Ash 2021 – Forma takes on a second Agios drug

Now in Servier’s hands, the Agios-discovered Tibsovo could soon face competition from Forma’s olutasidenib.

The sellside generally does not expect other IDH1-targeting acute myelogenous leukaemia drugs to displace Servier’s Tibsovo, but Forma now has not one but two datasets suggesting that its rival olutasidenib might set out to do just that.

Today’s Ash presentation of a Vidaza combo adds to olutasidenib monotherapy data from Asco, and both results are at least as good as the corresponding Tibsovo numbers. “It’s hard to make these kinds of comparisons without doing a head-to-head trial,” cautions Forma’s chief executive, Frank Lee, but he says the data could make olutasidenib a “very, very compelling choice”.

If this happens Forma will have taken on Agios twice, having on Saturday unveiled Ash data backing etavopivat, a sickle cell project rivalling Agios’s mitapivat. Agios had originated Tibsovo, which is now US-approved as monotherapy for front-line and relapsed IDH1-mutant AML, but has since divested the drug to Servier to focus on non-oncology indications.

At Asco this year Forma had presented olutasidenib monotherapy data showing a 46% remission rate in relapsed IDH1-mutant AML. Tibsovo’s label cites a rate of 33% in relapsed patients; though these remission data came from a single-arm study Tibsovo was greenlit under a full approval.

Vidaza combo duel

Now the battleground is moving to combinations with Vidaza, and Servier and Forma presented duelling datasets at Ash today. Servier’s came from the controlled front-line Agile study, which in May had been halted for efficacy.

Here Tibsovo plus Vidaza beat Vidaza alone in terms of remission rate, which came in at 63% versus 19%. More importantly, there was a statistically significant overall survival benefit, with an impressive separation in survival curves translating into a 56% reduction in risk of death across any point in Agile (p=0.0005).

The Agile data are important as they might back an EU filing for Tibsovo. The drug had been knocked back in the EU, where regulators had refused to accept an application based on a single-cohort trial.

For its part Forma hopes that its combo might get additional patients into remission if these can tolerate the hypomethylating agent Vidaza, and that a combo might catch some of the co-mutations that can occur along with IDH1, which is seen in about 5-10% of AML patients.

Its Ash presentation included front-line as well as relapsed/refractory disease, and in the former olutasidenib showed a 64% remission rate, albeit in just 11 evaluable subjects. Perhaps more impressive is the relapsed AML cohort, where the combo put 52% of the patients into remission – including 40% of those who had already failed an IDH1 inhibitor like Tibsovo.

Still, Mr Lee said the dataset that would be used to back an initial olutasidenib filing would be the monotherapy cohort presented at Asco, and said very good progress was being made towards a US filing. However, he also said Forma needed a partner to commercialise.

While cross-trial comparisons are dangerous, the monotherapy data for olutasidenib come from a very similar population to that backing Tibsovo’s approval. “You can draw a clear conclusion that we have a better response rate and a more durable response rate,” Patrick Kelly, Forma’s chief medical officer, tells Evaluate Vantage.

Admittedly, things will be tough in the Vidaza combo setting, as Forma’s dataset is uncontrolled whereas Servier is showing a comparison for the Tibsovo combo versus Vidaza alone in Agile that demonstrates an overall survival advantage to boot.

Hitting IDH mutations: the competitor landscape
Project Target Company Status Monotherapy Vidaza combo
Idhifa (enasidenib)  IDH2 Bristol Myers Squibb (ex Celgene/Agios) US approved for r/r mIDH2 AML; EU filing for AML pulled Dec 2019 ORR 23% in r/r AML; failed to improve OS in r/r mIDH2 AML; ph2 data for mIDH2 MDS at Asco 2021 ORR 74% in 1L AML vs 36% for Vidaza (n=107, p=0.0003)
Tibsovo (ivosidenib)  IDH1 Servier (ex Agios) US approved for 1L & r/r mIDH1 AML, & 2L mIDH1 cholangio; EU filing for AML pulled Oct 2020 ORR 43% in 1L AML; ORR 33% in r/r AML ORR 63% in 1L AML vs 19% for Vidaza (n=146); mOS 24.0mth vs 7.9mth (HR=0.44, p=0.0005)
Vorasidenib IDH1 & 2 Servier (ex Agios) Ph3 in mIDH1/2 glioma Ph1 showed mPFS of 36.8mth in nonenhancing glioma, 3.6mth in enhancing glioma NA
AB-218 (DS-1001) IDH1 Anheart (ex Daiichi Sankyo) Ph2 in 1st-line mIDH1 glioma No clinical data  NA
Olutasidenib (FT-2102) IDH1 Forma Therapeutics Ph1/2 in mIDH1 AML or MDS ORR 46% in r/r AML (n=123) ORR 64% (n=11) in 1L AML; ORR 52% in r/r AML (n=52), incl ORR 40% (n=20) in r/r AML after prior IDH1
LY3410738 IDH1 Lilly (ex Loxo) Ph1 in mIDH1/2 haem & solid tumours First-in-class covalent IDH1 inhibitor; no clinical data NA
HMPL-306 IDH1 & 2 Hutchmed Ph1 in mIDH1/2 haem & solid tumours No clinical data  NA
BAY1436032 IDH1 Bayer Ph1 in mIDH1 solid tumours ORR 15% (termed disappointing, n=27), mOS 6.6mth, in AML NA
IDH305 IDH1 Novartis Likely discontinued ORR 33% (n=7) in r/r AML NA
Source: Ash, Asco, product labels & company information.

Mr Kelly pointed to a separate opportunity for olutasidenib, in IDH1-mutant glioma. Interestingly, a separate Agios-originated, Servier-owned project, vorasidenib, is in phase 3 for glioma, but this targets IDH1 as well as IDH2, a mutation olutasidenib does not hit.

In the IDH1-mutant space at least two competitors, Bayer’s BAY1436032 and Novartis’s IDH305, have fallen by the wayside after showing data that were not competitive against Tibsovo. Perhaps with this in mind Mizuho analysts recently wrote that Tibsovo might be challenged in myelodysplastic syndromes but not in AML.

Do the olutasidenib data show that Forma might actually have an AML drug on its hands? “Absolutely,” states Mr Kelly.

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