ImmuneOnco takes a second project pivotal

China’s ImmuneOnco is most famous for getting – then losing – Instil Bio as a partner for its PD-L1 x VEGF fusion protein, but the company is about to take a different asset into phase 3. According to a new listing on clinicaltrials.gov, a Chinese pivotal trial of the group’s CD47 x CD20 fusion protein amulirafusp alfa will start in February.

The study will test amulirafusp alfa plus Revlimid, versus Revlimid alone, in CD20-positive follicular lymphoma patients who have received at least two prior therapies, including an anti-CD20 MAb like Rituxan. Co-primary endpoints are complete response rate and progression-free survival; ImmuneOnco will hope to replicate data from a phase 1/2 trial that found a 68% complete response rate among 34 post-CD20 patients.

However, the earlier trial, presented at last year’s ASH meeting, also raised questions about toxicity – which has been a problem with other CD47-targeting projects such as Gilead’s antibody magrolimab.

In phase 1/2, 94% of patients receiving amulirafusp alfa experienced a grade 3 or 4 treatment-related adverse event, the most common being neutropenia (62% at grade 3-4). And 23% of patients had treatment-related serious adverse events. However, treatment-related discontinuations were fairly low, at 4%, and there were no treatment-related deaths.

ImmuneOnco concluded that amulirafusp alfa was “well tolerated”, noting that most adverse events resolved a week or two after treatment.

Still, the earlier study tested a 1.6mg/kg dose of amulirafusp alfa, while the phase 3 trial is evaluating 2.0mg/kg, raising the possibility that adverse event rates could increase.

Fusion protein

Amulirafusp alfa comprises an anti-CD20 mAb fused with the CD47 binding domain of SIRPα, and appears to be designed to act only when both proteins are present, a design feature likely aimed at improving tolerability.

Like other anti-CD47 projects, it’s said to block the “don’t eat me” signal that allows malignant cells to escape a patient’s immune system. But unlike monospecific CD47-targeting MAbs, ImmuneOnco’s project is also thought to spur the killing of B cells expressing CD20.

It’s notable that, in both its phase 1/2 and its phase 3 trial, ImmuneOnco is targeting patients previously treated with anti-CD20 MAbs – suggesting that it’s relying on patients who relapsed despite still expressing some level of CD20.

In phase 1/2, amulirafusp alfa also produced a complete response rate of 67% among 18 CD20-refractory patients. ImmuneOnco is also evaluating the project in B-cell mediated autoimmune diseases like lupus.

The only other similarly acting project in clinical development, according to OncologyPipeline, is CSPC Pharmaceuticals’ JMT601 (CPO107), in phase 2 in DLBCL in China. However, a US trial was terminated last year for “business reasons”. 

ImmuneOnco also has an anti-CD47 Fc fusion protein, timdarpacept, in phase 3, with data in chronic myelomonocytic leukaemia expected this year.

Meanwhile, the company is persevering with its PD-L1 x VEGF fusion protein palverafusp alfa, despite Instil Bio handing back rights earlier this year. A pivotal trial of that project, in IO-resistant NSCLC, is due to start in the second quarter, according to ImmuneOnco’s JP Morgan presentation. 

Notable trials of amulirafusp alfa in CD20-positive follicular lymphoma

Notes: both are Chinese trials; CRR=complete response rate; DLT=dose-limiting toxicities; MTD=maximum tolerated dose; ORR=overall response rate; PFS=progression-free survival. Source: OncologyPipeline & clinicaltrials.gov.