Fodosine (forodesine) / Mundipharma, BioCryst - LARVOL DELTA

Outcomes of relapsed or refractory mature T/NK-cell lymphomas in the era of novel agents: A nationwide observational Study in Japan (ASH 2025) - P | "The median TTNT of each SA after 2nd- or later-linetherapies (mo, 95% CI) was 10.7 (3.9–17.3) for brentuximab vedotin (BV; n = 53, 21%), 5.0 (2.7–7.1) fortucidinostat (n = 36, 14%), 3.9 (2.6–4.8) for romidepsin (n = 80, 31%), 2.1 (0.4–5.2) for darinaparsin (n = 7,3%), 1.8 (1.3–2.5) for pralatrexate (n = 58, 23%), 1.5 (0.6–NE) for forodesine (n = 8, 3%), 1.1 (0.4–2.4) formogamulizumab (n = 22, 9%), 0.7 (0.4–3.5) for denileukin diftitox (n = 5, 2%), and NR (NE–NE) for alectinib(n = 1, 0.4%). In patients with TFHL, romidepsin (44%) and tucidinostat (18%) yielded median TTNTs (mo,95% CI) of 4.0 (2.6–8.7) and 5.5 (1.9–7.8), respectively... To the best of our knowledge, this study reports the most recent treatment patterns andprognoses for patients with R/R MTNKL. No standard of care has been established, as diverse treatmentpatterns have been observed. SAs resulted in similar survival outcomes to CCs in 2nd-line therapy,despite distinctive clinical Background of the groups."

Clinical • Observational data • Bone Marrow Transplantation • Cutaneous T-cell Lymphoma • Dermatology • Extranodal Natural Killer/T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK

Inhibition of Purine Nucleoside Phosphorylase Is a Promising Anti-Sickling Approach for Sickle Cell Disease (ASH 2024) - P=N/A | "We also collected blood prospectively from patients with SCD at steady state (n=3) and incubated it with vehicle, 8-AG or the potent PNP inhibitor forodesine (positive control), and then determined the point of sickling (PoS; the partial pressure of oxygen at which there is a 5% decrease in maximum RBC deformability) and assessed RBC deformability during normoxia (maximum elongation index EImax) and hypoxia (minimum elongation index EImin) using automated ektacytometry (Lorrca Oxygenscan) whereby a decrease in PoS or increase in RBC deformability suggests decreased RBC sickling...Conclusion : This is the first study to show that pharmacological modulation of PNP activity could be beneficial in SCD by improving RBC deformability and thereby reducing hemolysis. We suggest that PNP inhibition could be a novel anti-sickling strategy for the treatment of SCD."

Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Forodesine has anticancer immunomodulatory properties through the adenosine pathway (SITC 2025) - "I also tested forodesine in highly immunosuppressive Triple-Negative Breast Cancer (TNBC) mouse models and found that forodesine reduces tumor growth via stimulation of CD8 T-cell responses.Conclusions Based on our findings, nucleoside analogs, like forodesine, could be investigated as novel Immunotherapeutics to successfully stimulate T-cell responses against cancer.Acknowledgements Giulia Monticone, Ph.D., my mentor Zhi Huang, Ph.D. Kristina Larter Lucio Miele M.D., Ph.D., PI Laura Naldi LSU HSC Honors Program"

Immunomodulating • IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ADORA2A • CD8

A therapeutic effect of Forodesine for CNS relapsed primary testicular T cell lymphoma after allogeneic transplantation. (PubMed, J Clin Exp Hematop) - "Treatment with the purine nucleotide phosphorylase inhibitor Forodesine achieved a therapeutic response. This finding suggests that Forodesine might be useful as a treatment option for CNS relapse in heavily treated T-cell lymphoma."

Journal • Bone Marrow Transplantation • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Testicular Cancer • Transplantation

Coapplication of Adenine with Inosine or Guanosine Supports Rapid ATP Restoration by ATP-deprived Cultured Primary Astrocytes. (PubMed, Neurochem Res) - "The supporting effects of inosine and guanosine on ATP restoration were prevented by the presence of forodesine, demonstrating the contribution of purine nucleoside phosphorylase in the ATP restoration observed. These data demonstrate that ATP-deprived astrocytes need for rapid ATP restoration - in addition to glucose as energy substrate - an adenine source and inosine or guanosine as precursor for the ribose phosphate moiety of ATP."

Journal

Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease. (PubMed, Ann Neurol) - "Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024."

Journal • Hepatology • Myositis • Ophthalmology

Drug repurposing for diabetes mellitus: In silico and in vitro investigation of DrugBank database for α-glucosidase inhibitors. (PubMed, Int J Biol Macromol) - "Overall, our findings underscore the potential of Forodesine as a promising candidate for DM treatment through α-glucosidase inhibition. Further validation through in vitro and in vivo studies is imperative to confirm the therapeutic benefits of Forodesine in conformational diseases such as DM."

Journal • Preclinical • Diabetes • Metabolic Disorders

Perspectives and challenges in developing small molecules targeting purine nucleoside phosphorylase. (PubMed, Eur J Med Chem) - "However, only Peldesine, Forodesine and Ulodesine have entered clinical trials and exhibited some potential for the treatment of T-cell leukemia and gout. The most recent direction in PNP inhibitor development has been focused on PNP small-molecule inhibitors with better potency, selectivity, and pharmacokinetic property. In this perspective, considering the structure, biological functions, and disease relevance of PNP, we highlight the recent research progress in PNP small-molecule inhibitor development and discuss prospective strategies for designing additional PNP therapeutic agents."

Journal • Review • Developmental Disorders • Gout • Hematological Malignancies • Immunology • Inflammatory Arthritis • Leukemia • Lymphoma • Oncology • Rheumatology

Characterization and resistance mechanisms of PNP inhibitor forodesin-resistant cell lines. (AACR 2024) - "Forodesine (For, BCX-1777), a novel PNP inhibitor, was approved in Japan for the treatment of relapsed/refractory PTCL...When cross-resistance was examined in these For-R cells showed mild resistance to cytarabine... The established For-R cell line acquired a high resistance to For and showed high intracellular dGTP levels. Imbalance in intracellular GTP levels may be involved in the induction of cell death by For."

Preclinical • Hematological Malignancies • Leukemia • Oncology • DCK

Role of purine metabolism in CLL cell pathobiology and CLL disease progression (AACR 2024) - "But PNP inhibitor forodesine did not show any significant killing in high vs low/no PNP group. When we treated CLL cells from untreated patients with Bcl2 inhibitors venetoclax, S55746 and LP-118 (Bcl-2/Bcl-xl inhibitor, Newave), CLL cells showed increasing sensitivity to the Bcl2 inhibitors associated with their PNP expression (high>low>no PNP)...These results indicate that active purine metabolism in CLL cells can contribute to differential novel agent drug responses of CLL patients. Future studies to understand the exact mechanism of how PNP relates to this differential drug sensitivity should be instructive in regard to alternate maneuvers to treat CLL."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1

Plant nucleoside N-ribohydrolases: riboside binding and role in nitrogen storage mobilization. (PubMed, Plant J) - "We report the crystal structure of Zea mays NRH2b (subclass II) and NRH3 (subclass I) in complexes with the substrate analog forodesine...Dexamethasone-inducible ZmNRH overexpressor lines of Arabidopsis thaliana, as well as double nrh knockout lines of moss Physcomitrium patents, reveal a fine control of adenosine in contrast to other ribosides...We observe changes in the pathways related to nitrogen-containing compounds such as β-alanine and several polyamines, which allow plants to reprogram their metabolism to escape stress. Taken together, crop plant breeding targeting enhanced NRH-mediated nitrogen recycling could therefore be a strategy to enhance plant growth tolerance and productivity under adverse growth conditions."

Journal

Forodesine Enhances Immune Responses through Guanosine-Mediated TLR7 Activation while Preventing Graft-versus-Host Disease. (PubMed, J Immunol) - "Although forodesine ameliorated GVHD severity, mice treated with forodesine showed significantly higher levels of multiple proinflammatory cytokines and chemokines in plasma, suggesting in vivo upregulation of TLR7 signaling. Our study suggests that forodesine may activate a wide range of immune cells, including T cells, through TLR7 stimulation while inhibiting GVHD by inducing apoptosis of T cells, after allogeneic hematopoietic stem cell transplant."

Journal • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Inflammation • Transplantation • CD8 • IFNG • TLR7

Forodesine and Riboprine Exhibit Strong Anti-SARS-CoV-2 Repurposing Potential: In Silico and In Vitro Studies. (PubMed, ACS Bio Med Chem Au) - "The subsequent biological assessment proved for the first time that, among the six NAs, riboprine and forodesine are able to hyperpotently inhibit the replication of the Omicron strain of SARS-CoV-2 with extremely low in vitro anti-RdRp, anti-ExoN, and anti-SARS-CoV-2 EC values of about 0.18, 0.28, and 0.40 μM for riboprine and about 0.20, 0.31, and 0.65 μM for forodesine, respectively, surpassing remdesivir and molnupiravir. The prior in silico data supported these biochemical findings, suggesting that riboprine and forodesine molecules and their expected active TP metabolites strongly hit the key catalytic pockets of the SARS-CoV-2 RdRp's and ExoN's main active sites. In brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two bioactive nucleosides forodesine and riboprine and their TP nucleotides to effectively shut down the polymerase/exoribonuclease-RNA nucleotide interactions of..."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Dual computational and biological assessment of some promising nucleoside analogs against the COVID-19-Omicron variant. (PubMed, Comput Biol Chem) - "Successive in silico screening of known NAs finally disclosed six different promising NAs, which are riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir, respectively, that predictably can act through the planned dual-action mode...The two NAs are able to effectively antagonize the replication of the new virulent SARS-CoV-2 strains with considerably minute in vitro anti-RdRp and anti-SARS-CoV-2 EC values of 189 and 408 nM for riboprine and 207 and 657 nM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. Furthermore, the favorable structural characteristics of the two molecules qualify them for varied types of isosteric and analogistic chemical derivatization. In one word, the present important outcomes of this comprehensive dual study revealed the anticipating repurposing potentials of some known nucleosides, led by the two NAs riboprine and forodesine, to successfully discontinue the..."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

8-Aminoguanine and Its Actions on Renal Excretory Function. (PubMed, Hypertension) - "8-Aminoguanine induces diuresis/natriuresis/glucosuria by increasing renal interstitial levels of inosine which, via A receptor activation, increases renal excretory function, perhaps in part by increasing medullary blood flow."

Journal

A Series of Adenosine Analogs as the First Efficacious Anti-SARS-CoV-2 Drugs against the B.1.1.529.4 Lineage: A Preclinical Repurposing Research Study. (PubMed, ChemistrySelect) - "Gradual computational filtration gave rise to six different promising NAs, which are riboprine, forodesine, tecadenoson, nelarabine, vidarabine, and maribavir, respectively. Further biological assessment proved for the first time, using the in vitro anti-RdRp/ExoN and anti-SARS-CoV-2 bioassays, that riboprine and forodesine, among all the six tested NAs, are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC values of about 0.22 and 0.49 μM for riboprine and about 0.25 and 0.73 μM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir...Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading, with their relatively flexible structures open for diverse types of chemical derivatization. In Brief, the current important..."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Evaluation of a series of nucleoside analogs as effective anticoronaviral-2 drugs against the Omicron-B.1.1.529/BA.2 subvariant: A repurposing research study. (PubMed, Med Chem Res) - "Gradual computational filtration afforded six different promising NAs, riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir. Further biological assessment proved that riboprine and forodesine are able to powerfully inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC values of about 0.21 and 0.45 μM for riboprine and about 0.23 and 0.70 μM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir...These findings suggest that riboprine and forodesine could serve as prospective lead compounds against COVID-19. Graphical abstract."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Forodesine Amplifies Host Innate Immune Response through Toll-like Receptor 7 Activation While Preventing Experimental Graft-Versus-Host Disease (ASH 2022) - "Consistent with our in vitro experiments, forodesine-treated mice showed significantly higher levels of serum inflammatory cytokines, such as TNF-a and IL-6 (p < 0.001). Chemokine ligands, including CXCL1, CXCL10 and CCL5, were also elevated in the mice treated with forodesine, again suggesting in vivo upregulation of TLR7 signaling pathway (Figure 2).Conclusion : This study demonstrates that forodesine induces the selective T-cell death and ameliorates GVHD phenotype in xenogeneic GVHD mice, while amplifies host innate immune response through TLR7 signaling."

Graft versus Host Disease • Immunology • Transplantation • CXCL1 • CXCL10 • FLT3 • IFNG • IL12A • IL6 • TLR7 • TNFA

Updated Report of a Phase I/II Multicenter Study of Forodesine, a Purine Nucleoside Phosphorylase Inhibitor, in Japanese Patients with Relapsed Peripheral T-Cell Lymphoma (ASH 2017) - P1/2; "In the final data analysis, efficacy was confirmed against relapsed PTCL. The median DoR was 10.4 months (95% CI, 5.9–16.0 months), the responses to forodesine were durable in some patients. Compared with other PTCL options that require intravenous infusion with frequent clinic visits, the oral formulation makes forodesine easier to administer and, in turn, may be more convenient and less burdensome to patients."

Adverse events • Clinical • P1/2 data • Biosimilar • Diffuse Large B Cell Lymphoma • Peripheral T-cell Lymphoma

Forodesine maintenance therapy for newly diagnosed peripheral T-cell lymphoma: a single-institutional, observational, retrospective analysis. (PubMed, Ann Hematol) - No abstract available

Journal • Retrospective data • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

FORODESINE AMPLIFIES HOST INNATE IMMUNE RESPONSE THROUGH TOLL-LIKE RECEPTOR 7 ACTIVATION WHILE PREVENTING EXPERIMENTAL GRAFT-VERSUS-HOST DISEASE (EHA 2022) - "Conclusion This study demonstrates that forodesine amplifies host innate immune response through TLR7 signaling, while ameliorating T-cell GVH reaction. Further studies are needed to investigate whether forodesine can provide host protection against infections in a transplant setting."

Graft versus Host Disease • Immunology • Infectious Disease • Transplantation • FLT3 • IFNG • IL12A • TLR7 • TNFA

Biochemical Pathways of 8-Aminoguanine Production In Sprague-Dawley and Dahl Salt-Sensitive Rats. (PubMed, Biochem Pharmacol) - "8-Aminoguanine occurs naturally via two distinct pathways and kidney levels of 8-aminoguanine are increased in Dahl rats, likely due to increased production of 8-nitroguanosine, a by-product of peroxynitrite chemistry."

Journal • Preclinical

A forodesine-based regimen as a therapeutic option for PTCL-NOS with Central nervous system involvement. (PubMed, Leuk Lymphoma) - No abstract available

Journal

Cutaneous T cell Lymphoma: an Update on Pathogenesis and Systemic Therapy. (PubMed) - Curr Hematol Malig Rep - "Recent investigations into the pathogenesis of MF and SS have broadened the therapeutic targets; here, we review emerging concepts in the pathogenesis of MF and SS as well as novel and traditional systemic therapies for MF and SS. These include histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, and belinostat), monoclonal antibodies (alemtuzumab, brentuximab vedotin, and mogamulizumab) and single-agent cytotoxic chemotherapeutic agents (e.g., pralatrexate, doxorubicin, bendamustine, and forodesine), as well as multi-agent chemotherapy regimens."

Journal • Biosimilar • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Phase I study of BCX1777 (forodesine) in patients with relapsed or refractory peripheral T/NK-cell malignancies (Cancer Sci) - P1, N=13; BCX1777-J01; Disease control was achieved in approximately half of patients; One pt with ALCL (ALK negative) achieved a CR, and two pts with cutaneous T-cell lymphoma achieved partial responses

P1 data • Hematological Malignancies • Non-Hodgkin’s Lymphoma