The first real challenge to multiple myeloma CAR-T therapy

Amgen’s AMG 420 yielded early but spectacular remissions, leaving Boehringer Ingelheim with egg on its face.

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Surprise disclosure of the results from five multiple myeloma subjects given Amgen’s anti-BCMA bispecific AMG 420 on Sunday emerged as the first real threat to Bluebird Bio’s similarly acting CAR-T therapies bb2121 and bb21217.

Until now only CAR-T was thought capable of delivering these kinds of remissions, and bb2121 at present offers the most impressive example. Perhaps this explains why Boehringer Ingelheim gave up rights to AMG 420 just two years ago, despite trumpeting a push into oncology (Behold the son of Blincyto, September 2, 2016).

Numerous approaches have been taken to hitting the BCMA antigen, but the analogy in childhood leukaemia of targeting CD19 using Amgen’s Blincyto or Novartis’s Kymriah suggested that a bispecific’s efficacy could never match that of adoptive cell therapy.

This is why the AMG 420 data are spectacular: all five subjects treated at the highest dose reported complete responses, with four going minimum residual disease-negative and four still being in remission at up to 10 months, the Myeloma 2018 conference in San Diego heard.

The patients had had four to six prior lines of therapy, and four had had two or three stem cell transplants. Bluebird’s most recent bb2121 data cut, also in a heavily pretreated cohort, showed an 81-100% objective response rate, depending on the number of CAR-T cells infused.

BCMA-targeting approaches in clinical trials
Project Approach Company Trial ID
Phase III
bb2121 CAR-T Celgene/Bluebird NCT03651128
Phase II
GSK2857916 ADC Glaxosmithkline/Seattle Genetics NCT03525678
JCARH125 CAR-T Celgene (ex Juno) NCT03430011
Phase I
AMG 224 ADC Amgen NCT02561962
MEDI2228 ADC Astrazeneca NCT03489525
SEA-BCMA ADC Seattle Genetics NCT03582033
CC-93269 Bispecific MAb Celgene NCT03486067
AMG 701 Bispecific MAb Amgen NCT03287908
JNJ-7957 Bispecific MAb Johnson & Johnson/Genmab NCT03145181
PF-06863135 Bispecific MAb Pfizer NCT03269136
AMG 420 Bispecific MAb Amgen (ex Micromet/Boehringer) NCT02514239
bb21217 CAR-T Celgene/Bluebird NCT03274219
KITE-585 CAR-T Gilead (ex Kite) NCT03318861
CAR-BCMA-T cell CAR-T Carsgen Therapeutics NCT03380039
MTV273 CAR-T Novartis NCT02546167
AUTO2 CAR-T Autolus NCT03287804
JNJ-68284528 CAR-T Johnson & Johnson/Nanjing Legend NCT03548207
P-BCMA-101 CAR-T Poseida Therapeutics NCT03288493
Source: EvaluatePharma & clinicaltrials.gov.

AMG 420’s history is intriguing; like Blincyto the asset had been originated by Micromet, the biotech group acquired by Amgen for $1.6bn in 2012.

Boehringer had been Micromet’s partner on AMG 420, or BI 836909, as it was then called, but sold its remaining interest to Amgen for an undisclosed amount. With hindsight this seems strange, and presumably reflects a lukewarm attitude at the German group to either the BCMA antigen or bispecifics in general.

Boehringer told Vantage that its focus was on "treatments with breakthrough potential in lung and gastrointestinal cancers. This is why we are very satisfied that Amgen is further advancing [AMG 420]".

Though bispecifics have yet to shake up the markets, the threat they pose to cell therapy is real: owing to convenience, and presumably a lower cost, a bispecific would naturally be given before CAR-T, and a patient reporting an antigen-negative relapse on the former would logically no longer be a candidate for the latter, if the same antigen is targeted.

Further data from the AMG 420 trial are now one of the hottest tickets of December’s Ash meeting.

This article has been updated to add commentary from Boehringer.

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