Validation for a drug class, and for Sanofi

If imminent results of Sanofi’s amcenestrant in Ameera-3 are positive Serds could finally see late-stage validation.

Company events

Several big pharma companies have made significant investments in selective oestrogen degraders, or Serds, and the most advanced, Sanofi, is about to see whether this has been worth it. Its project, amcenestrant, will yield breast cancer data from the pivotal Ameera-3 trial in the coming weeks.

While the Serds have long held promise, Sanofi’s competitors Roche and Astrazeneca have had several false starts, and the approach still lacks late-stage validation – something amcenestrant could now bring. But amcenestrant is also a huge test for Sanofi management, which has dubbed it a key growth driver.

When Paul Hudson became Sanofi’s chief executive he called amcenestrant one of his company’s top six growth assets. While sellside consensus sees 2026 forecast revenues of $491m, according to Evaluate Pharma, Jefferies reckons peak sales could be much higher, at $3bn.

Project Amcenestrant (SAR439859)
Company Sanofi
Market cap $129bn
Product NPV $2.3bn
% of market cap 2%
Event type Results of registrational ph2 Ameera-3 trial
Indication 3rd-line ER+ Her2- breast cancer
Date Q2 2021

Still, much of this blockbuster figure will depend on oral Serds like amcenestrant breaking into early stages of breast cancer treatment, something that at present is far from assured.

Ameera-3 tests a third-line setting in ER-positive, Her2-negative breast cancer, a field revolutionised by the CDK4/6 inhibitors Ibrance, Kisqali and Verzenio. The space is further complicated by the availability of Novartis’s PI3K alpha inhibitor Piqray, for now in the second-line PIK3CA-mutant setting.

Ameera-3 compares amcenestrant versus physician’s choice, including Faslodex, a first-generation Serd whose use was held back by poor bioavailability and intramuscular delivery.

The primary endpoint is progression-free survival, with overall survival the key secondary metric. All patients in western cohorts should have progressed on CDK4/6 inhibition, and some – most, according to Jefferies analysts – will have got this first line.

However, some might not get this until second line, while others could get CDK4/6 plus aromatase inhibition front line, and then progress to another CDK4/6 inhibitor. These factors make handicapping survival in the control cohort difficult, and baseline characteristics could affect the result.

Jefferies also throws into the mix the wild card of ESR1 mutation, which is a key resistance mechanism to endocrine therapy, but whose presence apparently did not make a difference to amcenestrant’s clinical benefit in the phase 1 Ameera-1 trial in heavily pretreated patients.

Positive Ameera-3 data would allow Sanofi to file immediately for third-line use. The lucrative front-line setting is being tested in the 1,066-subject Ameera-5 trial, in combination with Ibrance, but this is not set to be completed until 2024.

Serds in late-stage development for ER+ve/Her2-ve breast cancer
Project Amcenestrant Elacestrant Giredestrant* Camizestrant
Company Sanofi Radius Health/Menarini Roche Astrazeneca
Late-line study/ design/ readout Ameera-3 Emerald Acelera Serena-2
3L, vs physician's choice 2L, postmenopausal, vs SoC 2L, vs physician's choice 2L, postmenopausal, vs Faslodex
Data Q2 2021 (PFS primary) Data H2 2021 (PFS in ESR1-mut & PFS in all-comers co-primaries) Ends 2022 (PFS primary) Ends 2022 (PFS primary)
1st-line study/ design/ readout Ameera-5 (none) Persevra Serena-4
+Ibrance, vs Femara+Ibrance +Ibrance, vs Femara+Ibrance +Ibrance, vs Arimidex+Ibrance
Ends 2024 (PFS primary) Ends 2024 (PFS primary) Ends 2025 (PFS primary)
*Also in the neoadjuvant Coopera study, ending Sep 2021. Source: clinicaltrials.gov.

It is fair to expect competitors to be paying close attention to Ameera-3, especially as as earlier efforts have foundered. Roche had paid $725m for the Serd specialist Seragon, all of whose assets it has since discontinued.

Astrazeneca had two Serds in development, but canned one this year (Astra places its bet in oestrogen receptor degradation, February 11, 2021). Its focus is now on camizestrant, while Roche has an in-house Serd, giredestrant; both are in phase 3 front-line studies, and have trials in later settings due to end next year.

The final competitor is the biotech company Radius Health, whose Serd elacestrant is not being studied first line. However, its second-line Emerald study is on track to yield topline data in the second half, and importantly will look specifically at PFS in ESR1 mutants.

Expect success in Ameera-3 to stimulate interest in Radius and elacestrant.

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