Debanjan Ray, Synthekine CEO

Sanofi’s success co-developing a blockbuster drug based on blocking the signaling of interleukin 4 and interleukin 13 (IL-4 and IL-13) makes it an ideal partner to collaborate on inflammatory treatments based on enhancing another cytokine that, until now, has proven an elusive target.

That’s certainly the reasoning of Synthekine, a five-year-old developer of engineered cytokine therapeutics that is partnering with Sanofi to develop and commercialize IL-10 receptor agonist therapies for inflammatory diseases, the companies said today, through a collaboration that will pay Synthekine at least $40 million upfront.

Sanofi teamed up with Regeneron Pharmaceuticals in 2017 to bring Dupixent® (dupilumab) to market as a treatment for adults with moderate-to-severe eczema (atopic dermatitis). Since then, the companies have won additional FDA approvals for indications as varied as asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis (EoE), and prurigo nodularis. On January 25, the FDA expanded Dupixent’s EoE indication to cover children ages one to eleven.

But the agency in October rejected the companies’ supplemental BLA for approval in chronic spontaneous urticaria (CSU), directing Sanofi and Regeneron instead to furnish additional efficacy data—something they said will come from an ongoing clinical trial (Study C) that is expected to release results late this year.

Sanofi is “on track to be a real leader in the immunology and inflammation space,” Debanjan Ray, Synthekine’s CEO, told GEN Edge. “They’re putting a lot of resources behind that space, and most importantly, in cytokines, they have lots of expertise in that space.”

“I think the way that they’ve developed Dupixent over the last several years is really impressive, and it shows their strength in that area, and it shows their commitment to that area. I’m excited to leverage all those capabilities that they’ve built on this program,” Ray added.

Dupixent has grown into Sanofi’s best-selling drug. Over the first nine months of 2023, Dupixent generated €7.725 billion ($8.35 billion) in sales for Sanofi, up 35% from a year ago, while Regeneron enjoyed a 57% third quarter increase, from $551.1 million to an even $863 million, in its share of profits from commercialization of antibodies, citing higher profits associated with the increase in Dupixent sales.

In addition to Dupixent, Regeneron records profits on two other fully human monoclonal antibodies it has co-developed with Sanofi, Kevzara® (sarilumab), which blocks IL-6; and itepekimab, which inhibits IL-33. For January-September 2023, Regeneron’s share of profits from its antibody collaboration with Sanofi jumped 54%, from $1.46 billion to $2.25 billion. The Q3 and nine-month figures are net of a one-time $56.9 million payment to Sanofi following an amendment to their collaboration agreement that doubled, from 10% to 20%, Regeneron’s share of profits used toward reimbursing Sanofi for global development costs.

One cytokine, two platforms

Synthekine aims to optimize IL-10, with the goal of developing selective agonists for the cytokine by applying two of Synthekine’s three platforms. One is the company’s cytokine partial agonist platform, through which Synthekine aims to deliver therapeutic specificity by focusing the activity of its cytokines to specific immune cell types. The platform alters or tunes the wild-type cytokine’s receptor binding surface to either enhance binding to immune cell types that drive efficacy or diminish binding to immune cell types that drive toxicity.

The other platform is Synthekine’s surrogate cytokine agonist platform, through which surrogate cytokine agonists are engineered as de novo structures specifically designed to dimerize or multimerize receptor sub-units in ways that cannot be done by wild-type cytokines of mutein-based approaches.

Synthekine’s IL-10 program is now in preclinical discovery phase.

“What we’ve shown internally, and I think what Sanofi was excited by, was this concept playing out both from an in vitro perspective, showing that in vitro we have this biased activity towards macrophage suppression, and then some early in vivo data showing the same thing in animal models,” Ray said. “That’s where the program stands right now. We’re going to be working quite broadly with Sanofi to advance both of these novel modalities, both the partial agonist and the surrogate cytokine agonist, forward and hopefully, ultimately, into the clinic with them.”

It’s too soon to say how quickly that program could advance into the clinic, he added.

In addition to the $40 million upfront, Sanofi agreed to pay Synthekine additional payments tied to achieving preclinical, development, regulatory, and commercial milestones, plus tiered royalties on net sales.

Synthekine and Sanofi will collaborate on research activities up to an undisclosed defined point of preclinical development. At that point, Sanofi will assume sole responsibility for subsequent preclinical, clinical, and commercial activities for the IL-10 therapeutics.

Next wave

“IL-10 plays a key role in immune regulation, and this collaboration aimed at developing precisely tailored IL-10 therapies reaffirms our commitment to deliver the next wave of novel therapies to treat inflammatory diseases,” John Bertin, global head of inflammation and immunology research at Sanofi, said in a statement. “We look forward to working with Synthekine, a leader in targeted cytokine engineering with outstanding technologies and scientific team.”

The Synthekine collaboration is not the first time Sanofi has contemplated developing treatments based on blocking IL-10. Sanofi inherited an unspecified number of preclinical engineered versions of IL-10 when it shelled out approximately $2.5 billion to acquire another cytokine drug developer, Synthorx, in 2019.

At the time, Synthorx’s lead drug was THOR-707, a novel investigational IL-2 that Sanofi renamed SAR444245, and launched into a set of Phase II platform trials that it ended by the third quarter of 2022: “The efficacy observed in the early look of the data was lower than projected,” Sanofi stated in announcing Q3 2022 results, adding: “This decision was not based on any safety-related issues.”

“Based on emerging external and internal data about non-alpha IL2’s mechanism of action and therapeutic potential, a new Phase I/II program is planned to be initiated for SAR444245,” Sanofi added.

Last year researchers from Sanofi and partners published a study in the journal HemaSphere based on in vitro and in vivo models of T cell exhaustion, to show that SAR444245 stimulated T cell proliferation and effector functions and mitigated T cell exhaustion following chronic stimulation. Those results provide a rationale for future clinical study of SAR444245 with CAR T cells, the researchers added.

Based in Menlo Park, CA, Synthekine was established in 2019 to commercialize cytokine discoveries by its founder K. Christopher Garcia, PhD, professor of molecular and cellular physiology and structural biology at Stanford University School of Medicine and a Howard Hughes Medical Institute (HHMI) investigator.

Garcia’s pioneering research on the interaction between cytokines and their receptors has resolved the structure and elucidated the structure-function relationships of multiple cytokines and their receptors. That, in turn, has enabled the engineering of modified cytokines to deliver selective activity to particular cell types of therapeutic interest, giving them the potential for optimized efficacy, a larger therapeutic window, and improved patient safety.

“The depth of the science we licensed from the Garcia lab at Stanford gave us a very fast start. Everything translated well in our hands, which sped up the company’s development,” Ray told GEN Edge in 2022.

Building on that research, Synthekine has worked to surmount two key challenges of using cytokines as therapeutics. Cytokines are pleiotropic, having biological functions on many immune cells, stimulating and suppressing the immune system in different contexts. And they are promiscuous, binding to a variety of targets, which makes it challenging to develop cytokine-based therapeutics.

Engineering IL-10 variants

In 2019, Garcia served as corresponding author of a study published in Science, in which a research team engineered additional variants of IL-10 with variable IL-10Rβ–binding affinities, by generating a high-affinity version of IL-10 (“super-10”) that allowed them to visualize IL-10 in complex with both IL-10Rα and IL-10Rβ by cryo–electron microscopy (cryo-EM).

“We engineered IL-10 variants exhibiting myeloid cell selectivity, which effectively uncoupled the pro- and anti-inflammatory functions of IL-10. These findings provide a conceptual framework for the development of improved cytokine-based therapeutics,” the researchers concluded.

Synthekine’s IL-10 program is one of four autoimmune and inflammation programs in the company’s pipeline. None have reached the clinic, although a wholly owned combination therapy is in IND-enabling phase, consisting of STK-009, an engineered pegylated IL-2 cytokine, and SYNCAR-001, a CD19-targeting chimeric antigen receptor (CAR) T cell  which expresses an engineered IL-2 receptor allowing it to selectively receive a signal from STK-009.

STK-009/SYNCAR-001 is also within Synthekine’s cancer pipeline in a Phase I trial (NCT05665062) designed to assess its ability to treat seven CD19+ blood cancers: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), non-Hodgkin’s lymphoma (NHL), mantle cell lymphoma, follicular lymphoma, large B-cell lymphoma, indolent B-cell non-Hodgkin lymphoma, and diffuse large B cell lymphoma (DLBCL). The study’s estimated primary completion date is June 2024.

A second Synthekine cancer candidate, STK-012, is an IL-2 partial agonist using the engineered cytokine partial agonist platform. STK-012 is in a Phase Ia/Ib study (NCT05098132) as both monotherapy and in combination with Merck & Co.’s Keytruda®, with an estimated primary completion date of October 2025.

Also in Synthekine’s cancer pipeline are a second IL-2 partial agonist, STK-026, based on the engineered cytokine partial agonist platform (IND-enabling phase); the combination of STK-009 and SYNCAR-002, a GPC3 OrthoCAR, using the orthogonal cytokine + cell therapy platform (IND-enabling); and an undisclosed discovery-phase program applying the surrogate cytokine agonist platform.

Within the autoimmune and inflammatory pipeline are an IL-22 program applying the cytokine partial agonist and surrogate cytokine agonist platforms; and an undisclosed program using the surrogate cytokine agonist platform.

Synthekine has grown its workforce to approximately 100 people—a level it plans to maintain this year. “I think we’ve got a really productive team. And we’ve got the right headcount to continue progressing all this work that we’re doing,” Ray said.

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