sevuparin (DF-02) / Modus Therap, Mahidol Oxford Tropical Medicine Research Unit - LARVOL DELTA

Biologic Assessment of RBC Biology and Neutrophil Activation: Correlation with Sickle Cell Disease Activity (ASH 2023) - "A subset of samples were examined for RBC reactive oxygen species (ROS) content and adhesivity to laminin with and without stimulation by epinephrine...Interestingly, we also found that RBC [ATP] was lower in the RBCs of patients with higher total Hb, while it was higher in individuals with higher retic counts, suggesting that more long-lived RBCs have diminished [ATP], despite the fact that both [ATP] and total Hb have been reported to rise substantially after treatment with pyruvate kinase activators etavopivat and mitapivat...Similarly, senicapoc, which also reduces hemolysis, although by a different mechanism, failed to lessen VOE frequency...Anti-adhesive agents (crizanlizumab, rivipansel, sevuparin) have thus far failed to yield marked improvements in VOE frequency, but our results suggest that, in order to decrease the frequency of VOEs, it is not sufficient to reduce sickling and hemolysis. On the other hand, higher HbF levels were associated with lower admission..."

Cardiovascular • Genetic Disorders • Hematological Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases • Sickle Cell Disease • MMP9

The Heparinoid Sevuparin Improves Anemia and Kidney Status in a Mouse Model of Chronic Kidney Disease (ASH 2023) - "Our data in this mouse CKD model add new insights to the role of hepcidin in the development of CKD anemia over time. Furthermore, the results are promising and support further mechanistic and clinical studies to elucidate the therapeutic role for sevuparin as a treatment in anemia of inflammatory and/or chronic diseases in monotherapy or in combination with EPO and to explore its role in kidney protection."

Preclinical • Anemia • Chronic Kidney Disease • Fibrosis • Hematological Disorders • Immunology • Inflammation • Nephrology • Renal Disease • BMP6 • IL6

Malaria: past, present, and future. (PubMed, Signal Transduct Target Ther) - "The FDA-approved regimens like Artemether-Lumefantrine, Atovaquone-Proguanil, and Primaquine are discussed, and their benefits and limitations are highlighted, especially in terms of drug resistance. Perspectives in the development of novel vaccines and new drugs, such as Sevuparin, Imatinib, and Cipargamin, and combination therapies with promise in overcoming resistance has been proposed. Overall, this review provides a detailed summary of the latest progress in malaria research and emphasizes the need for continuous monitoring and innovation in malaria treatment."

Journal • Review • Infectious Disease • Malaria

IMPROVEMENT OF ANEMIA AND KIDNEY STATUS BY SEVUPARIN TREATMENT IN A MOUSE MODEL OF CHRONIC KIDNEY DISEASE (EHA 2025) - "The data in a CKD mouse model are promising and are part of the rationale for the ongoing Phase II clinical trial (EUCT 2024-513864-24-00; Protocol TCDK01) in healthy volunteers and CKD patients, that may shed light on the effectiveness of sevuparin in CKD with anemia. However, further mechanistic studies are necessary to elucidate the potential therapeutic role for sevuparin in kidney protection."

Preclinical • Anemia • Chronic Kidney Disease • Fibrosis • Hematological Disorders • Immunology • Inflammation • Nephrology • Renal Disease • BMP6 • COL1A1 • COL1A2 • CTGF • IL6 • KIM1 • TGFB1

Sevuparin strongly reduces hepcidin expression in cells, mice, and healthy human volunteers. (PubMed, Hemasphere) - "Moreover, sevuparin was able to reduce hepcidin upregulation in a mouse model of acute inflammation induced by LPS, also showing an amelioration of the inflammatory markers. Combined with its excellent safety profile, these data suggest a role for sevuparin in treating high-hepcidin disorders."

Journal • Preclinical • Hematological Disorders • Inflammation • BMP6 • IL6

SEVUparin as a potential Adjunctive Treatment in children with severe malaria: A phase I trial safety and dose finding trial (SEVUSMAART). (PubMed, Wellcome Open Res) - "The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021)."

Journal • P1 data • Infectious Disease • Malaria • Metabolic Disorders

Metabolic engineering of Komagataella phaffii for the efficient utilization of methanol. (PubMed, Microb Cell Fact) - "The reduction of formaldehyde accumulation, the increase of NAD+/NADH ratio, and the enhancement of methanol oxidation effectively improved the efficient utilization of a high methanol concentration by strain ΔFLD strain lacking formaldehyde dehydrogenase. The modification strategies implemented in this study collectively serve as a foundational framework for advancing the efficient utilization of methanol in K. phaffii."

Journal

Synthesis of novel furan-based chalcone derivatives as anti-tuberculosis agents: in vitro, cytotoxicity assessment and in silico. (PubMed, Future Med Chem) - "All the other compounds had optimal concentrations 6.25-100 μg/ml against the H37Rv strain. Compounds DF02 and DF10 were further evaluated for cytotoxicity assay performed using HeLa cell lines."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

THE NON-ANTICOAGULANT HEPARINOID COMPOUND, SEVUPARIN, STRONGLY REDUCES HEPCIDIN EXPRESSION IN CELLS, IN MICE AND IN HEALTHY VOLUNTEERS (EHA 2023) - "The results are promising and support further mechanistic and clinical studies to elucidate a therapeutic role for sevuparin as a hepcidin inhibitor in anaemia of inflammatory and/or chronic diseases. Iron metabolism, Hepcidin, Heparin, Anemia"

Preclinical • Anemia • Hematological Disorders • IL6

Recent developments in antimalarial drug discovery. (PubMed, Bioorg Med Chem) - "Methods to fight malaria are being diversified, including the use of mosquito nets, the target candidate profiles (TCPs) and target product profiles (TPPs) of medicine for malarial venture (MMV) strategy, the search for newer and potent drugs that could reverse chloroquine resistance, and the use of adjuvants such as rosiglitazone and sevuparin. Although these adjuvants have no antiplasmodial activity, they can help to alleviate the effects which result from plasmodium invasion such as cytoadherence. The list of new antimalarial drugs under development is long, including the out of ordinary new drugs MMV048, CDRI-97/78 and INE963 from South Africa, India and Novartis, respectively."

Journal • Review • Infectious Disease • Malaria

Sevuparin trial for acute pain in sickle cell disease: the dog that did not bark. (PubMed, Lancet Haematol) - No abstract available

Journal • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

Sevuparin for the treatment of acute pain crisis in patients with sickle cell disease: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. (PubMed, Lancet Haematol) - P2 | "This result, as well as the results seen in other clinical studies of inhibitors of adhesion in sickle cell disease, suggest that selectin-mediated adhesion might be important in the initiation, but not maintenance of vaso-occlusion, indicating that strategies to treat vaso-occlusive crises differ from strategies to prevent this complication."

Clinical • Journal • P2 data • Beta-Thalassemia • Constipation • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

"BioStock: Karolinska Developments Modus Therapeutics utvecklar sevuparin mot sepsis https://t.co/cZgLVZvgb0" (@CisionNews)

Infectious Disease • Septic Shock

Heparinoid sevuparin inhibits Streptococcus-induced vascular leak through neutralizing neutrophil-derived proteins. (PubMed, FASEB J) - "By mass spectrometry of neutrophil secretion, we identify proteins, including serprocidins, S100 proteins, and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity. Collectively, our results demonstrate the critical role of neutrophil-derived proteins in vascular hyperpermeability caused by GAS and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation.-Rasmuson, J., Kenne, E., Wahlgren, M., Soehnlein, O., Lindbom, L. Heparinoid sevuparin inhibits Streptococcus-induced vascular leak through neutralizing neutrophil-derived proteins."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Immunology • Infectious Disease • Respiratory Diseases • Septic Shock

Sevuparin blocks sickle blood cell adhesion and sickle-leucocyte rolling on immobilized L-selectin in a dose dependent manner. (PubMed, Br J Haematol) - No abstract available

Journal

Efficacy and Safety of Sevuparin, a Novel Non-Anti-Coagulant Heparinoid, in Patients with Acute Painful Vaso-Occlusive Crisis; A Global, Multicenter Double-Blind, Randomized, Placebo-Controlled Phase 2 Trial (TVOC01) (ASH 2019) - "In this study, one of the largest VOC studies run to date, sevuparin failed to show an improvement of the VOC resolution time and associated measures (pain, opioid use, etc) in patients hospitalized with acute VOC. These results were surprising given both the promise from preclinical models and the clinical efficacy seen with selectin inhibition. It is possible that once full-blown, an acute VOC cannot be limited by sevuparin’s mode of action (MoA)."

Clinical • P2 data

Sevuparin Infusion for the Management of Acute VOC in Subjects With SCD (clinicaltrials.gov) - P2; N=147; Completed; Sponsor: Modus Therapeutics AB; Recruiting ➔ Completed

Clinical • Trial completion

Placebo-controlled Study to Determine the Safety and Tolerability of Subcutaneous Doses of Sevuparin (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Modus Therapeutics AB; Recruiting ➔ Completed; Trial completion date: Aug 2019 ➔ May 2019

Clinical • Trial completion • Trial completion date

HEPARIN-ANALOGUE SEVUPARIN INHIBITS STREPTOCOCCUS-INDUCED VASCULAR HYPERPERMEABILITY THROUGH NEUTRALIZING NEUTROPHIL-DERIVED PROTEINS (EHA 2019) - "By mass spectrometry of neutrophil secretion we identify candidate proteins, including serprocidins, S100 proteins and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity. Conclusion Collectively, our results corroborate the role of neutrophil-derived proteins in vascular hyperpermeability caused by Group A streptococci, and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation."

Sevuparin fails to show clinically meaningful improvements in managing VOCs, phase 2 study shows (Sickle Cell Anemia News) - P2, N=133; NCT02515838; Sponsor: Modus Therapeutics; "Unfortunately, according to statements from Karolinska Development, findings from the trial failed to show clinical benefits associated with the use of sevuparin. 'It is disappointing that sevuparin did not demonstrate a meaningful clinical benefit in the Phase 2 study conducted by Modus Therapeutics, particularly as patients with sickle cell disease have no treatment options that can reduce the length of their vaso-occlusive crises or manage their pain, other than opioids....'"

P2 data

Karolinska Development’s portfolio company Modus Therapeutics announces results from a Phase 2 study of sevuparin in patients with sickle cell disease (GlobeNewswire, Karolinska Development AB (publ)) - Karolinska Development AB (Nasdaq Stockholm: KDEV) (“Karolinska Development” or the “Company”) announces that the data from its portfolio company Modus Therapeutics’ Phase 2 study of sevuparin did not show a meaningful benefit in the management of acute vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). Modus is now considering its options for further development of sevuparin.

Clinical • Clinical data • P2 data

Placebo-controlled Study to Determine the Safety and Tolerability of Subcutaneous Doses of Sevuparin (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Modus Therapeutics AB

Clinical • New P1 trial

Karolinska Development's portfolio company Modus Therapeutics has successfully dosed first cohort in phase 1 study of subcutaneously administered sevuparin (GlobeNewswire) - "Karolinska Development's portfolio company Modus Therapeutics announces today that the first cohort has been successfully dosed in its phase 1 study to explore the pharmacokinetics, safety and tolerability of subcutaneous sevuparin injections in healthy adults. Modus Therapeutic develops sevuparin for diseases with high unmet medical need with a focus on sickle cell disease...Intravenously administered sevuparin is currently being tested in a phase 2 study which completed enrollment in January 2019 and will report data in mid-2019."

P2 data • Trial status