SABCS 2024 – Lilly's PI3Kα push is no longer mutation-specific
Lilly sheds more light on its second PI3Kα take, as Relay's combo data improve.
Lilly sheds more light on its second PI3Kα take, as Relay's combo data improve.
It didn't take long for Lilly to renew its push into PI3Kα inhibition, after the recent discontinuation of the initial lead molecule LOXO-783. A poster at San Antonio Breast Cancer Symposium has revealed a slightly different mechanism of action for the group's second attempt at this target, LY4045004, which is expected to enter clinical trials next year.
LY4045004 has been revealed to be a "pan-mutant-selective" inhibitor, meaning that it is wild-type sparing, but – like competitors from Relay and Scorpion, but unlike LOXO-783 – it's not specific for a single PI3Kα mutation. That Lilly should have taken a step back like this is strange, as is the fact that LY4045004 has actually sat quietly in its pipeline for four years.
The molecule was originated by a private entity called Petra Pharma, which Lilly acquired in May 2020. The acquisition price wasn't disclosed, but Lilly had been required to make future payments – a liability Lilly extinguished in 2022, paying the sellers of Petra a one-off $334m, according to an SEC filing.
However, after buying out this liability Lilly proceeded with the development of LOXO-783, a molecule specific for the H1047R mutation in PI3Kα, while LY4045004 languished as a preclinical asset. LOXO-783 entered the phase 1 Pikasso-01 study in May 2022, but was discontinued this year, with Lilly saying it would focus on a next-generation asset – now revealed to be LY4045004.
3% response rate
A separate SABCS poster this week concerned LOXO-783, and showed why Lilly decided to scrap the molecule: among 32 patients with PIK3CA H1047R-mutant advanced breast cancer LOXO-783 monotherapy gave a response rate of just 3%, while in 79 subjects given LOXO-783 with endocrine therapy ORR was 6%.
ORRs were slightly better in combination with endocrine therapy and Verzenio (17%) and Taxol (24%), but the poster concluded that high rates of diarrhoea limited the ability to achieve the optimal, preclinically identified LOXO-783 dose.
Meanwhile, the SABCS poster on LY4045004 said this molecule had preclinically been shown to inhibit kinase and helical PI3Kα mutations, while sparing wild-type PI3Kα and not inhibiting other PI3K isoforms. In particular tumour regression was seen in PI3Kα H1047R and E545K-mutant breast cancer models.
As such LY4045004 employs a similar mechanism to Relay's RLY-2608 and Scorpion's STX-478, which both spare wild-type PI3Kα without being specific for a particular mutation. Both molecules impressed clinically in PIK3CA-mutated breast cancer earlier this year, Scorpion's as monotherapy and Relay's in combination with Faslodex.
Relay presented an update at SABCS, now reporting a 39% confirmed ORR among 31 patients, up from the 30% in 30 patients it press released in September. For its part Scorpion had a SABCS poster repeating the dataset it presented at its ESMO late-breaker.
Too specific?
The idea behind developing ever more specific PI3K inhibitors is to avoid toxicity. Two PI3Kα inhibitors are now approved, Novartis's Piqray and Roche's Itovebi, though both hit wild-type as well as mutant forms of the protein and come with warnings on their US labels.
Lilly's discontinuation of LOXO-783, and the successes of Relay and Scorpion, suggests that there might be a limit to this specificity. Where this now leaves companies like OnKure and Cogent, which are continuing to plough the mutant-specific furrow, is an open question.
The PI3Kα inhibitor evolution
Project | Company | Note | Status |
---|---|---|---|
PI3Kα selective (mutant & wild-type) | |||
Piqray | Novartis | Warnings over hypersensitivity, skin reactions, hyperglycaemia, pneumonitis, diarrhoea & embryo-fetal toxicity | US approved in 2019 |
Itovebi | Roche | Warnings over hyperglycaemia, stomatitis, diarrhoea & embryo-fetal toxicity | US approved in 2024 |
PI3Kα mutant-selective (wild-type sparing) | |||
RLY-2608 | Relay | 39% ORR (n=31) in Faslodex combo | Ph1 |
STX-478 | Scorpion | 23% ORR (n=22) as monotherapy | Ph1 |
LY4045004 | Lilly (ex Petra) | Said to be active in H1047R and E545K-mutant models | Preclinical (ph1 due 2025) |
RLY-5836 | Relay | Said to be active in H1047R and E545K-mutant models | Discontinued in ph1 |
PI3Kα mutant-specific | |||
OKI-219 | OnKure | Specific for H1047R | Ph1 Pikture-01 study |
CGT6297 | Cogent | Specific for H1047R | Preclinical |
LOXO-783 | Lilly | Specific for H1047R | Discontinued in ph1 Pikasso-01 trial (3% ORR as monotherapy, diarrhoea limiting) |
CGT4824 | Cogent | Specific for H1047R | Discontinued in preclinical |
Source: OncologyPipeline.
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