AMY-101 / Amyndas - LARVOL DELTA

Design, Synthesis, and Biological Evaluation of a Novel Long-Acting Human Complement C3 Inhibitor Synthesized via the PASylation-Lipidation Modular (PLM) Platform. (PubMed, Bioconjug Chem) - "CP40 (a cyclic peptide also known as AMY101), effectively inhibits complement activation by preventing the initial binding of the C3 substrate to convertase. In a clinically relevant in vitro model of complement-mediated hemolysis in PNH, 6C1 effectively reduced erythrocyte lysis. The PLM platform thus offers a versatile strategy for enhancing peptide therapeutics by improving solubility, extending circulation time, and increasing efficacy, broadening their therapeutic potential."

Journal • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Clinical C3 Inhibition With AMY-101 Reveals Novel Insights Into IL-8-Driven Inflammation in COVID-19. (PubMed, Immunology) - No abstract available

Journal • Infectious Disease • Inflammation • Novel Coronavirus Disease • CXCL8

Complement Biosensors Can be Used to Identify Classical Pathway and Alternative Pathway Dysregulation in Complement-Mediated Thrombotic Microangiopathy (ASH 2024) - "This stimulus is blocked by sutimlimab and eculizumab, but not by alternative pathway inhibitors including, AMY-101 (C3 inhibitor), iptacopan (factor B inhibitor, FBi), danicopan (factor D inhibitor, FDi), or even a combination of all three. In summary, these biosensors can be used as a sensitive method for investigating individual mechanisms of complement pathway activation in CM-TMA and help monitor therapeutic complement blockade. Identification of a CP stimulus in CM-TMA provides a potential explanation for ~50% of CM-TMA patients who lack an AP "driving" variant and suggests at least a subset of CM-TMA is characterized by a breakdown of IgM immunologic tolerance."

Atypical Hemolytic Uremic Syndrome • Complement-mediated Rare Disorders • Hematological Disorders • Nephrology • Thrombocytopenic Purpura • CD46 • CD55 • CD59

C3 Targeted Complement Therapy for Chronic Periodontitis - A Scoping Review. (PubMed, J Int Soc Prev Community Dent) - "Animal studies have shown that targeting complement C3 with its inhibitor like AMY-101 may help reduce inflammatory bone loss in CP...C3 targeted complement therapy may be regarded as a valuable adjunct to non-surgical periodontal treatment for CP. However, the results are still under investigation and require further verification through clinical trials."

Journal • Review • Dental Disorders • Immunology • Inflammation • Osteoporosis • Periodontitis

Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors. (PubMed, Nat Commun) - "Moreover, compstatin derivatives with enhanced pharmacodynamic and pharmacokinetic profiles are in clinical development (e.g., Cp40/AMY-101)...Functional studies provide further insight into physiological complement activation and corroborate the mechanism of its compstatin-mediated inhibition. Our study may thereby guide the application of existing and development of next-generation compstatin analogs."

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Complement Is Required for Microbe-Driven Induction of Th17 and Periodontitis. (PubMed, J Immunol) - "A recent clinical trial showed that a complement C3 inhibitor (AMY-101) causes sustainable resolution of periodontal inflammation, the main effector of tissue destruction in this oral disease...Experiments in human gingival epithelial cells showed that C3a upregulated IL-6 production in cooperation with microbial stimuli that upregulated C3a receptor expression in ERK1/2- and JNK-dependent manner. In conclusion, complement links the periodontal microbiota challenge to Th17 cell accumulation and thus integrates complement- and Th17-driven immunopathology in periodontitis."

Journal • Dental Disorders • Immunology • Inflammation • Osteoporosis • Periodontitis • IL17A • IL23A • IL6

Complement C3 inhibition in severe COVID-19 using compstatin AMY-101. (PubMed, Sci Adv) - "Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases."

Journal • Infectious Disease • Novel Coronavirus Disease

Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy. (PubMed, Pharmaceuticals (Basel)) - "Thus, it seems reasonable to propose complement inhibition therapy only to those patients exhibiting a clear complement activation according to the available biomarkers. Several agents are now available to inhibit complement activity: two drugs have been successfully used in TA-TMA, particularly in pediatric cases (eculizumab and narsoplimab) and others are at different stages of development (ravulizumab, coversin, pegcetacoplan, crovalimab, avacopan, iptacopan, danicopan, BCX9930, and AMY-101)."

Journal • Review • Bone Marrow Transplantation • Cardiovascular • Hematological Disorders • Hypertension • Infectious Disease • Pediatrics • Thrombosis • Transplantation

C3-targeted host-modulation approaches to oral inflammatory conditions. (PubMed, Semin Immunol) - "AMY-101 has shown safety and efficacy in reducing gingival inflammation in a recent Phase 2a clinical study. We also discuss the potential of AMY-101 to treat peri-implant inflammatory conditions, where complement also seems to be involved and there is an urgent unmet need for effective treatment."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dental Disorders • Diabetes • Immunology • Inflammation • Inflammatory Arthritis • Metabolic Disorders • Periodontitis • Rheumatoid Arthritis • Rheumatology • Type 2 Diabetes Mellitus

How the Innate Immune System of the Blood Contributes to Systemic Pathology in COVID-19-Induced ARDS and Provides Potential Targets for Treatment. (PubMed, Front Immunol) - "Examples of such compounds include complement inhibitors AMY-101 and eculizumab (targeting C3 and C5, respectively) as well as kallikrein inhibitors ecallantide and lanadelumab and the bradykinin receptor (BKR) 2 antagonist icatibant. In this conceptual review we discuss the activation, crosstalk and the therapeutic options that are available for regulation of the IIIS."

Journal • Review • Acute Kidney Injury • Acute Respiratory Distress Syndrome • Cardiovascular • Critical care • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Nephrology • Novel Coronavirus Disease • Pneumonia • Pulmonary Disease • Renal Disease • Respiratory Diseases • IL6

Phase 2a clinical trial of complement C3 inhibitor AMY-101 in adults with periodontal inflammation. (PubMed, J Clin Invest) - P2a | "AMY-101 causes significant and sustainable reduction in gingival inflammation without adverse events and merits further investigation for the treatment of periodontitis and other oral or peri-implant inflammatory conditions."

Clinical • Journal • P2a data • Dental Disorders • Immunology • Inflammation • Periodontitis • MMP9

Inflammatory stress in SARS-COV-2 associated Acute Kidney Injury. (PubMed, Int J Biol Sci) - "It is highly possible that SARS-COV-2 infection may trigger the activation of multiple inflammatory pathways including angiotensin II, cytokine storm such as interleukin-6 (IL-6), C-reactive protein (CRP), TGF-β signaling, complement activation, and lung-kidney crosstalk to cause AKI. Thus, treatments by targeting these inflammatory molecules and pathways with a monoclonal antibody against IL-6 (Tocilizumab), C3 inhibitor AMY-101, anti-C5 antibody, anti-TGF-β OT-101, and the use of CRRT in critically ill patients may represent as novel and specific therapies for AKI in COVID-19 patients."

Journal • Review • Acute Kidney Injury • Cardiovascular • Diabetes • Hypertension • Immunology • Infectious Disease • Inflammation • Metabolic Disorders • Nephrology • Novel Coronavirus Disease • Renal Disease • Respiratory Diseases • CRP • IL6 • TGFB1

A Study of the C3 Complement Inhibitor AMY-101 in Adults With Gingivitis (clinicaltrials.gov) - P2a; N=39; Completed; Sponsor: Amyndas Pharmaceuticals S.A.; Recruiting ➔ Completed; N=30 ➔ 39

Clinical • Enrollment change • Trial completion • Dental Disorders

A Study of the C3 Inhibitor AMY-101 in Patients With ARDS Due to COVID-19 (SAVE) (clinicaltrials.gov) - P2; N=144; Not yet recruiting; Sponsor: Amyndas Pharmaceuticals S.A.; Trial completion date: Mar 2021 ➔ Dec 2022; Initiation date: Jul 2020 ➔ Sep 2021; Trial primary completion date: Jan 2021 ➔ Sep 2022

Clinical • Trial completion date • Trial initiation date • Trial primary completion date • Acute Respiratory Distress Syndrome • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • IL12A • IL6

Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy. (PubMed, Clin Immunol) - "Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials."

Clinical • Journal • Acute Respiratory Distress Syndrome • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • Thrombosis

Clinical trial of the investigational drug AMY-101 for the treatment of patients with severe COVID-19. Κλινική μελέτη του πειραματικού φαρμάκου AMY-101 για τη θεραπεία ασθενών με βαριά μορφή COVID-19. (clinicaltrialsregister.eu) - P2; N=62; Ongoing; Sponsor: Amyndas Pharmaceuticals S.A.

Clinical • New P2 trial • Acute Respiratory Distress Syndrome • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Complement-Dependent Mechanisms and Interventions in Periodontal Disease. (PubMed, Front Immunol) - "Specifically, interception of the complement cascade at its central component, C3, using a locally administered small peptidic compound (Cp40/AMY-101) protected non-human primates from induced or naturally occurring periodontitis. These studies indicate that C3-targeted intervention merits investigation as an adjunctive treatment of periodontal disease in humans."

Journal • Review • Dental Disorders • Immunology • Periodontitis

The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. (PubMed, Clin Immunol) - "C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101."

Clinical • Journal • Acute Respiratory Distress Syndrome • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

A Study of the C3 Complement Inhibitor AMY-101 in Adults With Gingivitis (clinicaltrials.gov) - P2a; N=30; Recruiting; Sponsor: Amyndas Pharmaceuticals S.A.; Not yet recruiting ➔ Recruiting; Trial completion date: Mar 2020 ➔ Dec 2020; Trial primary completion date: Jan 2020 ➔ Sep 2020

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Dental Disorders

A Phase 2 Study of the C3 Inhibitor AMY-101 in Patients With ARDS Due to COVID-19 (SAVE) (clinicaltrials.gov) - P2; N=144; Not yet recruiting; Sponsor: Amyndas Pharmaceuticals S.A.

Clinical • New P2 trial • Acute Respiratory Distress Syndrome • Novel Coronavirus Disease • Respiratory Diseases

Taming hemodialysis-induced inflammation: Are complement C3 inhibitors a viable option? (PubMed, Clin Immunol) - "Complement activation, early during the HD process, has been shown to fuel a multitude of detrimental thromboinflammatory reactions that collectively contribute to patient morbidity. Here we discuss emerging aspects of complement's involvement in HD-induced inflammation and put forth the concept that targeted intervention at the level of C3 might constitute a promising therapeutic approach in HD patients."

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Safety profile after prolonged C3 inhibition. (PubMed, Clin Immunol) - "In addition, a biodistribution study in a rhesus monkey indicated that the distribution of Cp40 in the body is associated with the presence of C3, concentrating in organs that accumulate blood and produce C3. Overall, our data suggest that systemic C3 inhibition in healthy adult non-human primates is not associated with a weakened immune system or susceptibility to infections."

Clinical • Journal

Gingival exudatome dynamics implicate inhibition of the alternative complement pathway in the protective action of the C3 inhibitor Cp40 in non-human primate periodontitis. (PubMed, J Proteome Res) - "We mapped the proteomic fingerprint changes in local tissue exudate of cynomolgus monkey periodontitis in response to C3 inhibition and identified the alternative pathway of complement activation and leukocyte degranulation as main targets, which are thus likely to play significant roles in periodontal disease pathogenesis. Label-free quantitative proteomics strategies utilizing GCF are powerful tools for the identification of treatment targets and providing insights into disease mechanisms."

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