Epkin is an affiliate of Owkin

Sponsor of the clinical trial of OKN4395

OKN4395The INVOKE trial

What is OKN4395?

A First-in-Class EP2/EP4/DP1 Triple Inhibitor
OKN4395 is an investigational drug
OKN4395 is a selective triple inhibitor of EP2, EP4, and DP1.
First-in-class profile
First-in-class profile with Phase 1 underway.
AI-powered study design
OKN4395 is the first Owkin program to leverage Owkin’s AI, from asset selection to clinical development optimization.

Mechanism of action

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Prostaglandin E2 and Prostaglandin D2 (or PGE2 and PGD2) are hormone-like molecules that are produced naturally in the body, but that can also be produced in tumors.

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PGE2 and PGD2 interact with certain kinds of immune cells, through prostanoid receptors on their surface.

PGE2 interacts with EP2 and EP4 prostanoid receptors, and PGD2 interacts with DP1 prostanoid receptors.

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When these interactions happen in immune cells, the immune cells become less active.

In certain cancers, PGE2 is known to allow tumors to avoid the immune system’s protection mechanisms, leading to cancer growth or cancer spreading to other parts of the body.

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The role of PGD2 - on DP1 - is less well understood, but is thought to be similar to PGE2.

Epkin is developing a medicine called OKN4395, which blocks EP2, EP4, and DP1 receptors. This interferes with the prostaglandins’ immunosuppressive effects.

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This could allow a patient’s immune system to better target the cancer cells and help their body fight cancer, to improve their outcomes.

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The biology of EP2, EP4, and DP1

A schematic view of prostaglandin synthesis and their receptors, including EP2, EP4, and DP1.
Mechanism of action

Context

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The role of EP2/4
The role of DP1
EP2/EP4 are implicated in cancer
  • PGE2 signalling through EP2 and EP4 contributes to an immunosuppressive network in cancer by inhibiting effector cells and promoting immunosuppressive cells.
  • This mechanism is hijacked by specific tumors creates an immunosuppressive environment, inhibiting essential steps of anti-tumoral immune responses.
  • EP4 in particular appears more clearly to be a pro-cancer mediator in many different types of malignancies due to its high expression. This is supported by evidence that deletion or inhibition of EP4 can inhibit tumor growth and suppress metastasis in some cancers supporting a role of EP4 in tumor development.
  • The EP4 receptor plays a critical role in immune evasion by mediating the immunosuppressive effects of prostaglandin E2 (PGE2) within the tumor microenvironment (TME).
  • PGE2-EP4 signaling promotes the development of immune-suppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs) while inhibiting immune-stimulated M1 macrophages.
  • This pathway also suppresses natural killer (NK) cell cytotoxicity and cytokine production, as observed in breast and thyroid cancers, and impairs the ability of CD8+ T cells to kill tumor cells by activating immunosuppressive cells in the TME.
  • EP4 inhibition has been shown to restore immune function by increasing MHC molecule expression, enhancing antigen presentation by dendritic cells, and improving NK cell-mediated tumor control.
EP2/4 Biology
The role of PGD2 in tumors is less well understood, but may be similar to PGE2
  • OKN4395 builds upon well-characterized EP2/EP4 inhibition, through a newly identified and equipotent inhibition of DP1. The clinical significance of this first-in-class triple inhibition is being evaluated in the INVOKE clinical trial. 
The INVOKE trial

OKN4395's mechanism of action

Video
The mechanism of action for OKN4395, now in clinical development.
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The INVOKE clinical trial

The INVOKE study (OKN-4395-121) is a global, multicenter, Phase 1a/1b, first-in-human, open-label trial evaluating OKN4395 in patients with advanced solid tumors.
The INVOKE study schemaThe INVOKE study schema
Phase 1a focuses on dose escalation of OKN4395 as both a monotherapy and in combination with pembrolizumab. Phase 1b will expand into a further four cohorts.

References

Jin, K., Qian, C., Lin, J., & Liu, B. (2023). Cyclooxygenase-2–Prostaglandin E2 pathway: A key player in tumor-associated immune cells. Frontiers in Oncology, 13, 1099811.
The INVOKE study (OKN-4395-121; NCT06789172) is sponsored by Epkin (an affiliate of Owkin France).
BOIN = Bayesian Optimal Interval; SOCres = resistant to standard of care; n = number of participants; OBD = optimal biological dose; MTD = maximum tolerated dose; DLT = dose-limiting toxicity; PK = Pharmacokinetics;  1L/2L/3L = first/second/third line; SARC = Sarcoma; aPD1 ref/res = anti-PD1 refractory or resistant; NSCLC = Non-small cell lung cancer; MESO = Mesothelioma; HNSCC= Head & Neck squamous-cell carcinoma; R = randomized; ORR = Overall Response Rate.