DUBLIN – Amarna Therapeutics BV raised €10 million (US$11.1 million) in new financing to move its SV40-based gene therapy platform, SVac, toward the clinic.

The company, based in Leiden, the Netherlands, has been around for some time. It was founded back in 2008 but has largely remained below the radar screen while developing a stable production system involving replication-deficient SV40 viruses and a Vero-based cell line that supports efficient packaging of vector particles.

The company has been supported by private investors, including friends and family, until now. The present injection of cash comprises €6 million in equity and a €4 million innovation credit – or soft loan – from the Dutch government. It coincides with the appointment of a new board, chaired by Thomas Eldered, a Swedish entrepreneur and investor, whose investment vehicle Flerie Invest AB led the present investment round, and plans to move into first-in-human trials within the next three years. Its manufacturing process is reaching maturity. "We are now in the process of transferring the whole process to a CMO," Peter de Haan, Amarna's chief scientific officer and co-founder, told BioWorld. "We are approaching a scale that is sufficient for running a first clinical study."

The shortcomings of the most widely used gene therapy vectors are well known. Lentiviral vectors have a large packaging capacity and, because they are integrating vectors, they are stably inherited during cell division, but they still carry the risk of insertional mutagenesis and also lack specificity for target cells. Adeno-associated viruses (AAVs) do not integrate with the host chromosome and are therefore better suited to quiescent cells that are not actively dividing. Insertional mutagenesis is not an issue, but their packaging size is limited to about 4.7 kilobases of DNA. Immunogenicity due to prior exposure is a significant issue and can limit their use.

Simian virus 40 (SV40) has long been studied as a model eukaryotic virus, but its potential as a gene therapy vector has been largely neglected. In large part, according to Amarna, that was due to the lack of a suitable cell line for packaging replication-deficient vector particles. The most widely used cell lines, COS-1 and COS-7, give rise to replication-competent viruses after several passages, which rules out their use in gene therapy settings. De Haan and colleagues reported on the development of a Vero cell line, dubbed SuperVero, where that problem does not arise. "The whole process is comparable with a vaccine production process," De Haan said. "You do not need complicated transfection steps." Their study appeared in the Sept. 15, 2017, issue of Molecular Therapy – Methods & Clinical Development.

The packaging capacity of the first-generation vector is limited to about 2.7 kb, but that is still large enough for the initial set of indications it plans to target. A second generation is in development, which will have a substantially larger capacity, but the big selling point of the SVac platform is its lack of immunogenicity. "We are immunologically naïve to the virus and to the vector," de Haan said. "We and others – many others – have done repeat administration in animals." The virus infects macaque monkeys only, but it also evades the immune system by avoiding lysosomal degradation. The viral vector induces tolerance during expression in the liver, he said. "It's a T-reg-mediated process," he said.

The company's lead program, AMA-001, is in development for primary hyperoxaluria type 1 (PH-1), an ultra-rare genetic condition arising from mutations in the gene encoding serine-pyruvate aminotransferase, which normally converts glyoxylate to glycine. In its absence, glyoxylate is instead converted to oxalate, which combines with calcium to form kidney stones. Amarna comprises a replication-deficient SV40 vector encoding the missing enzyme. The company has established a partnership with the main treatment center for the condition in the Netherlands. Up to 140 patients in the Benelux region are eligible for the trial, although only a fraction of those will be enrolled. A study start is still two to three years away.

There could be a therapy available by then. Cambridge, Mass.-based Alnylam Pharmaceuticals Inc. recently completed enrollment in a phase III trial of lumasiran, an siRNA targeting glycolate oxidase, which depletes levels of glyoxylate, the substrate required for oxalate production. Top-line data are expected before year-end. Dicerna Pharmaceuticals Inc., also of Cambridge, is in a phase II pivotal trial with another siRNA-based drug, DCR-PHXC, which targets the liver enzyme lactate dehydrogenase A. Newton, Mass.-based Allena Pharmaceuticals Inc. is also in the mix. It is in phase II in PH-1 with reloxaliase (formerly ALLN-177), an orally administered formulation of oxalate decarboxylase, which converts oxalate to formate. The same drug is also in phase III in enteric hyperoxaluria, which can occur after intestinal resection or bypass surgery.

Amarna, which maintains an R&D unit in Seville, Spain, in addition to its base in Leiden, has a "lean-and-mean" operating model, and the present infusion of cash should take it to clinic, CEO and co-founder Ben van Leent told BioWorld. In addition to PH-1, it also has early stage programs in type 1 diabetes, age-related macular degeneration and arthritis. It is also open to licensing the SVac platform to third parties.

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