Four months after Johnson & Johnson spent $3bn to acquire the private US biotech Halda Therapeutics, the target company’s second pipeline asset is entering its first-in-human study. That project, HLD-0117, hits the estrogen receptor, and like Halda’s lead, the androgen receptor-targeting HLD-0915, it uses a novel modality that Halda christened "Riptac".
The phase 1 start has been revealed in the latest new listings on the clinicaltrials.gov registry, which also disclose a new clinical player in pan-mutant PI3Kα inhibition, as well as yet another Steap2-targeting asset from AstraZeneca; Astra’s latest move means that this company is now developing anti-Steap2 projects across five distinct approaches.
Halda’s Riptac (regulated induced proximity targeting chimera) approach involves the simultaneous binding of a tumour-specific antigen – ER in the case of HLD-0117 – and a protein with an essential function for cell survival, with the resulting formation of a complex that disrupts the essential protein and triggers tumour cell death.
Evidently J&J was sufficiently sold on this approach by early human data from HLD-0915’s prostate cancer trial last October to buy Halda for $3.05bn a month later. Now it’s setting out to show that HLD-0117 can repeat the Riptac trick, this time in HER2-negative breast cancer; ER-targeting Riptacs featured in a preclinical presentation at last year’s San Antonio Breast Cancer Symposium.
Steap2
Astra has emerged as a key player in Steap2, a target with a role in prostate cancer, and until now had four relevant assets: the ADC AZD0516, the Car-T therapy AZD0754, the radiopharmaceutical AZD2284, and the T-cell engager AZD6621.
To these it’s now adding another T-cell engager, AZD8359, which started its phase 1 Crius-1 study earlier this month. AZD6621 and AZD8359 are both T-cell engagers, but they have a key difference; the former uses a multispecific format Astra calls the “TED4 design”, using CD8 guiding as well as an affinity-optimised CD3-binding domain to anchor to T cells.
Meanwhile, AZD8359 uses Astra’s “Titan” technology, whereby CD8-guiding is combined with a TCR-targeting domain, and CD3 is avoided, thereby preventing activation of T regulatory cells. An AACR poster this month disclosed that AZD8359 has two Steap2-targeting arms.
Recently disclosed first-in-human studies*
Elsewhere, interest in pan-mutant PI3Kα inhibition has been driven by takeovers of Synnovation by Novartis, and of Scorpion by Lilly. Now Regor is entering the clinic with its shot at this mechanism, RGT-490; Regor is best known as the originator of a portfolio of CDK4 inhibitors that was licensed to Roche for $850m up front.
With Lilly recently prioritising one of its two anti-Nectin-4 ADCs, the entry of yet another player into this space, Samsung Bioepis’s SBE303, is of interest. So is the start of a phase 1 trial of the LSD1 inhibitor REC-4539, which is the result of the takeover by Recursion of Exscientia in November 2024.
And the private US biotech Eilean Therapeutics is advancing two new molecules into the clinic: a CDK2 inhibitor (at least one of the Roche/Regor assets also has activity at CDK2), and a JAK2 V617F inhibitor. In the latter mechanism Incyte is a key player, with an in-house molecule, INCB160058, as well an an option over Prelude’s PRT12396.
