Nerviano becomes a targeted PARP player

As soon as Merck KGaA licensed rights to Jiangsu Hengrui's PARP1 inhibitor HRS-1167 the writing was on the wall for Merck's similarly acting second asset, NMS-293. And this week the German group handed NMS-293 back to its originator, Nerviano Medical.

This came in spite of Merck's protestations a year ago that both tie-ups remained in play, which suggested that the company wanted to take two shots at PARP1 inhibition – a synthetic lethality mechanism that has also seen buy-in from AstraZeneca and Gilead. Nerviano aims to begin fresh trials of NMS-293, which along with the PARP7 inhibitor atamparib now forms a key part of its small-molecule pipeline.

However, Nerviano's ownership of atamparib too is a result of bigger companies' lack of faith. That molecule had been originated by Ribon Therapeutics, a private US biotech backed by Pfizer, among others; but in May Ribon ceased operations, and its assets were put up for sale to pay back creditors. Nerviano announced two weeks ago that it had acquired atamparib.

PARP1

As for NMS-293 (also known as NMS-03305293), that had been licensed to Merck in 2022, at a time of growing interest in PARP1 inhibition that later saw Gilead buy Xinthera, a company with three such molecules at the preclinical stage.

Nerviano claims that NMS-293's non-trapping nature sets it apart from other PARP1 inhibitors, adding that it will now seek to expand clinical work beyond glioblastoma. The company also has other clinical-stage small molecules, as well as an early presence in ADCs.

In glioblastoma, in October 2023 NMS-293 scored a late-breaking poster at the Triple (EORTC-NCI-AACR) symposium, but at the same time Merck paid €160m up front for a second PARP1 inhibitor, Jiangsu Hengrui's HRS-1167, now coded M9466. This second project yielded clinical data at this year's ASCO, showing a 42% ORR among 24 patients with various HRR-mutated tumours, including one response among six PARP inhibitor-preteated subjects.

Though the ASCO data comprised no glioblastoma patients, the contrast with NMS-293's Triple poster was clear. Among 21 glioblastoma patients NMS-293 yielded just two partial responses by RANO criteria, and one of these failed to be confirmed – not great for a molecule said to be brain penetrant. It's likely that Merck simply wanted to stick with the most obviously active project.

In an analogous situation, Astra is still working on two separate PARP1 inhibitors, the brain-penetrant AZD9574 (in phase 1/2) and the non-CNS penetrant saruparib (phase 3). Nerviano wouldn't comment on Merck's decision, and didn't reveal to ApexOnco what it has had to pay to regain NMS-293 rights and any Merck-generated data. 

The idea is that PARP1 plays a key role in DNA repair, but that unwanted activity also at PARP2 adds toxicity and limits efficacy, though clinical backing for this remains limited.

Ribon wind-up

Meanwhile, work on inhibiting PARP7, said to be overexpressed in several cancers, is even less advanced. Ribon had taken atamparib into three early clinical studies, but first data with the project, presented at ASCO 2021, showed just one partial response, in a breast cancer patient, among 33 evaluable subjects.

Ribon closed a $65m series B round in 2019, and last year secured a $25m investment from Pfizer to support development of atamparib and a PARP14 inhibitor, RBN-3143. However, by 2024 it was out of money, and a winding-up asset sale aimed at recovering $9m of secured loan obligations took place in May.

Nerviano hasn't disclosed how much it paid for atamparib, but says it plans to take the molecule into phase 2 next next year.

PARP7 inhibitors

Notes: *in 2021 Ribon licensed Asia rights to Ono Pharmaceutical; **also said to inhibit PARP1; ***also said to inhibit PARP14. Source: OncologyPipeline.