Macrogenics’ bispecific antibody duvortuxizumab is an early casualty of increasing competition in the B-cell cancer space. Johnson & Johnson handed back rights to the project in the same week that Novartis’s CAR-T therapy Kymriah was approved in acute lymphoblastic leukaemia, adding to a field that includes Amgen’s Blincyto and Pfizer’s Besponsa.
Macrogenics also blamed toxicity as a factor in J&J’s decision, but others developing CD19-targeting assets might now be wondering whether there will be a place for their candidates if they make it to market (see table below).
|CD19-targeting bispecifics and antibody-drug conjugates (ADCs)|
|Blincyto||Amgen||Anti-CD19 & CD3 bispecific||ALL|
|OXS-1550||Oxis International||Anti-CD19 & CD22 bispecific ADC||General blood malignancies|
|Denintuzumab mafodotin||Seattle Genetics||Anti-CD19 ADC||Non-Hodgkin lymphoma, ALL|
|Coltuximab ravtansine||Immunogen||Anti-CD19 ADC||Non-Hodgkin lymphoma|
|AFM11||Affimed||Anti-CD19 & CD3 bispecific||Non-Hodgkin lymphoma, ALL|
|SGN-CD123A||Seattle Genetics||Anti-CD19 ADC||AML|
|SGN-CD19B||Seattle Genetics||Anti-CD19 ADC||Non-Hodgkin lymphoma|
|ADCT-402||ADC Therapeutics||Anti-CD19 ADC||Non-Hodgkin lymphoma, ALL|
|AFM12||Affimed||Anti-CD19 & CD16A bispecific||Non-Hodgkin lymphoma|
|ZW38||Zymeworks||Anti-CD19 & CD3 bispecific||Acute leukaemia, Hodgkin lymphoma|
|Anti CD19 drug conjugate||Immunomedics||Anti-CD19 ADC||CLL|
|NI-1701||Novimmune||Anti-CD47 & CD19 MAb||Cancer|
As for Macrogenics, it still has six more bispecifics in phase I and another J&J-partnered asset, MGD015, in preclinical development. The group said J&J remained committed to this project, and would take it into human trials next year.
Macrogenics will hope that the safety signal with duvortuxizumab is not down to its Dart platform, and is already suggesting that this is not the case: the company noted that the neurotoxicity seen in a phase I trial of duvortuxizumab was similar to that observed with other CD19-targeted T-cell therapies, and said this had not been linked with its other programmes.
Nonetheless, news that the collaboration had ended was taken as bad news by investors – shares fell 10% in early trading today.
If the group turns out to be right, its remaining projects could have more success as they target areas where CAR-T has not managed to make a mark so far, including solid tumours. Macrogenics also has a bispecific against PD-1 and Lag-3, tapping into the trend for immuno-oncology combinations.
However, its lead project, flotetuzumab, targets CD123, which has been hit by safety concerns of its own: Johnson & Johnson’s anti-CD123 bispecific JNJ-63709178 was until recently on clinical hold after a serious adverse event, while deaths have been seen in a study of Stemline Therapeutics’ SL-401.
Macrogenics is due to present an update with flotetuzumab in acute myeloid leukaemia at the upcoming Esmo meeting.
|Macrogenics' bispecific pipeline|
|Flotetuzumab||CD123 x CD3||AML/MDS||Phase I||Data due at Esmo|
|PF-06671008||P-cadherin x CD3||Solid tumours||Phase I||Being developed by Pfizer|
|MGD007||gpA33 x CD3||Colorectal cancer||Phase I|
|MGD009||B7-H3 x CD3||Solid tumours||Phase I|
|MGD013||PD-1 x LAG-3||Solid tumours/haematological cancers||Phase I|
|MGD010||CD32B x CD79B||Autoimmune disorders||Phase I|
|MGD014||HIV x CD3||HIV||Preclinical|
|MGD015||CD3 x undisclosed||Haematological and lung cancers||Preclinical||J&J partnership continues|
|Duvortuxizumab/MGD011||CD19 x CD3||B-cell cancers||Discontinued||J&J ended partnership Aug 2017|
|Source: Company website.|
In addition to the toxicity concerns, given the mounting competition it is perhaps not surprising that J&J decided to discontinue development of duvortuxizumab. The project had been in a phase I trial in B-cell cancers including ALL, chronic lymphocytic leukaemia and diffuse-large B cell lymphoma.
Amgen’s anti-CD19 bispecific Blincyto has been available for ALL since 2014, and was recently joined by Pfizer’s antibody-drug conjugate Besponsa, which has a different target, CD22 (Snippet roundup: Transparency for Straumann but a black box for Pfizer, August 18, 2017). Both products are approved for patients with relapsed or refractory B-cell precursor ALL.
Meanwhile, this week’s approval of Novartis’s anti-CD19 CAR-T therapy Kymriah gives a new option for paediatric ALL patients (World’s first CAR-T approval sweeps away more cell therapy doubts, August 30, 2017).
And Kite Pharma/Gilead are expecting an FDA approval decision on the CAR-T candidate KTE-C19 in non-Hodgkin lymphoma by November – another popular indication for the bispecific antibody and antibody-drug conjugates listed above.
Of course, CAR-T is also associated with neurotoxicity, but the high remission rates in patients who have failed to respond to other therapies mean that this is a risk worth taking.
Efficacy has been less impressive with bispecifics, but with the latter being cheaper and less complex to manufacture they might be tried in earlier lines of therapy. It is worth noting that a Blincyto patient relapsing through CD19 antigen escape would no longer be a candidate for an anti-CD19 CAR.
These details will no longer concern J&J. Meanwhile, Macrogenics will hope that it can find a niche for its remaining projects – if it does not uncover more safety problems first.