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Cellectis death casts more doubt on CD123

Date September 05, 2017

Safety worries around targeting CD123 will only intensify with news of a patient death with Cellectis’s off-the-shelf CAR-T therapy UCART123. Others working on projects against CD123, including Johnson & Johnson and Novartis, will be hoping that this is not a problem common to this target, something that now looks like a distinct possibility (see table below).

Two ongoing phase I studies of UCART123 have now been suspended and, while Cellectis hopes to restart them with a lower dose, the FDA will surely be cautious after a string of problems with similarly acting agents.

CD123-targeting projects in development 
Product  Company  Mechanism  Notes 
Phase III        
Talacotuzumab/JNJ-56022473  Xencor/J&J  MAb   
Phase II        
SL-401  Stemline Therapeutics  Protein/drug conjugate  Two deaths in phase II 
Phase I        
UCART123  Cellectis  Allogeneic CAR-T  On hold 
MB-102  Fortress Biotech/Mustang Bio/City of Hope  Autologous CAR-T   
MIH911  Novartis  Autologous CAR-T   
SGN-CD123A  Seattle Genetics  Antibody-drug conjugate   
Flotetuzumab  Macrogenics  Bispecific MAb   
JNJ-63709178  Genmab/J&J  Bispecific MAb  Clinical hold lifted April 2017 
XmAb14045  Xencor  Bispecific MAb   
SQZ622  Novartis  Bispecific MAb   
KHK2823  Kyowa Hakko Kirin  MAb   
Source: EvaluatePharma. 

It is unclear whether the CD123 antigen is the issue, but three safety scares over the past year could be more than a coincidence. First, a study of Genmab and Johnson & Johnson’s bispecific antibody JNJ-63709178 was suspended last September after a unnamed serious adverse event – although the clinical hold was lifted in April.

Then came two deaths in a pivotal study of Stemline Therapeutics’ SL-401, but this trial has continued (Stemline patient death becomes secondary investors’ problem, February 03, 2017).

The death with UCART123, in the first patient treated in a phase I study in blastic plasmacytoid dendritic cell neoplasm (BPDCN), was blamed on cytokine release syndrome and capillary leak syndrome. While the former is a known side effect of CAR-T therapy, the latter has also been associated with Stemline’s SL-401, suggesting that it could be an issue with hitting CD123.

And this was not the end of the bad news for Cellectis. The first patient in a second phase I trial of UCART123, in acute myeloid leukaemia (AML), also experienced grade 3 cytokine release syndrome and grade 4 capillary leak syndrome that put her into intensive care, though these adverse events were resolved.

Cellectis’s project incorporates a Rituxan-based “suicide switch” to inactivate the T-cell therapy in the event of safety problems, but it seems that the trial investigators had not attempted to use this. One drawback with this approach is that infusing Rituxan can trigger an inflammatory response, so would be risky in frail patients.

This has raised questions about whether this switch is a real safety solution. In any case, Cellectis executives had told EP Vantage at last year’s Ash meeting that the company was working on different suicide switches, which could encompass small molecules or monoclonal antibodies.

Not as easy as 123

Targeting CD123 could be problematic because, while it is overexpressed in haematological cancers, it is also present on many healthy cells, which could lead to on-target, off-tumour effects.

When asked about this potential issue at last year’s Ash conference, Cellectis’s chief medical officer Loan Hoang-Sayag seemed unconcerned and said that the company remained confident in spite of the problems with JNJ-63709178.

Nonetheless, the latest death is yet another worry for others attempting to hit CD123. Johnson & Johnson is well represented here with two candidates: the aforementioned JNJ-63709178, and talacotuzumab, the most advanced CD123-targeting asset, which is in a phase III trial in AML due for completion next year.

However, it is smaller companies like Macrogenics that have more to lose. This group will present phase I data with its bispecific antibody flotetuzumab in AML and myelodysplastic syndrome at this week’s Esmo meeting in Madrid. Based on the abstract released safety appears to be acceptable so far, but this is something that will remain closely watched.

As for Cellectis, it believes it has a way forward for UCART123: reducing the dose from 6.25x105 to 6.25x104 cells per kilogram. However, the French group’s share price was down as much as 31% today, suggesting that investors do not fancy its chances of finding a therapeutic window here.

The company has a more advanced allogeneic CAR-T project, UCART19, in phase I – this has a better-validated target in CD19, but this area is already crowded, and in any case the asset is now in the hands of Pfizer and Servier.

If CD123 turns out to be a dud, it would be bad news for many companies – but it would be a disaster for Cellectis.

Trial  ID 
Phase I trial of UCART 123 in BPDCN  NCT03203369 
Phase I trial of UCART 123 in AML  NCT03190278 

This story has been updated to reflect the fact that talacotuzumab is a MAb, and the addition of Seattle Genetics' SGN-CD123A.

To contact the writers of this story email Madeleine Armstrong or Jacob Plieth in London at news@epvantage.com or follow  @ByMadeleineA or @JacobPlieth on Twitter

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