDCs have been discussed along with recent advancements in the different types of PDCs, i.e., polymer-small molecular weight drug conjugates, polymer-protein conjugates, and stimuli-responsive PDCs, which are under clinical/preclinical investigation. Current impediments and regulatory hurdles hindering the clinical translation of PDC into effective therapeutic regimens for the amelioration of disease conditions have been addressed."

Journal • Review

Evolution of drug delivery systems: From 1950 to 2020 and beyond. (PubMed, J Control Release) - "The introduction of Lupron Depot® in 1989 opened the door for long-acting injectables and implantables, extending the drug delivery duration from days to months and occasionally years...The introduction of the first PEGylated protein, Adagen®, in 1990 marked the new era of PEGylation, resulting in Doxil® (doxorubicin in PEGylated liposome) in 1995, Movantik® (PEGylated naloxone - naloxegol) in 2014, and Onpattro® (Patisiran - siRNA in PEGylated lipid nanoparticle) in 2018. Drug-polymer complexes were introduced, e.g., InFed® (iron-dextran complex injection) in 1974 and Abraxane® (paclitaxel-albumin complex) in 2005. In 2000, both Mylotarg™ (antibody-drug conjugate - gemtuzumab ozogamicin) and Rapamune® (sirolimus nanocrystal formulation) were introduced...As the development of COVID-19 vaccines demonstrated, meeting the unforeseen crisis of the uncertain future requires continuous cumulation of failures (as learning experiences),..."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology

Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy. (PubMed, Sci Rep) - "Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients...We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency."

Journal • Preclinical • Genetic Disorders • Immunology • Primary Immunodeficiency • TRB

Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene (clinicaltrials.gov) - P1/2; N=46; Completed; Sponsor: Orchard Therapeutics; N=20 ➔ 46

Enrollment change • Preclinical • Genetic Disorders • Immunology • Primary Immunodeficiency • Transplantation

Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID (clinicaltrials.gov) - P1/2; N=13; Active, not recruiting; Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust; Recruiting ➔ Active, not recruiting; N=10 ➔ 13

Enrollment change • Enrollment closed • Genetic Disorders • Immunology • Primary Immunodeficiency

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Clinical

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Oncology

Comparison of elapegademase and pegademase in ADA-deficient patients and mice. (PubMed, Clin Exp Immunol) - "ELA-ADA has similar in vitro and possibly better in vivo activity than ADAGEN. Future studies will determine whether ELA-ADA results in improved long-term immune reconstitution."

Journal • Genetic Disorders • Immunology • Primary Immunodeficiency

Single enzyme nanoparticle, an effective tool for enzyme replacement therapy. (PubMed, Arch Pharm Res) - "As shown in the cases of Adagen®, Revcovi®, Palynziq®, and Strensiq®, SEN can be an effective technology for overcoming these obstacles. Additionally, we summarize different types of enzyme deficiency disorders and the corresponding therapeutic enzymes. Finally, we focus on the current status of SENs in ERT by reviewing FDA-approved products."

Journal • Review

Development and validation of a novel immunogenicity assay to detect anti-drug and anti-PEG antibodies simultaneously with high sensitivity. (PubMed, J Immunol Methods) - "In addition, the fact that some anti-PEG antibodies are known to circulate as low-affinity IgM, drives the need for an assay able to detect low affinity anti-PEG ADA even in the presence of high concentrations of the biotherapeutic...The ACE-AGL assay is easy to perform and has been successfully validated at two separate CROs. We propose the ACE-AGL format as a valid and effective alternative to the currently available assay methods."

Journal

[VIRTUAL] LONG-TERM ENZYME REPLACEMENT THERAPY (ERT) IN ADA-SCID PATIENTS: THE SHADOW OF MALIGNANCIES (EBMT 2020) - "Our experience shows that ERT gives a good therapeutic option as bridge therapy for HSCT. For patients in long-term ERT, would be beneficial the use of the newly approved recombinant PEG-ADA. Nevertheless strict monitoring would be necessary to check the results of this new therapeutical approach."

Clinical • Gene Therapies • Hematological Malignancies • Oncology • Rare Diseases

[VIRTUAL] LONG-TERM ENZYME REPLACEMENT THERAPY (ERT) IN ADA-SCID PATIENTS: THE SHADOW OF MALIGNANCIES (EBMT 2020) - "Our experience shows that ERT gives a good therapeutic option as bridge therapy for HSCT. For patients in long-term ERT, would be beneficial the use of the newly approved recombinant PEG-ADA. Nevertheless strict monitoring would be necessary to check the results of this new therapeutical approach."

Clinical • Gene Therapies • Hematological Malignancies • Oncology • Rare Diseases

[VIRTUAL] LONG-TERM ENZYME REPLACEMENT THERAPY (ERT) IN ADA-SCID PATIENTS: THE SHADOW OF MALIGNANCIES (EBMT 2020) - "Our experience shows that ERT gives a good therapeutic option as bridge therapy for HSCT. For patients in long-term ERT, would be beneficial the use of the newly approved recombinant PEG-ADA. Nevertheless strict monitoring would be necessary to check the results of this new therapeutical approach."

Clinical • Gene Therapies • Hematological Malignancies • Oncology • Rare Diseases

[VIRTUAL] LONG-TERM ENZYME REPLACEMENT THERAPY (ERT) IN ADA-SCID PATIENTS: THE SHADOW OF MALIGNANCIES (EBMT 2020) - "Our experience shows that ERT gives a good therapeutic option as bridge therapy for HSCT. For patients in long-term ERT, would be beneficial the use of the newly approved recombinant PEG-ADA. Nevertheless strict monitoring would be necessary to check the results of this new therapeutical approach."

Clinical • Gene Therapies • Hematological Malignancies • Oncology • Rare Diseases