Marrying precision drug repurposing and systems medicine

The H2020 EU project REPOTRIAL is approaching its final year. This is a good time to share what we have already achieved –although the most significant news are expected only during the first half of 2023, when the phase II clinical studies are finalized, or near completion.

Our European consortium is exploring new ways to treat two conditions with a high unmet medical need – acute ischemic stroke and heart failure with preserved ejection fraction (HFpEF). We do not aim to develop new compounds along the classical one drug – one target approach, nor do we believe that diseases should continue to be defined by symptoms and organs. Rather, we have applied the principles of organ-agnostic systems medicine to identify underlying disease mechanisms caused by a dysregulated signaling network.

Cutting-edge bioinformatics were employed to define the disease mechanisms that are dysregulated in stroke or HFpEF, and to identify promising drug repurposing candidates that could rectify these pathological conditions. Soluble guanylate cyclase (sGC) is pivotal in both target therapy areas, but no single drug can restore a complicated pathway with multiple molecular targets; and so we resorted to triple combinations. From this work a new tool was developed – the NeDRex platform, recently published in Nature Communications.

Only the absolute minimum of animal experiments was performed to achieve the required preliminary proof-of-principle to start clinical trials with known compounds in their new uses. By May 2022 one triple repurposed drug combination that is centered around a sGC stimulator/activator has been successfully safety-tested in healthy volunteers for each of the two therapeutic applications, and regulatory approval is pending for the trial investigating the stroke combination in patients. You can read more about the underlying science in our 2019 PNAS paper (“From single drug targets to synergistic network pharmacology in ischemic stroke”).

International patent applications have been filed, and most are published by now. WO-2021172982 covers treatment of acute ischemic stroke with combinations comprising two or three of at least one NADPH oxidase (NOX) inhibitor, at least one nitric oxide synthase (NOS) inhibitor and at least one soluble guanylate cyclase agonist. WO-2021239623 and WO-2021239627, two sister applications claiming new methods for diagnosing and treating essential arterial hypertension that often causes heart failure), also are products of REPO-TRIAL science – exceptional science, showing that a subset of these patients that hardly respond to conventional antihypertensive drug regimens overexpress NADPH oxidase type 5 (NOX5), and can be treated with combinations of repurposed drugs. A priority filing for HFpEF drug combinations has also been made.

But there are more fundamental matters as well: REPO-trial science has resolved the long-standing confusion surrounding sGC “stimulators” and “activators” – which the literature has always treated as mechanistically different agent classes that either stimulate sGC which has compromised activity but is basically intact or re-activate the apoenzyme that had no activity left because it has lost its heme cofactor. In WO/2021/167458 our team has shown that sGC stimulators can restore activity of apo-sGC just fine; in effect, there is no distinction between the stimulator and activator “classes”. A separate publication on this is in preparation and data are to be communicated at the June Conference

All four patents – including the one for HFpEF that has not yet been published — have already been sublicensed to a pharmaceutical company, a success that few H2020 projects have achieved.

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This article was first posted on LinkedIn on May 25, 2022 under