DUBLIN – Roche Holding AG has joined Jnana Therapeutics Inc. in its quest to drug the human repertoire of solute carrier (SLC) metabolite transporters as a means of tackling a swath of immune-mediated and neurological diseases. The Basel, Switzerland-based pharma is paying Boston-based Jnana $40 million up front and could pay over $1 billion more in research funding, preclinical, development and commercial milestones, as well as sales royalties, in a multitarget deal.

The alliance is the second Jnana has entered since closing a $50 million series A round in 2017. In 2018, it partnered with San-Diego-based Neurocrine Biosciences Inc. on a multitarget deal focused on central nervous system (CNS) disorders. The present transaction is further evidence that the company’s efforts to take a systematic approach to prising open the 450 members of the superfamily of SLC transporters is resonating with biopharma firms that are interested in broadening their small-molecule drug development portfolios. “We really see this as a big, broad strategic collaboration for the company,” CEO and co-founder Joanne Kotz told BioWorld.

The agreement grew out of a longstanding connection between Roche’s global head of immunology discovery, Kara Lassen, and the company’s founders. Lassen had previously worked at the Broad Institute in Cambridge, Mass., in the group of Jnana co-founder Ramnik Xavier, and had stayed in contact with the science. That connection crystallized in deal talks that kicked off at this year’s J.P. Morgan meeting in January. “Roche moved with astonishing speed,” Kotz said.

Joanne Kotz, CEO, Jnana

Jnana has yet to reveal any details about the specific targets it is working with. About 20 of the known 450 SLC transporters have already been drugged, although some of the early examples were derived through phenotypic screening, Kotz said, and the targets involved were only identified after the fact.

Jnana has developed a screening platform, Rapid (Reactive Affinity Probe Interaction Discovery), which employs molecular probes that bind an SLC transporter of interest. Those can be deployed in cell-based assay systems, which can be exposed to high-throughput screening libraries of drug-like compounds, in order to identify leads that can displace the probes through competitive binding. Additional assays can further characterize the binding interaction. “We can triage hits we get out of high-throughput screening very quickly,” Kotz said.

Although G protein-coupled receptors (GPCRs) offer a ready analogy as a broad target class of integral membrane proteins, they differ from SLC transporters in sharing similar structural characteristics. They also operate through the same intracellular signal pathways. SLC transporters are, in contrast, Kotz said, much more diverse both in terms of structure and downstream signaling pathways. Their locations are also highly diverse. “They tend to be expressed in a remarkably cell-selective way,” she said.

SLC transporters play a key gatekeeping role in maintaining appropriate levels of myriad metabolites, including amino acids, glucose, metal ions, neurotransmitters, urea cycle intermediates, nucleotide sugars, inorganic ions and organic anions, among others, as described in one comprehensive review of the subject. Many are explicitly implicated in disease. “About a third of them, when mutated, directly cause a monogenic disease,” Kotz said.

Jnana’s clinical focus is on conditions characterized by an excess or deficiency of a particular metabolite – be it systemic or organ-specific – where there is human biological evidence that an SLC transporter is an important disease lever and where there is a biomarker available that would inform the design of a clinical trial. Its lead internal program is an undisclosed metabolite-defined rare disease, in which there is an excess of the molecule in question. The basic aim of the program, which is currently in lead optimization, is to correct the dysfunction by inhibiting the associated SLC transporter.

Immune-mediated diseases represent an important opportunity for the company. By its very nature, it is focused on the emerging field of immunometabolism, which is concerned with modulating immune dysfunction by targeting the unusual metabolic pathways that immune cells can avail of under certain conditions. Companies like Oxford, U.K.-based Sitryx Ltd., which entered a deal earlier this year with Eli Lilly and Co., of Indianapolis, and Cambridge, Mass.-based Rheos Medicine Inc., which entered an alliance with Roche late last year, are also active in the space.

But Jnana’s focus differs, Kotz said, as those firms are focused on internal pathways, whereas it is focused upstream, on the gatekeepers that determine whether or not certain metabolites enter or leave a particular cell. “We think these transporters are key nodes in these pathways and very exciting points of intervention,” she said.

SLC transporter infographic

 

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