Aplidin (plitidepsin) / Megapharm, TTY Biopharm, PharmaMar, Boryung Group, Roche, Specialised Therap - LARVOL DELTA

THALASSA: Study to Evaluate the Efficacy and Safety of Plitidepsin in Adults with Post-COVID-19 Condition (PCC) (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Novel Coronavirus Disease

Targeting eEF1A reprograms translation and uncovers broad-spectrum antivirals against cap or m6A protein synthesis routes. (PubMed, Nat Commun) - "Plitidepsin is an antitumoral compound safe for treating COVID-19 that targets the translation elongation factor eEF1A...Yet, it fails to inhibit retroviruses that exploit m6A synthesis routes and are blocked by drugs targeting IGF2BP2 m6A reader. By deciphering the molecular fingerprint of cells treated with therapies targeting translation we identify a rational approach to select broad-spectrum antivirals with potential to counteract future pandemic viruses."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • EEF1A1 • EIF2AK3 • EIF4G2 • IGF2BP2 • PERK

Leveraging Cryptic Ligand Envelopes through Enhanced Molecular Simulations. (PubMed, J Phys Chem Lett) - "We apply this approach to quantify hidden conformational heterogeneity in structurally complex ligands including the marine natural product plitidepsin. The computed conformational heterogeneity expands the small-molecule footprint beyond that typically observed in experiments, also revealing key thermodynamic and kinetic properties of single ligand-target interactions. The model agrees quantitatively with solution NMR, X-ray crystallography, and biochemical measurements, showcasing a versatile strategy to integrate receptor-bound ligand conformational ensembles in molecular design."

Journal

Didemnins as marine-derived anticancer agents: mechanistic insights and clinical potential. (PubMed, Med Oncol) - "Recent progress in developing semisynthetic derivatives, including Dehydrodidemnin B (Plitidepsin, Aplidin), have led to improved efficacy and reduced toxicity. Didemnins, especially Didemnin B, hold promise as anticancer agents. However, future research should focus on optimizing delivery methods, reducing toxicity, and exploring combination therapies to enhance their therapeutic potential in oncology."

Journal • Review • Oncology

THALASSA: Study to Evaluate the Efficacy and Safety of Plitidepsin in Adults with Post-COVID-19 Condition (PCC) (clinicaltrials.gov) - P2 | N=90 | Not yet recruiting | Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

New P2 trial • Infectious Disease • Novel Coronavirus Disease

Exploring the Biosynthetic Potential of Tistrella Species for Producing Didemnin Antitumor Agents. (PubMed, ACS Chem Biol) - "Furthermore, we increased the titers of nordidemnin B and [hysp2]didemnin B by supplementing the fermentation medium with l-valine and l-isoleucine, respectively. Finally, both compounds undergo side-chain oxidation to enhance their biological activity, with their anticancer properties found to be as potent as plitidepsin."

Journal • Oncology

Exploring the seas for cancer cures: the promise of marine-derived bioactive peptide. (PubMed, Int J Biochem Mol Biol) - "Additionally, peptides from ascidians and mollusks, including Aplidine and Kahalalide F, demonstrate significant anticancer properties. The study delves into peptides affecting apoptosis, microtubule dynamics, and angiogenesis inhibition, offering insights into potential cancer treatment mechanisms. Marine-derived peptides hold great promise as valuable candidates for novel anticancer therapies, with ongoing research aimed at unlocking their full therapeutic benefits."

Journal • Review • Oncology

Marine bioactive peptides with anticancer potential, a narrative review. (PubMed, Int J Biochem Mol Biol) - "Additionally, peptides from ascidians and mollusks, such as Aplidine and Kahalalide F, demonstrate significant anticancer properties. While peptides like Neovastat and mycothiazole target known pathways, others such as patellamides act through unknown mechanisms, highlighting the intricate interactions of marine peptides with cancer cells. Overall, marine-derived peptides show promise as valuable candidates for developing novel anticancer therapies."

Journal • Review • Oncology

A phase III randomized controlled trial of plitidepsin, a marine derived compound, in hospitalized adults with moderate COVID-19. (PubMed, Clin Infect Dis) - "Despite the trial limitations, these results suggest that plitidepsin may have a positive benefit-risk ratio in the management of patients requiring oxygen therapy. Further studies with plitidepsin, including those in immunosuppressed patients, are warranted."

Journal • P3 data • Critical care • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

The Variation in the Traits Ameliorated by Inhibitors of JAK1/2, TGF-β, P-Selectin, and CXCR1/CXCR2 in the Gata1low Model Suggests That Myelofibrosis Should Be Treated by These Drugs in Combination. (PubMed, Int J Mol Sci) - "To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-β (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-β) signaling and TGF-β trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-β or CXCL1)."

Journal • Fibrosis • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CXCL1 • CXCR1 • CXCR2 • JAK1 • TGFB1 • TGFBR1

Aplidin will be re-evaluated by the EMA. The European Commission revokes the decision that initially denied PharmaMar's Marketing Authorization for Multiple Myeloma due to a conflict of interest (Pharmamar Press Release) - "PharmaMar...has received a notification from the European Commission (EC) informing the Company of its decision to revoke the refusal to grant Marketing Authorization for Aplidin in Multiple Myeloma...The EC notes that one of the experts of the Scientific Advisory Group (SAG) involved in the development of a rival product, was allowed to participate in the Marketing Authorization procedure for Aplidin, in accordance with the EMA rules applicable at the time. Consequently, in order to avoid any doubt as to the objective impartiality of the assessment of the application, the Commission has decided it is appropriate to revoke the decision to refuse Marketing Authorization for Aplidin. It is also reported that the Commission has forwarded to the EMA the opinions of the Committee for Medicinal Products for Human Use (CHMP), to request the re-evaluation of the application from the time of the onset of the detected procedural irregularity."

CHMP • European regulatory • Multiple Myeloma

Outcomes and clinical characteristics of the compassionate use of plitidepsin in COVID-19 patients with solid tumours, haematological malignancies or anti-CD20 antibody treatment. (PubMed, Infect Dis (Lond)) - P2 | "These findings support plitidepsin as a well-tolerated treatment in this high-risk group. A phase II clinical trial (NCT05705167) is ongoing to evaluate plitidepsin as an antiviral drug in this population.KEY POINTSHaematological patients face an increased risk for severe COVID-19.Anti-CD20 therapies could increase fatal outcomes in COVID-19 patients.Persistent viral replication is increased in immunocompromised patients.Plitidepsin does not lead to new serious adverse events in immunocompromised patients."

Journal • Hematological Disorders • Hematological Malignancies • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor

Marine-Derived Leads as Anticancer Candidates by Disrupting Hypoxic Signaling through Hypoxia-Inducible Factors Inhibition. (PubMed, Mar Drugs) - "However, despite the massive increase in the number of marine natural products classified as 'anticancer leads,' most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy."

Journal • Review • Oncology • Solid Tumor • HIF1A

The eEF1A Protein in Cancer: Clinical Significance, Oncogenic Mechanisms, and Targeted Therapeutic Strategies. (PubMed, Pharmacol Res) - "Among them, plitidepsin was approved for the treatment of multiple myeloma whereas metarrestin was currently under clinical development. Despite significant achievements in these two interrelated fields, hitherto there lacks a systematic examination of the eEF1A protein in the context of cancer research. Therefore, the present work aims to delineate its clinical implications, molecular oncogenic mechanisms, and targeted therapeutic strategies as reflected in the ever expanding body of literature, so as to deepen mechanistic understanding of eEF1A-involved tumorigenesis and inspire the development of eEF1A-targeted chemotherapeutics and biologics."

Journal • Review • Hematological Malignancies • Multiple Myeloma • Oncology • EEF1A1

NEREIDA: Plitidepsin Versus Control in Immunocompromised Adult Participants With Symptomatic COVID-19 Requiring Hospital Care (clinicaltrials.gov) - P2 | N=37 | Terminated | Sponsor: PharmaMar | N=150 ➔ 37 | Active, not recruiting ➔ Terminated; Significant difficulties in the recruitment of patients

Enrollment change • Trial termination • Infectious Disease • Myelodysplastic Syndrome • Novel Coronavirus Disease • CD4

A phase III randomised controlled study of plitidepsin, a marine derived compound, in hospitalised adults with moderate COVID-19 (NEPTUNO) (ECCMID 2024) - No abstract available

Clinical • P3 data • Infectious Disease • Novel Coronavirus Disease

NEREIDA: Plitidepsin Versus Control in Immunocompromised Adult Participants With Symptomatic COVID-19 Requiring Hospital Care (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: PharmaMar | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2025 ➔ Apr 2024 | Trial primary completion date: Jun 2025 ➔ Mar 2024

Enrollment closed • Trial completion date • Trial primary completion date • Infectious Disease • Myelodysplastic Syndrome • Novel Coronavirus Disease • CD4

Plitidepsin as an Immunomodulator against Respiratory Viral Infections. (PubMed, J Immunol) - "Moreover, decreases of IL-6 levels and other proinflammatory cytokines were also seen in either SARS-CoV-2 or H1N1 influenza virus-infected mice, which were treated at low enough plitidepsin doses to not induce antiviral effects. In summary, plitidepsin is a promising therapeutic agent for the treatment of viral infections, not only because of its host-targeted antiviral effect, but also for its immunomodulatory effect, both of which were evidenced in vitro and in vivo by the decrease of proinflammatory cytokines."

Immunomodulating • Journal • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Influenza • Novel Coronavirus Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • GLI2 • IL6 • TLR7

An organic extract from ascidian Ciona robusta induces cytotoxic autophagy in human malignant cell lines. (PubMed, Front Chem) - "In this regard, ascidians, which are included in the subphylum Tunicata, represent successful examples with two drugs, Aplidin"

Journal • Preclinical • Oncology

A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs. (PubMed, Angew Chem Int Ed Engl) - "Plitidepsin (or dehydrodidemnin B), an approved anti-cancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine tunicate extracts...Furthermore, we synthesised 13 new didemnin derivatives and three didemnin probes, enabling research into structure-activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale."

Journal • Oncology

Elongation factor 1A1 regulates metabolic substrate preference in mammalian cells. (PubMed, J Biol Chem) - "These effects were also observed with EEF1A1 knockdown in human hepatocyte-like HepG2 cells, and in wild type CHO-K1 and HepG2 cells treated with selective EEF1A inhibitors, didemnin B or plitidepsin...Thus, EEF1A1 deficiency may perturb glycolysis by limiting NFKB- and MYC-mediated gene expression, leading to decreased hexokinase expression and activity. This is the first evidence of a role for a translation elongation factor, EEF1A1, in regulating metabolic substrate utilization in mammalian cells."

Journal • EEF1A1 • HK2 • MYC • TNFA

NEREIDA: Plitidepsin Versus Control in Immunocompromised Adult Participants With Symptomatic COVID-19 Requiring Hospital Care (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: PharmaMar

Trial completion date • Trial primary completion date • Infectious Disease • Myelodysplastic Syndrome • Novel Coronavirus Disease • CD4

EEF1A2 promotes HIF1A mediated breast cancer angiogenesis in normoxia and participates in a positive feedback loop with HIF1A in hypoxia. (PubMed, Br J Cancer) - "EEF1A2 exhibits angiogenic potential in both normoxic and hypoxic conditions, underscoring its dual role in promoting EMT and angiogenesis, rendering it a promising target for cancer therapy."

Journal • Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HIF1A • MYC • PGR

NEREIDA: Plitidepsin Versus Control in Immunocompromised Adult Participants With Symptomatic COVID-19 Requiring Hospital Care (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: PharmaMar | Trial completion date: Aug 2024 ➔ Jul 2025 | Trial primary completion date: Jul 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Infectious Disease • Myelodysplastic Syndrome • Novel Coronavirus Disease • CD4

Compassionate Use of Plitidepsin in Patients With Non‑Hodgkin Lymphoma (NHL) and SARS‑CoV‑2 Infection (SOHO 2023) - P2 | "Sixty percent (3/5) had received 6 cycles of obitunuzumab and bendamustine (the last dose in patients 1 and 2 were administered 2 years prior to admission). Patients 2 and 5 had received rituximab maintenance, the last dose being administered in both < 2 months prior to admission for SARS-CoV-2. Patient 3 had received 6 cycles of obinutuzumab-COMP and maintenance with obinutuzumab, with the last dose administered 9 months before admission for SARS-COV-2... Plitidepsin shows a good safety profile in patients with NHL and SARS-CoV-2 infection. Four of the 5 patients presented resolution of SARS-CoV-2 infection. Prospective studies are needed to confirm the effectiveness of plitidepsin as a treatment for SARS-CoV-2 infection in patients with NHL who have received immunochemotherapy."

Clinical • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EEF1A1