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

Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in relapsed/refractory multiple myeloma: Results for patients aged < 75 years (ASH 2025) - "Tolerance to treatment was also evaluated by the time to performance status deterioration or death, indicative of patient general status, which was 5.7 months (95%CI, 3.8-9.0 months) for the plitidepsin plus DXM arm and 2.1 months (95%CI, 1.4-3.8 months) for the DXM arm (HR=0.5680; 95%CI, 0.394-0.820; p=0.0021). In conclusion, larger differences in efficacy outcomes while maintaining a similar safety profile together with a novel mechanism of action suggest that this combination can be a valid option for patients with r/r MM aged < 75 years."

Clinical • Combination therapy • P3 data • Hematological Malignancies • Multiple Myeloma • Musculoskeletal Pain

Plitidepsin in combination with dexamethasone (ADMYRE trial) versus an external control arm of pomalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma (ASH 2025) - "Safety profile of POM+LD-DXM was associated to a higher rate of AEs, as expected for a combination. In conclusion, P+LD-DXM can be considered an alternative therapeutic option in r/r MM as this comparison in terms of OS shows that P+LD-DXM is non-inferior to POM+LD-DXM with an advantageous safety profile in terms of hematological and infection events."

Clinical • Combination therapy • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Musculoskeletal Pain • Neutropenia • Thrombocytopenia

Can plitidepsin be used as an antiviral against RSV? (PubMed, mSphere) - "So, we think that our results are new and original and that this information should be useful for the community working either with plitidepsin or eEF1A, with viruses, or other topics. We think that, in contrast to what is suggested by previous studies, it is risky to use plitidepsin as an antiviral in humans."

Journal • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • EEF1A1

Pharmacological reprogramming of plitidepsin as a SARS-CoV-2 inhibitor. (PubMed, Mol Aspects Med) - "The pharmacokinetic and pharmacodynamic data on plitidepsin will be analyzed, and the various experimental lines of evidence in support of the molecule's multifactorial mechanism of action will be explored. Finally, the available data on the use of plitidepsin in patients with COVID-19 will be presented, including results from a Phase I proof-of-concept study, real-world data from immunocompromised patients, and a look of results from a Phase III clinical trial that confirms the working hypothesis."

Journal • Review • Hematological Malignancies • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Randomized Phase III Study (ADMYRE) of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Relapsed/Refractory Multiple Myeloma: Results for Patients Aged <75 Years. (PubMed, Cancers (Basel)) - "The most common adverse events (all grades) related to the study treatment in patients < 75 years were fatigue (39.2% of patients), gastrointestinal (nausea, 39.2%; vomiting, 19.6%; diarrhea, 14.7%), and myalgia (14.0%). Larger differences in efficacy outcomes while maintaining a similar safety profile, together with a novel mechanism of action, suggest that this combination can be a valid option for patients with r/r MM aged <75 years."

Journal • P3 data • Fatigue • Hematological Malignancies • Multiple Myeloma • Musculoskeletal Pain • Oncology • Pain

Randomized Phase III Study (ADMYRE) of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Relapsed/Refractory Multiple Myeloma: Results for Patients Aged <75 Years (Multidisciplinary Digital Publishing Institute) - "Compared to the overall ADMYRE population, a higher reduction was found with plitidepsin plus DXM for the risk of progression or death in the primary endpoint: 47.7% vs. 35.0% (Hazard ratio [HR] = 0.523 vs. HR = 0.6509). Higher reduction in the risk of death was also found (28.9% vs. 20.3%; HR = 0.711 vs. HR = 0.797), with a clinically meaningful 5-month difference in median overall survival (13.0 months vs. 8.1 months; p = 0.0350)."

P3 data • Multiple Myeloma

Marine-Derived Compounds: A New Horizon in Cancer, Renal, and Metabolic Disease Therapeutics. (PubMed, Mar Drugs) - "This review systematically evaluates recent advances, highlighting compounds such as Microcolin H, Benzosceptrin C, S14, HN-001, Equisetin, glycosides (e.g., cucumarioside A2-2), ilimaquinone, and Aplidin (plitidepsin)...Pharmacokinetic challenges and structure-activity relationships are critically analyzed, emphasizing nanodelivery systems and synthetic analog development. This review bridges mechanistic insights with translational potential, offering a cohesive framework for future drug development."

Journal • Review • Atherosclerosis • Cardiovascular • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Nephrology • Oncology • Renal Disease

Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 21-24 July 2025 (European Medicines Agency) - "PharmaMar withdrew its application for a marketing authorisation of Aplidin for the treatment of multiple myeloma. The company withdrew the application on 23 July 2025 during a re-examination."

European regulatory • Multiple Myeloma

Functional characteristics of plitidepsin as an antiviral treatment against monkeypox virus infection. (PubMed, Antiviral Res) - "Additionally, the limited efficacy of current smallpox antivirals, such as Tecovirimat and Brincidofovir, alongside growing concerns about the emergency of tecovirimat resistance mutants, underscores the need for new therapeutic options. These findings indicate plitidepsin as a promising candidate for mpox treatment. Further studies are needed to explore its potential as a standalone or combination therapy, supporting clinical evaluation for mpox treatment."

Journal • Infectious Disease • Oncology • EEF1A1

Comprehensive investigation of SARS-CoV-2 intestinal pathogenesis in Drosophila. (PubMed, bioRxiv) - "Treatment with Plitidepsin, a COVID-19 drug candidate, mitigates most SARS-CoV-2 pathogenic features in both the Drosophila midgut and human pulmonary cells, while modulating basal lipid droplet homeostasis in uninfected conditions. These findings establish the Drosophila midgut as a potent model for studying SARS-CoV-2 GI pathogenesis and evaluating antiviral compounds."

Journal • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Respiratory Diseases

Multidimensional Regulatory Mechanisms and Targeting Strategies of the eEF1 Family in RNA Virus Infection. (PubMed, Viruses) - "Current eEF1-targeting compounds like plitidepsin demonstrate efficacy against diverse viral families, though therapeutic development faces challenges in balancing antiviral activity with host toxicity. This review provides a theoretical foundation for developing novel antiviral strategies targeting host-virus interaction interfaces and offers insights into addressing emerging infectious diseases."

Journal • Review • Infectious Disease • EEF1A1

Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 19-22 May 2025 (European Medicines Agency) - "By its judgment of 28 October 2020 in Case T-594/18, the General Court annulled the Commission Implementing Decision of 17 July 2018 refusing marketing authorisation for Aplidin. The judgment was subsequently appealed before the Court of Justice in Joined Cases C-6/21 P and C-16/21 P. On 22 June 2023, the Court of Justice set aside the judgment and referred the case back to the General Court (Case T-594/18 RENV). On 28 June 2024, the European Commission revoked the Commission Implementing Decision of 17 July 2018 refusing marketing authorisation for Aplidin. Following the adoption of this decision, the Commission has requested EMA to re-assess the application for Aplidin. EMA is currently taking the appropriate steps to implement this decision."

European regulatory • Multiple Myeloma

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