Bolt’s setback didn’t come out of the blue

Bolt Biotherapeutics yesterday discovered that combining an anti-HER2 MAb with a toll-like receptor (TLR) agonist doesn’t work – less than two years after Silverback Therapeutics found out precisely the same thing. Bolt has pulled the plug on its lead asset, trastuzumab imbotolimod, cleaned out its C-suite, replacing its chief executive officer, and slashed 50% of its staff.

The setback is analogous to the story of Silverback’s similarly acting SBT6050, but for its part Silverback moved quickly to cease operations and be reverse merged with another biotech with a different focus. Bolt, on the other hand, is pressing on with follow-on projects, including another that, like trastuzumab imbotolimod, uses TLR stimulation.

Time will tell whether this is a smart move, but for now the markets have spoken. Today Bolt stock opened down 27%, meaning that the company’s valuation has slumped below $40m; first-quarter cash, reported yesterday, stands at $113m, which after the cost cutting Bolt expects to last into the second half of 2026.

HER2 no-go

The idea behind Bolt’s immune stimulating antibody conjugates (ISACs), of which trastuzumab imbotolimod was the lead example, was that an antigen-targeting MAb could be linked to a TLR7/8 agonist, resulting in tumour-specific activity plus immune system activation.

The company yesterday claimed to have shown that ISACs can be safely delivered and have solid tumour activity, but said the near-30% ORR trastuzumab imbotolimod had shown in phase 1 wasn’t replicated in early phase 2 data. One new complete response was seen in dose escalation at last year’s ESMO, but overall the data disappointed, and Bolt was one of the meeting’s losers.

Bolt now admits that trastuzumab imbotolimod came up short of predefined success criteria, which had presumably been set high as a result of Daiichi Sankyo/AstraZeneca’s anti-HER2 juggernaut Enhertu. Bolt earlier discontinued the CEACAM5-targeting ISAC BDC-2034 after deaths in non-human primate studies, blaming these on binding to other CEACAM family members.

Bolt’s focus now turns to BDC-3042, a Dectin-2 agonist MAb seeking to “repolarise” macrophages that started phase 1 last year, and BDC-4182, which targets Claudin18.2. While the former is a naked MAb, the latter is, like trastuzumab imbotolimod, an ISAC that uses a TLR7/8 agonist, albeit a different one; apart from the fact that pressing on with ISACs might be questioned, Claudin18.2 is a hugely competitive target.

Silverback 2.0?

The canary in the coalmine for such ISACs came courtesy of Silverback Therapeutics, which pulled off a $278m IPO in December 2020 on the strength of three ISAC projects that used TLR8 agonism; not only that, but the lead, SBT6050, targeted HER2.

Just a year later SBT6050 disappointed at ESMO, and shortly afterwards it and the Nectin-4-targeting/TLR8 agonist ISAC SBT6290 were discontinued. In mid-2022 Silverback served as a listed shell into which ARS Pharmaceuticals was merged, meaning that Silverback had taken just 595 days to go from Nasdaq flotation to an effective bust.

The disappointments of TLR-based approaches to some extent mirror other immune system-activating strategies, including 4-1BB co-stimulation. The latter has been pursued extensively despite delivering little positive data, and Inhibrx and Numab Therapeutics have both discontinued projects this year; nevertheless, Nanjing Leads Biolabs is among those pressing on.

And OncologyPipeline identifies several groups pressing on with TLR agonist-based ISACs specifically, namely the private US biotech Tallac Therapeutics, China’s GeneQuantum Healthcare and (preclinically) Sanofi, Eikon and Innovent.

Selected immune stimulating antibody conjugates (ISACs)

Note: *discontinued by Silverback Therapeutics, which was reverse merged with ARS. Source: OncologyPipeline.