The antiviral drug plitidepsin is between 10 and 100 times more effective against SARS-CoV-2, including the new UK variant, than the NHS approved drug remdesivir, finds new preclinical research involving UCL scientists.
As part of a coronavirus collaboration with US researchers, a UCL team was asked to test the efficacy of the drug plitidepsin on the newly identified UK variant mutant strain B.1.1.7.
The UK arm of the study, published on the pre-print server bioRxiv, found plitidepsin was around 10 times more potent than remdesivir in vitro (in human epithelial cells) – at reducing B.1.1.7 infectivity.
This UCL research mirrors the results of the larger arm of the study based in the US, which has been through peer-review, and was conducted by collaborators at the Quantitative Biosciences Institute (QBI), part of University of California San Francisco, and the Icahn School of Medicine at Mount Sinai, New York (ISMMS).
For the US-led paper, published in Science, researchers screened numerous clinically approved drugs, in order to identify those with inhibitory activity against SARS-CoV-2. Specifically they were looking for ‘host-directed therapies,” those which target host (human) proteins, rather than virus proteins, which are usually targeted to inhibit infection.
Plitidepsin, also known as Aplidin, is a novel drug approved by the Australian Regulatory Agency for the treatment of multiple myeloma, and is part of numerous other Phase II/III clinical cancer trials around the world.
The US arm of the study found that plitidepsin was 27.5 times more potent than remdesivir in vitro, at inhibiting (preventing further infection) SARS-CoV-2, the virus that causes COVID-19. This research was also carried out in vitro – in cells in the laboratory, not in patients.
In addition, the study found that plitidepsin was 100 times more effective than remdesivir at reducing the viral replication in the lungs and demonstrated an ability to reduce lung inflammation – one of the most serious side effects of COVID-19. This element was conducted in vitro in an established mouse model of human lung cells.
The UCL arm of the study only studied the UK variant and found comparable anti-viral activity in vitro against B.1.1.7, but did not measure lung inflammation.
Senior author, Professor Greg Towers (UCL Infection & Immunity) said: “These studies show plitidpesin is a highly potent inhibitor of SARS-CoV-2, and is significantly more effective than the widely approved remdesivir against both early and more recent lineages of the virus.
“But it’s most important strength is that it targets a host protein rather than a viral protein. This is really exciting; by targeting a host (human) protein, the effectiveness of plitidpesin will not be altered by mutant variants in SARS-CoV-2.
“We now have a broad range of approved drugs with activity against the virus and we can consider using them directly and improving them. It is also realistic to expect some of these drugs to be effective against a range of zoonotic coronaviruses.”
The researchers say plitidpesin should now be further evaluated as a COVID-19 therapy.
The US arm of the study also assessed the dynamics between the antiviral effects of plitidepsin and remdesivir when used together in vitro. This analysis suggested that plitidepsin has an additive effect with remdesivir and would be a potential candidate to be considered in a combined therapy.
Corresponding author, Associate Professor Clare Jolly (UCL Infection & Immunity), added: “These results highlight the importance of continued development of host-directed therapeutics to combat current and future coronavirus variant outbreaks.”
In the UCL study, human epithelial cells, infected with the UK variant B.1.1.7, were treated with plitidepsin. In basic terms, researchers found it took 10 times less plitidepsin, than remdesivir, to reduce the infection by half. Meaning plitidepsin is 10 times more potent.
The same experiment was conducted by the US arm and found plitidepsin was 27.5 times potent. Researchers in the US also carried out similar tests on a mouse model of lungs, which found plitidepsin was 100 times more effective. Researchers say these findings point to the same conclusion that plitidepsin is significantly more potent.
The Madrid (Spain-) based and oncology-focused biotech company PharmaMar reports positive results for plitidepsin (Aplidin®; formally known as dehydrodidemnin B) against coronavirus HCoV-229E, a genus of enveloped, single-stranded positive-sense RNA viruses known as Coronaviridae family which are within the Nidovirales order
HCoV-229E is linked to common cold symptoms in healthy adults. Younger children and the elderly as well immunocompromised patients and patients with comorbidities are considered (extremely) vulnerable to developing lower respiratory tract infections (LRTIs). In some cases severe and life-threatening LRTIs have been attributed to HCoV-229E.
COVID19
The in vitro studies results of plitidepsin on the human coronavirus HCoV-229E, which has a multiplication and propagation mechanism very similar to COVID19, have been positive with a potency of the nanomolar order.
These studies have been carried out at the National Biotechnology Center (Centro Nacional de Biotecnología) of the Spanish National Research Council (CSIC) by Luis Enjuanes, MD, Isabel Solá, MD, and Sonia Zúñiga, Ph.D.
These results confirm the hypothesis that the therapeutic target of plitidepsin, which includes the eukaryotic elongation factor 1A (EF1A), is key to the multiplication and spread of the virus. [1]
As part of the next step in the drug development and regulatory approval of the drug for this indication, PharmaMar will contact regulatory authorities to analyze the possibilities of studies on patients infected with COVID19.
Anti-cancer agent
Plitidepsin is an anticancer agent of marine origin. The drug is a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans and is commercially produced by chemical synthesis. [2]
The investigational drug displays a broad spectrum of anticancer activities, including induction of apoptosis and G1/G2 cell cycle arrest.
In ongoing research, plitidepsin has shown reproducible activity against a variety of malignant cell lines, including leukemias and lymphomas. A phase II trial evaluated plitidepsin in 67 patients, which included 34 patients with relapsed/refractory noncutaneous Peripheral T-Cell Lymphoma (PTCL). Of the 29 evaluable patients with noncutaneous PTCL, six patients demonstrated an objective response to plitidepsin (two CRs and four PRs; ORR = 20.7%) with a median PFS and duration of response of 1.6 and 2.2 months, respectively.
Clinical studies have also shown anti-myeloma activity even in myelomas resistant to other agents.
In vitro studies have demonstrated that plitidepsin has anti-myeloma activity against 19 multiple myeloma cell lines including cells resistant to anti-myeloma agents frequently used in the clinic (i.e. melphalan, doxorubicin, thalidomide derivatives, and dexamethasone) and primary multiple myeloma cells isolated from patients (13 out 16 showed a response to plitidepsin).[3]
Researchers have also shown that plitidepsin targets the eukaryotic elongation factor 1A2 (EF1A2), which is overexpressed in multiple myeloma cells. Mechanistically, scientists have identified several pathways mediating the effects of plitidepsin on the viability of multiple myeloma cells. [3]
Mechanism of action
Plitidepsin induces apoptosis in multiple myeloma cells, which involves activation of p38 and c-jun NH(2)-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and ultimately caspase activation. The investigational agent also decreases the proliferation of multiple myeloma cells, an effect mediated by the suppression of several proliferative genes.[3]
In a pivotal phase III trial of patients with relapsed or refractory multiple myeloma, plitidepsin in combination with dexamethasone (Dex) significantly reduced the risk of progression or death compared to Dex alone.
Plitidepsin has been approved by TGA in Australia for the treatment of multiple myeloma in combination with dexamethasone for patients that relapse after three lines of treatment, including proteasome inhibitors or immunomodulators.
Clinical trials
Study of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Patients With Multiple Myeloma – NCT02100657
Aplidin – Dexamethasone in Relapsed/Refractory Myeloma (ADMYRE) – NCT01102426
Study of Plitidepsin in Combination With Sorafenib or Gemcitabine in Patients With Advanced Solid Tumors or Lymphomas – NCT00788099
A Study of Aplidin (Plitidepsin) 3 h iv in Subjects With Relapsing or Refractory Multiple Myeloma – NCT00229203
Reference
[1] Sasikumar AN, Perez WB, Kinzy TG. The many roles of the eukaryotic elongation factor 1 complex. Wiley Interdiscip Rev RNA. 2012;3(4):543–555. doi:10.1002/wrna.1118
[2] Cragg GM, Newman DJ. Natural Product Sources of Drugs: Plants, Microbes, Marine Organisms, and Animals. In: Comprehensive Medicinal Chemistry II | Pages 355-403 | Reference Work | 2nd Edition | 2007. ISBN 978 0 08 045044 5. Published by Elsevier Science.
[2] Delgado-Calle J, Kurihara N, Atkinson EG, et al. Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts. Oncotarget. 2019;10(28):2709–2721. Published 2019 Apr 12. doi:10.18632/oncotarget.26831 [Article]
More information: Ann-Kathrin Reuschl et al. Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant, (2021). DOI: 10.1101/2021.01.24.427991
