DUBLIN – Step Pharma SAS added €8.6 million (US$10.1 million) in a second closing of its series A round to take the total to €14.5 million. The Paris-based startup will use the cash to bring a class of small-molecule immunosuppressive drugs into clinical trials in autoimmune disease.

The company's scientific founders, who include gene therapy pioneer Alain Fischer, have identified a novel target by characterizing a previously unrecognized rare homozygous mutation found in a small number of families in the northwest of England, which causes a life-threatening form of immunodeficiency. The company aims to capture that effect in order to dampen excessive immune activity in patients with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Fischer made his name by developing at the Necker Hospital for Sick Children in Paris an experimental gene therapy for boys with X-linked severe combined immunodeficiency (SCID-X1) who had no matched donors for bone marrow transplants. The approach was based on the administration of a retroviral vector encoding the interleukin-2 receptor gamma chain, to restore T-cell and natural-killer cell development in patients.

In 2014, Fischer and Step Pharma co-founder Sylvain Latour, both of the Imagine Institute in Paris, and collaborator Peter Arkwright, of the University of Manchester, U.K., published a letter, in the June 12 issue of Nature, which described a different form of immunodeficiency. It was originally observed in four children, from two unrelated families, who suffered severe and recurrent Epstein-Barr virus (EBV) infection but who did not carry any of the mutations associated with known immunodeficiency syndromes. Four more children from another three families in the region were later identified with the same problem, which increases their susceptibility to other viral infections and to bacterial infections as well.

All of them share the same mutation, a homozygous loss-of-function mutation, rs145092287, in the gene encoding cytidine triphosphate synthase 1 (CTPS1), which catalyzes the conversion of uridine triphosphate to cytidine 5′ triphosphate (CTP), an important step in DNA biosynthesis. The patients exhibited impaired T-cell and B-cell replication following antigen-mediated activation. In cell-based experiments, that deficit was restored by the addition of exogenous CTP or its nucleoside precursor cytidine.

DNA and RNA synthesis inhibitors, including methotrexate, leflunomide, azathioprine and mycophenolic acid, are routinely used for treating autoimmune disease, but their lack of selectivity narrows their therapeutic index.

"We only target the activated cells, which is where the biology could be completely new compared to other approaches, which are broadly targeting B or T cells," Step Pharma CEO and co-founder Geoffroy de Ribains told BioWorld.

CTPS1 has a distinctive expression profile, which lends weight to the hypothesis that it could offer a more targeted approach to immune modulation. "It's expressed at a very low rate in all cells," he said. "It's dramatically overexpressed in activated T cells." At the RNA level, expression increases about 4,000-fold following activation, he added.

A closely related isoform, CTPS2, does not appear to be highly active in any cell type, and its expression does not appear to be unregulated in the same fashion.

A group at Takeda Pharmaceutical Co. Ltd. recently published data on what they claimed is the first selective CTPS1 inhibitor, CT-pep3, a peptide with nanomolar binding affinity for the enzyme. The group appears to have been disbanded, de Ribains said, and the compound does not appear to be cell penetrant. It was more likely a tool compound than a drug lead – but the existence of the program is evidence of big pharma's interest in the target, he said.

Although the absence of CTPS1 activity is highly immunosuppressive in patients carrying the homozygous mutation, de Ribains said he did not expect the consequences of targeting the enzyme to be as severe in autoimmune disease patients. Targeting the functioning enzyme does not ablate entire T-cell or B-cell populations. Moreover, the patients who receive the drug will, unlike those who lack the functioning enzyme, already have immunological memory against a wide range of pathogens, which should provide a degree of protection against opportunistic infections. Because it is working on an oral drug, it will, in any case, be rapidly eliminated from the circulation.

Because it is active in tetrameric form, CTPS1 is a complex target to work with, de Ribains said, although the company is now in lead optimization. "Maybe we're lucky. In our hands, it was not as difficult as we thought initially."

That may have been helped by the circumstances surrounding the company's formation. Its institutional founders include the Imagine Institute, the Paris-based venture capital fund Kurma Partners and the Nottingham, U.K.-based drug discovery services firm Sygnature Discovery Ltd. The involvement of the latter as an equity participant in the company – it receives shares in return for services – ensures that Step Pharma receives high-level attention from its senior management team.

"You don't just get FTEs – chemists and biologists," de Ribains said.

The company aims to complete lead optimization by January and then spend some additional time working in multiple animal models in order to build up its understanding of the mechanism of action in various settings. It aims to enter formal preclinical development by June of next year and to begin clinical trials about a year after that.

It has yet to select a lead indication. That will be determined by a fuller understanding of the drug's mechanism and its clinical potential – and by the wider competitive landscape. "The picture is changing rapidly," de Ribains said.

Pontifax Venture Capital, of Herzeliya, Israel, joined Step Pharma's investor roster, which, in addition to the Imagine Institute, Kurma and Sygnature, also includes BPI France, Inserm Transfert Initiative and Idinvest.