Asco 2022 – Abbvie goes back to basics with navitoclax

Abbvie’s decades-old work into Bcl-2 inhibition gave rise to Venclexta, but the group has gone back to studying a Venclexta predecessor compound.

The coming 12 months should see the results of two pivotal trials of Abbvie’s navitoclax in myelofibrosis, events that the group hopes will back approval of this Bcl inhibitor by the end of 2023.

In the meantime, data just discussed at Asco from a single-cohort study have set the expectations, with navitoclax’s efficacy in combination with Novartis/Incyte’s Jakafi, the standard of care, outperforming Jakafi alone on a cross-trial basis. True, navitoclax will not become a blockbuster, but its development path – the project was an early iteration of the drug that became Venclexta – is an interesting study in serendipity.

Navitoclax and Venclexta alike are the result of decades of work into Bcl-2 inhibition, but the former had gone on hiatus while Abbvie and its partner Roche focused efforts on the latter, a blockbuster drug that now forms a major part of the armamentarium in chronic lymphoblastic and acute myelogenous leukaemias.

Going pivotal

It was not until two years ago that pivotal trials of navitoclax got under way. Transform-1 tests the project’s Jakafi combination versus Jakafi alone in front-line myelofibrosis, while Transform-2 pits the combo against best available therapy in relapsed/refractory disease.

Data from the phase 2 Refine study discussed at Asco concern Jak-naive patients, and complement results from the same trial but in relapsed disease, published in the Journal of Clinical Oncology recently.

In the Asco dataset spleen volume reduction of at least 35% at week 24 was achieved by 63% of the 32 evaluable patients given navitoclax plus Jakafi. For comparison Jakafi’s label cites efficacy on the same endpoint of 42% in one study, and 29% in another, so – at least on a cross-trial basis – addition of navitoclax seems beneficial.

There was a toxicity price, however, with high rates of thrombocytopenia (47%), anaemia (34%) and neutropenia (25%) at grade 3 and above, and three deaths – two unrelated to treatment and one unknown.

Promising while this might seem, when the poster was discussed at an oral Asco session today Memorial Sloan Kettering’s Dr Kamal Menghrajani poured some cold water on navitoclax. She said it was unclear whether spleen volume reduction would translate into a survival benefit, and suggested that what myelofibrosis needed was not multiple mechanistic pathways but a more potent Jak2 inhibitor than Jakafi.

Source: Dr Kamal Menghrajani & Asco.

But why navitoclax, and why myelofibrosis? For the answer you need to go back 23 years, when Abbott, as Abbvie was then known, partnered with Idun Pharmaceuticals to develop cancer drugs that work by apoptosis, including Bcl-2 inhibitors. Idun was later bought by Pfizer, which sold it to Conatus, now part of Histogen.

But in 2007 Abbott struck a second deal, with Roche, to develop compounds including the Bcl-2 inhibitor ABT-263 and follow-ons. It is not clear whether any of this work was derived from Idun, and whether Histogen retains an interest, but ABT-263 is the molecule now known as navitoclax.

Still, though navitoclax moved into the clinic in CLL it became associated with thrombocytopenia as a result of binding not only Bcl-2 but also Bcl-XL, a protein platelets rely on for survival. Navitoclax was found to have modest activity, largely because it could not be dosed high enough.

Instead, Roche and Abbvie brought a third party to the table, the Walter and Eliza Hall Institute of Medical Research, and navitoclax was re-engineered to give rise to ABT-199, an improved inhibitor with more specificity for Bcl-2.

Navitoclax went to the back burner. ABT-199 was prioritised, to be approved as Venclexta, first for CLL and then for AML, bringing in sales of $1.8bn last year. 2028 revenue is set to approach $4bn, according to Evaluate Pharma sellside consensus.

But in 2017 Abbvie went back to navitoclax and put it into trials in myelofibrosis, seeking to take advantage of its action on platelets and on Bcl-XL. This is the state of play today.

The competitor pipeline in Bcl-2 inhibition remains quite thin, numbering discontinued assets like Teva’s obatoclax, found to have little clinical activity, and early Abbvie projects like ABT-737, which lacked oral bioavailability. Ascentage Pharma’s lisaftoclax is in phase 2, and big pharma groups with an interest include Novartis and Lilly.

As for navitoclax, that no longer appears in Roche’s pipeline.

Selected inhibitors of Bcl-2
Project Company Mechanism Clinical trial
Venclexta (ABT-199) Roche/ Abbvie Bcl-2 selective CLL14
Viale-A (AML)
Phase 3
Navitoclax (ABT-263/ RG7433) Abbvie/ Roche Also hits Bcl-XL Transform-1 (Jakafi combo vs Jakafi in MF)
Transform-2 (Jakafi combo vs BAT in MF)
Phase 2
Lisaftoclax (APG-2575) Ascentage Pharma/ Innovent Bcl-2 selective NCT05147467 (CLL)
NCT04496349 (T-cell leukaemia)
Phase 1/2
Pelcitoclax (APG-1252) Ascentage Pharma Also hits Bcl-XL NCT05186012 (lymphoma)
NCT04354727 (MF)
AZD0466 Astrazeneca Also hits Bcl-XL NCT04865419 (haem cancers)
ZN-d5 Zentalis Bcl-2 selective NCT05199337 (light-chain amyloidosis)
Phase 1
S65487/ VOB560 Servier/ Novartis Bcl-2 selective NCT04702425 (MIK665 combo in haem cancers)
TQB3909 Sino Biopharmaceutical Bcl-2 selective NCT04975204
LOXO-338/ FCN-338 Lilly (ex Fosun) Bcl-2 selective NCT05024045 (haem cancers)
LP-118 Newave Pharmaceutical Also hits Bcl-XL NCT04771572 (haem cancers incl MF)
CLL=chronic lymphoblastic leukaemia; MF=myelofibrosis. Source: Evaluate Pharma &

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