Asco preview – A second wind for antibody-drug conjugates
Antibody-drug conjugates are enjoying something of a resurgence, notwithstanding the fact that Seattle Genetics’ Adcetris and Roche’s Kadcyla are still this technology’s only notable successes.
Several presentations at next month’s Asco conference could show how much further this approach could go. Already one company, Immunomedics, has enjoyed an Asco-assisted share price run-up, after shaking Seattle off as a suitor a year ago, while several others including Takeda and Daiichi Sankyo are attempting to ride on Kadcyla’s coattails (see table below).
However, developing an efficacious antibody-drug conjugate (ADC) is not easy, and the technology relies on several elements coming together: an appropriate linker must release a payload after targeting a relevant protein. Just last month ADC Therapeutics ditched ADCT-502, an asset that like Kadcyla targeted Her2.
No doubt Takeda and Daiichi are paying attention. Asco updates are expected from clinical trials of their respective anti-Her2 assets trastuzumab deruxtecan and XMT-1522, licensed from Mersana Therapeutics, while Remegen, a virtually unknown Chinese group, will present several posters on another Her2-targeting ADC, RC48-ADC.
The biggest spotlight might fall on Immunomedics’ sacituzumab govitecan, due to feature in the Asco presentation of data from HR-positive/Her2-negative breast cancer patients in a phase I/II basket study.
This company is notorious for having fended off the advances of Seattle Genetics almost exactly a year ago. The senior party had signed a deal over sacituzumab worth $250m up front, but this was scrapped with the help of a group of activist investors (Venbio completes its Immunomedics rout, May 5, 2017).
The deal’s termination lumbered Immunomedics with the cost of developing sacituzumab, and the project’s timeline has slipped – filing had been pushed back from late 2017 to early 2018, and was only submitted yesterday. Nevertheless, the market has reacted well, with Immunomedics stock almost tripling since May 2017; the shares rose 8% on the Asco abstract release last week.
Seattle had intended the Immunomedics deal to serve as part of a plan to diversify beyond Adcetris. That plan suffered another blow last year when the anti-CD33 ADC vadastuximab talirine was discontinued, and now rests on assets like enfortumab vedotin, which will feature at Asco in the setting of a urothelial cancer trial.
A January data cut 122 of 155 heavily pretreated subjects received the recommended phase II dose, yielding a 33% confirmed remission rate.
Don’t mention Rova-T
Attention will also fall on results of a study in several cancers of Pfizer/Abbvie’s cofetuzumab pelidotin, especially as this asset was originated by Stemcentrx, a group bought by Abbvie for $5.8bn.
Abbvie’s business development team was left with egg on its face when Stemcentrx’s lead ADC asset, Rova-T, crashed and burned in a small cell lung cancer trial in March. Cofetuzumab represents one chance for Abbvie to show that it had not thrown $5.8bn down the toilet, and Asco promises an update on remissions and survival beyond the October 2017 data cut cited in the abstract.
Also of interest will be the next big regulatory test of the ADC approach – Astrazeneca’s moxetumomab pasudotox, which has been filed for hairy cell leukaemia. Moxetumomab has a likely PDUFA date of October 3, and the Asco data will include an analysis of its pivotal ’1053 trial.
The recent ADC field might have more failures than successes to its name, but companies and investors have not given up yet.
|Selected Asco 2018 presentations on antibody-drug conjugates|
|Project||Company||Target||Payload||Detail||Trial ID||Asco abstract|
|Moxetumomab pasudotox||Astrazeneca||CD22||PE38||Pivotal hairly cell leukaemia trial||NCT01829711||7060|
|Sacituzumab govitecan||Immunomedics||Trop-2||SN-38||Basket trial, data from HR+/Her2-ve breast cancer||NCT01631552||1004|
|Mirvetuximab soravtansine||Immunogen||Folate receptor α||DM4||Forward II Avastin combo trial in Pt-resistant ovarian cancer||NCT02606305||5549|
|Enfortumab vedotin||Seattle Genetics||Nectin-3||MMAE||Urothelial cancer||NCT02091999||4504|
|Trastuzumab deruxtecan||Daiichi Sankyo||Her2||Topoisomerase I inhibitor||Various Her2-expressing cancers (to be updated)||NCT02564900||2501|
|U3-1402||Daiichi Sankyo||Her3||Topoisomerase I inhibitor||Her3-expressing breast cancer||NCT02980341||2512|
|Cofetuzumab pelidotin||Pfizer/Abbvie||PTK7||Auristatin||ORR & PFS, various cancers (Oct 2017 cut)||NCT02222922||5565|
|XMT-1522||Mersana Therapeutics/Takeda||Her2||AF-HPA||Various Her2-expressing cancers||NCT02952729||2546|
|RC48-ADC||Remegen||Her2||MMAE||Her2+ve breast cancer||NCT02881138||1030|
|Tisotumab vedotin||Seattle Genetics||Tissue factor||MMAE||2nd-line cervical cancer||NCT02001623||TPS5601|
|MEN1309/OBT076||Menarini/Oxford Biotherapeutics||CD205/Ly75||DM4||Dose escalation in CD205+ve patients||NCT03403725||TPS2606|
This story was corrected to reflect the filing of sacituzumab govitecan.