Triple meeting 2023 – PRMT5 has a wobble

First human data with Amgen’s PRMT5 inhibitor AMG 193 appear to have underwhelmed. The results, presented on Friday at the Triple (EORTC-NCI-AACR) meeting, caused a wobble in the share price of another key second-generation PRMT5 player, Tango Therapeutics, although the stock later recovered.

Expectations had been high given the early promise shown by the industry’s most advanced second-generation anti-PRMT5 agent, Mirati’s MRTX1719, and that company’s subsequent takeover by Bristol Myers Squibb. Still, it’s important to note that the Bristol deal was predicated mostly on Mirati’s KRAS drug Krazati, so perhaps expectations over PRMT5 blockade simply got a bit overblown.

This certainly seems the case for Amgen’s AMG 193, one of nine PRMT5 inhibitors in active clinical development, according to a recent analysis of OncologyPipeline. The mechanism had got a boost after Mirati’s MRTX1719 data were published in Cancer Discovery in August, especially as the mechanism is an example of synthetic lethality – a hot theme at present.

A mixed dataset

The Amgen trial of AMG 193 has so far enrolled 48 safety-evaluable patients, mostly with NSCLC and pancreatic adenocarcinoma, bearing p53, KRAS and/or EGFR mutations, but also in various other tumour types, the Triple meeting heard on Friday.

35 of the patients were efficacy evaluable at the 1 September data cutoff presented, and Amgen zeroed in on 18 subjects given AMG 193 doses of 800mg or higher. Among these it reported five partial remissions, in patients with oesophageal, pancreatic, renal cell, gallbladder and Sertoli-Leydig cell cancers.

Evercore ISI analysts called the 28% ORR at such high doses “quite good”, with a decent response duration; patients had failed a median three lines of prior therapy. It was also noteworthy that Amgen claimed to have found a blood-based biomarker that correlated with responses.

Analysts at Jones Research, however, called the AMG 193 data “underwhelming”, and investors in Tango clearly thought the response rate – just 14% if all doses are considered – was poor. Safety was also somewhat concerning, with Amgen reporting a 21% rate of serious treatment-related adverse events, all of which led to dose reduction and/or interruption, and 6% rate of resulting treatment discontinuation.

The company said the 1.6g dose was “intolerable” owing to nausea and fatigue, while evaluation of 1.2g is ongoing. First-generation PRMT5 inhibitors had struggled with lack of a therapeutic window, and at least it was positive that AMG 193 wasn’t causing myelosuppression.

Second-gen PRMT5 inhibitors: a cross-trial comparison

Source: Cancer Discovery for MRTX1719 (27 Jun cutoff), Triple meeting for AMG 193 (1 Sep cutoff).

Perhaps Amgen also wasn’t helped by a cross-trial comparison versus MRTX1719, which according to the August publication had put six of 18 patients into remissions, across a range of doses. MRTX1719 was also highlighted as resulting in none of the dose-limiting toxicities associated with first-generation PRMT5 inhibitors.

Either way, MRTX1719 will soon be Bristol's property, and much of its value is captured as a contingent value right payable to Mirati shareholders at some future point.

And perhaps the most important message for Tango is that not all PRMT5 inhibitors are equal, even if they boast a second-generation profile. Tango’s own test will come soon enough: the company is developing two PRMT5-targeting projects, TNG908 and TNG462, and both could yield their first efficacy data in humans over the next 12 months.