Novartis prunes its pipeline

Novartis disclosed several discontinuations from its phase 1 pipeline during its fourth-quarter earnings, the most high-profile of which were its next-generation actinium-based PSMA-targeting ligand Ac-PSMA-R2, and the Werner helicase inhibitor HRO761.

In total six oncology projects have disappeared from phase 1, as well as an early study of Pluvicto in neuroendocrine prostate cancer. Meanwhile, the group listed two new assets in the clinic: the DNA repair project AMO959, which appears to have been originated by Chengdu Baiyu, and a mystery compound, GCJ904.

Pluvicto is approved for second-line metastatic castration-resistant prostate cancer (mCRPC). However, it looks like it will go no further in the niche of neuroendocrine prostate cancer, where Novartis had been carrying out a phase 1 trial coded CAAA617H12101. 

This use appeared in the group’s third-quarter update, but wasn’t in Wednesday’s fourth-quarter presentation; recruitment into the study was stopped at 28 patients of a planned 36, and its status changed from “recruiting” to “active, not recruiting” in January.

Novartis still sees mileage in targeting PSMA, and to this end is pursuing projects labelled with the alpha emitter actinium-225, which is said to be more potent and precise than the beta-emitter lutetium-177 used in Pluvicto.

Until recently, the company had two actinium-based shots: Ac-PSMA-617, which went into phase 3 last year, and the next-generation Ac-PSMA-R2; the latter was missing from the latest update. Perhaps Novartis didn’t see the need to keep developing two similar projects, but there were signs that not all was well with Ac-PSMA-R2.

Recruitment into the phase 1/2 Satisfaction study in second-line prostate cancer was stopped at 29 patients out of a planned 100. And the phase 1/2 NeoPSMA trial in neoadjuvant prostate cancer had been due to start in June 2026, but was withdrawn in December, with the clinicaltrial.gov entry noting “acceptable safety but limited benefit” with Ac-PSMA-R2 and another project being tested, Lu-PSMA-R2.

Meanwhile, one of the phase 1 newcomers, AMO959, is a DNA-PK inhibitor developed by Baiyu, also coded BY101298. Novartis signed a deal with Baiyu in October 2024 thought to include the project; the Swiss group began a phase 1/2 trial combining AMO959 with Pluvicto in December 2025.

Changes to Novartis’s phase 1 oncology/haematology pipeline in Q4 2025

Source: OncologyPipeline & company Q4 2025 presentation.

The writing was also on the wall for the Werner helicase inhibitor HRO761 following lacklustre data at last year’s ESMO meeting from a phase 1 study that began back in 2023. The omens haven't been good for this target, with Roche earlier dumping the Vividion (Bayer) project RO7589831, and GSK walking away from Ideaya’s IDE275 late last year.

Pit stop

Another Novartis project that had been in phase 1 for years with no data was the CD19 x CD2 trispecific T-cell engager PIT565, which has finally been put out of its misery in cancer, although autoimmune indications continue. A big contender in the CD19-targeting T-cell engager space is AstraZeneca, which took its contender surovatamig into phase 3 last year.

Novartis has also ditched KFA115, a protein degrader with an undisclosed target, and DFV890, an NLRP3 inhibitor that came via the 2019 acquisition of IFM Tre for $310m up front. Other clinical-stage NLRP3 inhibitors include Halia’s ofirnoflast (which also blocks NEK7), while Bristol Myers Squibb terminated a phase 1 study of its contender, BMS-986299.

Novartis also formalised the discontinuation of its NFE2L2/KEAP1/CUL3 inhibitor MGY825 – although news of that project’s demise already emerged last year.