Merck’s latest move is in bispecifics

The first day of the JP Morgan healthcare conference might have been slightly quieter than usual, but there were still two sizeable oncology deals: Johnson & Johnson’s $2bn purchase of Ambrx, and Merck & Co’s $680m move for Harpoon Therapeutics. Although the latter acquisition is smaller, it is still a notable one for Merck.

The company has been busy building its pipeline ahead of patent expiries for its checkpoint inhibitor behemoth Keytruda from 2028 – but so far the focus has been largely on antibody-drug conjugates. Indeed, a look at Merck’s pipeline shows a lack of T-cell engagers, the area in which Harpoon is active.

A takeout therefore makes sense for Merck, and the price tag is undemanding – although it is still a massive premium over Harpoon’s closing share price on Friday, when its market cap sat at just $179m.

DLL3 and BCMA

Harpoon’s low valuation has been a puzzle for some time, as the company’s two lead projects, the DLL3-targeting HPN328 and the BCMA-targeting HPN217, have produced respectable data. 

These both use the group’s TriTAC technology, comprising a targeting moiety, a CD3-binding T-cell engaging domain and an anti-albumin domain. According to the company, this design is intended to minimise non-specific T-cell activation, thereby cutting down off-target toxicity. 

In a phase 1/2 study presented at ESMO 2023 HPN328 produced a confirmed response rate of 32% among 19 small-cell lung cancer patients receiving a 1mg priming dose – not too far off the 40% response rate seen with a 10mg dose of Amgen’s rival DLL3-targeting T-cell engager tarlatamab in the Dellphi-301 trial, with the usual caveats about cross-trial comparisons.

It is worth noting, however, that Harpoon lowered the priming dose from 2mg after the death of a patient who experienced cytokine release syndrome. No high-grade CRS was seen with the 1mg priming dose, the company said.

Meanwhile, HPN217 looks competitive, although the BCMA field is crowded. The latest update from a phase 1 study of the project, at ASH 2023, found a 63% response rate in relapsed/refractory multiple myeloma patients receiving 12mg of HPN217, the recommended phase 2 dose. There was also no grade 3 CRS at this dose.

By way of comparison, Johnson & Johnson’s BCMA-targeting bispecific Tecvayli produced an ORR of 62% in the Masjestec-1 study in late-line multiple myeloma.

Still, AbbVie declined an option to acquire rights to HPN217 last year, instead preferring another BCMA project from TeneoOne. While at the time this looked like bad news for Harpoon, it might ultimately have been for the best, leaving the group free to be acquired in its entirety by Merck.

As well as HPN328 and HPN217, Merck will pick up HPN601, an Epcam-targeting project, and preclinical candidates hitting the likes of FLT3 and TROP2. Some of these use Harpoon’s so-called ProTriTAC technology, designed to create T-cell engagers that are inactive until they reach the tumour.

A look at Merck’s existing pipeline by the Mizuho analyst Mara Goldstein flagged six oncology projects to watch as Keytruda’s patent cliff nears. Harpoon’s T-cell engagers will soon be going onto this list.

Keytruda’s successors? Merck’s notable oncology pipeline projects

Source: Mizuho note, 5 Jan 2024.