Ash 2021 – Bristol reveals its sons of Revlimid

Data in multiple myeloma and non-Hodgkin’s lymphoma make Bristol optimistic about follow-ons to Revlimid and Pomalyst.

US patents on Revlimid, the multiple myeloma blockbuster that was a key reason why Bristol Myers Squibb bought Celgene, will start to expire next year. But Celgene also brought a pipeline of follow-on “celmods”, and Bristol is now betting on these to help it weather the Revlimid cliff.

The Ash conference this weekend highlighted two of these multiple myeloma wannabes, iberdomide and CC-92480, which Bristol describes as acting similarly to Revlimid but with greater potency. And today brought the first look at clinical efficacy data for a third celmod, CC-99282, which while having the same mechanism of action is “optimised” for lymphoma.

The ‘282 data will be of interest because they provide the first evidence of the activity of this project – as monotherapy – in a cohort of non-Hodgkin’s lymphoma subjects who had failed a median three prior therapies.

The Ash presentation showed a 39% remission rate in 36 subjects. Kristen Hege, a Bristol senior vice-president of early clinical development who joined from the Celgene business, told Evaluate Vantage that this was “very encouraging for a single agent in these highly refractory patients, many of whom had failed transplant and Car-T”.

The late-line lymphoma space is becoming competitive, with Car-T establishing itself and various anti-CD20 bispecifics vying for attention. The data could back moving ‘282 into earlier settings and combining it with other agents, though it is too early to talk about a potentially registrational study.

How they act

“Celmods are small molecules that bind to cereblon [a cellular protein] and lead to the degradation of certain substrates. Key substrates for their activity in multiple myeloma and lymphoma are Ikaros and Aiolos,” explains Ms Hege.

Interestingly, imids like Revlimid and Pomalyst work this same way, though it has taken some time since the discovery of these thalidomide analogues to arrive at this pharmacology definition.

“But the next-generation celmods ... are much more potent, and are active in patients who have failed on imids,” says Ms Hege. “They work in the setting of patients with lower cereblon expression levels, and they lead to much deeper and durable degradation of the substrates.”

Data presented at Ash this weekend for iberdomide and ‘480 appear to bear this out. The phase 2 portion of a fourth-line or later multiple myeloma study of the former yielded 33 remissions in 131 subjects, all of whom had failed Revlimid or Pomalyst.

Winship Cancer Institute’s Dr Sagar Lonial described iberdomide as “tumouricidal rather than tumouristatic”, and was especially pleased that only five subjects withdrew owing to adverse events, and none for neutropenia – a common problem with imids. Bristol’s hope is that this side-effect profile will make iberdomide especially apt for combinations in early-line regimens.

Meanwhile, the idea with CC-92480 is that it is very active in Revlimid/Pomalyst-refractory myeloma, so Bristol is gunning for later-line combo regimens. An Ash poster of a trial in 19 third to fifth-line imid-refractory subjects (37% also refractory to an anti-CD38 MAb) showed 74% responding to a CC-92480/Velcade combo, with maximum tolerated dose still not reached.

Oral small-molecule cereblon E3 ligase modulator (celmod) agents
Project/drug Substrate Positioning Note
Bristol Myers Squibb (ex Celgene)*
Revlimid (lenalidomide) Aiolos & Ikaros** Established 1st-line multiple myeloma therapy, also approved for r/r lymphoma US patents start expiring 2022
Pomalyst (pomalidomide) Aiolos & Ikaros Approved for 3rd-line multiple myeloma US patents start expiring 2025
Iberdomide (CC-220) Aiolos & Ikaros To replace Revlimid as foundation for 1st-line multiple myeloma Dex combo in 4th+ line: ORR 26% (n=107) in BCMA-naive, ORR 25% (n=24) in post-BCMA
CC-92480 Aiolos & Ikaros To replace Pomalyst in r/r multiple myeloma Dex + Velcade combo in 3rd-5th line: ORR 74% (n=19)
CC-99282 Aiolos & Ikaros Non-Hodgkin's lymphoma MonoRx 39% ORR (n=36), incl 32% (n=28) in DLBCL & 75% (n=9) in follicular lymphoma
Avadomide (CC-122) Aiolos & Ikaros Earlier celmod for lymphoma Discontinued in favour of CC-99282
CC-91633 (BMS-986397) CK1α^ AML & MDS Ph1 started Dec 2021
CC-90009 GSPT1^^ AML Preclinical
CC-885 GSPT1 AML Discontinued in favour of CC-90009
C4 Therapeutics
CFT7455  Aiolos & Ikaros Multiple myeloma & non-Hodgkin's lymphoma Ph1 started Apr 2021
NX-2127  BTK & Aiolos# B-cell malignancies Ph1 started May 2021
Monte Rosa Therapeutics
MRT-2359 GSPT1  Myc-driven cancers IND submission due mid-2022
*Bristol additionally claims five preclinical-stage "novel celmods" targeting undisclosed substrates; **Aiolos (IKZF3) & Ikaros (IKZF1) are zinc finger protein lymphoid transcription factors essential for myeloma cell survival; ^CK1α is casein kinase 1α; ^^GSPT1 is a translation termination factor; #aim is to degrade wild-type & mutant (including C481S) BTK while retaining imid-like activity. Source: company filings & Ash. 

Bristol also has several other celmods in its pipeline, including two for AML: CC-91633 degrades a different substrate, CK1α, and recently started phase 1; CC-90009 is a GSPT1 degrader still in preclinical study.

“When you engage cereblon with different small molecules it can result in the degradation of different substrates, and those different substrates have activity in different diseases,” says Ms Hege. Determining which should be used in which disease is a result of preclinical interrogation of several molecules and observing their activity in different settings.

Bristol’s bold claim is that iberdomide will one day replace Revlimid in front-line multiple myeloma, while CC-92480 will become the new Pomalyst. Sellside consensus compiled by Evaluate Pharma shows Revlimid and Pomalyst generating 2022 sales of $11.3bn and $3.6bn respectively, but in four years these numbers will fall to just $2.2bn and $723m.

Bristol knows that bold moves are called for, and aims to run a trial demonstrating iberdomide’s head-to-head superiority versus Revlimid in the post-transplant maintenance setting. It has no time to waste.

This story has been updated to add Monte Rosa.

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