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A new dawn for tovorafenib

The FDA's tough stance notwithstanding, Ojemda gets an accelerated green light.

Some old drugs never die – they just get spun into new biotechs and recycled, and might even end up on the market. Witness yesterday’s US approval for Day One’s RAF kinase inhibitor tovorafenib, a drug that’s been around the block and then some.

Work on tovorafenib dates back at least 20 years to a discovery collaboration between Biogen and Sunesis, a now defunct biotech, and it was only Day One’s decision to focus on BRAF-altered low-grade glioma that brought success. The accelerated approval also offers a headscratcher of sorts for Regeneron, which recently suffered as the FDA toughened its stance on accelerated green lights.

Of course the indications are completely different. Tovorafenib, now branded Ojemda, has been greenlit for a common childhood brain cancer, whereas Regeneron was seeking the go-ahead for odronextamab, a worryingly toxic CD20-targeting T-cell engager in a lymphoma setting already well served by similar molecules as well as other drugs.

Confirmatory requirements

But the fact remains that the FDA “strongly recommends” that a confirmatory phase 3 study be “well under way if not fully enrolled at the time of accelerated approval”. This tripped up Regeneron’s odronextamab, whose phase 3 trial is enrolling, but which is still in dose finding.

How far advanced is Day One? Ojemda’s confirmatory phase 3, Firefly-2, only dosed its first patient in March 2023. The target enrolment is 400, and as of today the study is still recruiting, according to Data aren’t expected until late 2025 or early 2026, which seems late given that the primary endpoint is response rate rather than survival.

That said, the approval, a week before the FDA’s PDUFA date, is good news in a field that’s seen much disappointment. Setbacks in brain tumour trials include Kintara’s VAL-083, AstraZeneca’s cediranib, Lilly’s enzastaurin, Celldex’s rindopepimut and Merck KGaA's cilengitide.

The specific setting for Ojemda is second-line BRAF-positive low-grade glioma, based on response rates in the uncontrolled Firefly-1 trial. B Riley’s Yuan Zhu wrote yesterday that the success could embolden Tango Therapeutics, whose PRMT5 inhibitor TNG908 is being studied in glioblastoma, and Chimerix, which is testing the DRD2 antagonist ONC201 in H3K27-mutant diffuse midline glioma.

Memory lane

One intriguing aspect for long-time biotech watchers is just how long tovorafenib had been kicking around various pipelines before its development was taken up by Day One.

Work on the molecule dates back at least to 2004, when Sunesis and Biogen signed a collaboration to discover kinase inhibitors. Tovorafnib later passed through Takeda’s hands – the Japanese group’s mistake was to test it in melanoma, a well-served setting where it didn’t focus on specific BRAF mutations – and survived Sunesis’s winding up and reverse merger with Viracta.

Remaining questions remain how big a royalty, if any, Day One will owe Biogen, Takeda, Viracta and/or the former holders of Sunesis, and the length of Ojemda’s composition-of-matter patent life, given the molecule’s lengthy development. With the unmet need here, and tovorafenib’s orphan drug designation, that last point might not be too relevant, however.


A brief history of tovorafenib

Aug 2004Sunesis and Biogen Idec sign collaboration to discover and develop kinase inhibitors
Jun 2008Research term of the original deal ends
Jul 2009Biogen selects a lead RAF kinase inhibitor, triggering milestone payment to Sunesis
Nov 2010Biogen discontinues oncology development, with the RAF kinase work reverting to Sunesis
Apr 2011Sunesis licenses tovorafenib (then known as MLN2480/TAK-580) to Takeda
2011-18Takeda carries out several unsuccessful tovorafenib trials in melanoma
May 2020Day One acquires Takeda’s rights to tovorafenib, and renegotiates terms of the Sunesis/Takeda licensing deal
Jul 2020Sunesis cuts costs, and later winds down operations
Feb 2021Sunesis is reverse merged with Viracta Therapeutics
Jun 2022Day One announces first positive results from Firefly-1 study
Mar 2023Day One doses first patient in confirmatory Firefly-2 phase 3 trial
Oct 2023FDA accepts tovorafenib filing, with priority review and a 30 Apr 2024 PDUFA date
Apr 2024Tovorafenib gets accelerated approval for 2nd-line BRAF-altered low-grade glioma

Source: company statements.


Molecular Drug Targets