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PsiVac Ltdpsivac.com
Gamechanger: how PsiVac is unleashingthe full power of oncolytic virusesBiotech company PsiVac is developing Ixovex-1, the first patented virus with a single base pair mutationable to replicate rapidly, opening potential new treatment options for solid tumors and beyond.
PsiVac is set to end decades of disappointing dataon oncolytic viruses with a radical new approachthat upends conventional wisdom about the modal-ity. Rather than engineer the viral genome, PsiVacintroduces a critical single base pair mutation tocreate viruses that are highly selective and replicaterapidly. The result is a virus, Ixovex-1, that delivers astep change in efficacy and enhanced safety.
Oncolytic viruses can be incredibly powerful.Selectively replicating oncolytic viruses infecttumor cells, make copies of themselves and lysetheir hosts, releasing progeny that infect adjacenttumor cells and repeat the process. Oncolyticviruses thereby directly kill cancer cells and causethe release of tumor-associated antigens thatenable the immune system to recognize a cancertype and develop long-term memory against it. Theone-two punch of direct killing and the triggering ofthe immune system are potentially highly potent.
Yet, oncolytic viruses have so far failed to fullydeliver on that promise. The problem stems fromthe deletion of part of the viral genome to achieveselectivity for tumor cells. Deletions enhance safetybut reduce replication efficiency, significantly limit-ing efficacy.
Many companies are pitching armed oncolyticviruses as the solution to limited efficacy. By add-ing a gene encoding for an immunomodulatorycytokine, such as GM-CSF, researchers can cre-ate viruses that cause local expression of immunetherapeutics and alter the tumor microenvironment.
That approach fails to fix the reduced replicationefficiency that is the fundamental weakness ofengineered viruses, though, and is unlikely to workbetter than systemic administration of a cytokine.The amount of cytokine produced using armedoncolytic viruses is unknown, making the dosage andtiming less controllable than systemic delivery. Theuncertain benefits are offset by the demonstrateddownside of weakening replication efficiency.
Efforts to develop drugs without that downsidehave been undermined by the refusal of patentson viruses without insertions or deletions. PsiVac,a UK-based biotech, overcame that barrier using acritical single base pair mutation, making it the firstcompany with a patented virus that has no insertion
or deletion. PsiVac will soon prove its hypothesisclinically. A phase 1 clinical trial will commence inlate 2021, followed shortly by a phase 2 study.
Validating a breakthrough conceptIxovex-1 is almost identical to the wild-type form of thehuman adenovirus serotype 5. The only difference is asingle base pair mutation at a specific splice site. Thatlimited modification enables PsiVac to maintain thestructural integrity of the virus while inhibiting replica-tion in normal cells and enhancing efficacy (Fig. 1).
In preclinical tests, Ixovex-1 replication was sig-nificantly attenuated in healthy cells comparedwith wild-type virus and H101 virus; a gene-deletedadenovirus sold as Oncorine. PsiVac’s findingssuggest Ixovex-1 will be safer than an approvedoncolytic virus.
PsiVac has generated compelling efficacy data, too.In large and non-small cell lung cancer (NSCLC) cells,Ixovex-1 replicated as well as the wild-type controland significantly better than H101 virus, validatingPsiVac’s hypothesis that its modification maintainsreplication efficiency. An evaluation of Ixovex-1 in16 solid tumor cell lines provided further validation.
In a preclinical proof-of-concept study, Ixovex-1was better at controlling NSCLC than H101 virus andas effective as the wild-type virus. Two of the sevenmice treated with Ixovex-1 were cured, showing thatthe maintained replication efficiency translates intosuperior efficacy.
Advancing a life-saving medicineHaving shown that Ixovex-1 is safe, powerful andreplication efficient in all tested solid tumor celllines, PsiVac is planning human clinical trials. Lonza
carried out successful small-scale feasibility pro-duction studies, paving the way for upscaling andcurrent good manufacturing practice (cGMP) pro-duction. Lonza is a leader in contract manufacturing,and employs top cell and gene therapy experts,offering services ranging from process develop-ment to clinical and commercial supply. PsiVac haspartnered with Lonza for the process developmentand GMP manufacture of Ixovex-1.
Kevin Harrington will oversee trials in London atthe Royal Marsden and University College Londonhospitals. Harrington was lead investigator onthe pivotal trial of T-Vec, the first oncolytic virusapproved in the USA.
PsiVac plans to test Ixovex-1 in combination withanother drug, possibly a checkpoint inhibitor, inphase 2 trials. That plan is informing PsiVac’s criteriafor selecting a partner. PsiVac is looking for a partnerwith immuno-oncology assets and expertise, andthe capabilities and drive needed to quickly takeIxovex-1 to market. The biotech company may alter-natively seek investment and advance Ixovex-1 itself.
Organizations that partner, license, or invest willgain exposure to a potentially game-changing assetin one of the hottest immuno-oncology subsectorsand help PsiVac realize the full, life-saving potentialof oncolytic viruses.
Ixovex-1 is injected intratumorally. Ixovex-1 replicates in and lyses tumor cells. The released cytokines attract dendritic cells that then are exposed to the newly released tumor-associated antigens . Dendritic cells would then prime T cells to specifically attack tumor cells in other parts of the body
Ixovex-1 - Oncolytic Immunotherapy
Fig. 1 | The mode of action of Ixovex-1 developed by PsiVac.
Imad MardiniPsiVac LtdLondon, UKTel: +44 20 7971 1100Email: [email protected]
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“PsiVac is the firstcompany with a
patented virus that hasno insertion or deletion
www.nature.com/biopharmdeal | September 2020 | B27
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