Ziopharm stalls its CAR yet again

If Ziopharm’s frequent presentations at industry and scientific conferences were anything to go by the company would now be well on the way to revolutionising cell therapy for cancer. Reality, however, is well short of the hype.

The US FDA yesterday slapped a clinical hold on one of Ziopharm’s most heavily touted advances – a CAR-T project eliminating the need for central manufacture, enabling patients to be treated within two days of cell collection. Seasoned CAR-T watchers will simply shrug and ask: what’s new? Since Ziopharm entered the world of cell therapy three years ago it has made negligible clinical progress.

The market certainly bought into the hype: Ziopharm’s stock slumped 18% on the hold, which might have been due to the risk of uncontrolled cell proliferation with the project in question or its risky ablation switch. The company is still valued at nearly $500m – an astonishing amount for what is clearly one of the sector’s laggards. 

Chopping and changing

True, some investors might not fully grasp the amount of chopping and changing that has gone on behind the scenes as Ziopharm scrabbled to put together a viable CAR-T programme based on the Sleeping Beauty technology it bought from MD Anderson in January 2015 (Sleeping Beauty wakes up to $115m deal, January 14, 2015).

Yet it does not take much to appreciate that things have not gone smoothly. When it did that deal the plan was to have “up to five” CAR-T projects using Sleeping Beauty in the clinic in 2015; three years on the total stands at four CARs, one of which uses not Sleeping Beauty but a traditional lentivirus.

Active studies of Ziopharm-sponsored cell therapies
Project Indications Gene transfer Ablation switch Detail Trial ID
Anti-CD19 CAR Leukaemia & lymphoma Sleeping Beauty None Donor-derived CAR-T cells NCT01497184
Anti-CD19 CAR Leukaemia & lymphoma Sleeping Beauty None 1st-generation  manufacturing NCT00968760
Anti-CD19 CAR Leukaemia & lymphoma Sleeping Beauty None 2nd-generation  manufacturing NCT02529813
Anti-CD33 CAR Acute myeloid leukaemia Lentivirus Erbitux-activated EGFRt Change to Sleeping Beauty possible 2018 NCT03126864
Source: Clinicaltrials.gov & company presentations.

It has long been apparent that Sleeping Beauty – a virus-free method of getting T cells to express a CAR construct – had problems; remissions with a CD19-targeted CAR were underwhelming and cell persistence was poor, likely explaining highly touted low rates of toxicity.

Ziopharm undertook a redesign, all the while talking about novel targets. What the group terms a “second-generation” asset is now in the clinic, apparently offering shortened manufacturing, though this still comprises the same CD28-co-stimulated CD19 construct; years ago MD Anderson had talked of changing CD28 to 4-1BB co-stimulation to improve persistence.

Yesterday’s US clinical hold relates to a “third-generation” asset whose entry into the clinic would, Ziopharm claimed, have made the company “the first in the world to deliver [to patients] autologous T cells manufactured in two days or less with a simple process and ultimately a lower cost”.

This CD19-directed project additionally uses membrane-bound IL-15 to aid proliferation. It also includes a cell ablation off-switch that Ziopharm followers might logically have expected to be the company’s long-touted Rheoswitch, a technology affecting transcriptional control using the small molecule veledimex.

No such luck: a poster at last year’s Ash meeting reveals it to be nothing more than the Erbitux-triggered truncated EGFR (Her1t) technology used by Juno and dismissed by many in the industry.

No viability?

It might not be too farfetched to suggest that doubts about the viability of this switch lie behind the FDA’s hold. Erbitux is known to trigger an inflammatory response, making doctors fear using it and clouding the logic of using Erbitux as the basis for something that is ultimately supposed to be a safety switch.

None other than Merck KGaA, a company to which Ziopharm sublicensed Sleeping Beauty CAR-T work, has admitted that things have proceeded cautiously.

Two years ago Ziopharm aborted a $50m equity raise after a death in its gene therapy study, and it now has enough cash only to the end of 2018.

Yet in addition to the two-day manufacturing boast, over the past six months executives have talked about allogeneic CAR-T, natural killer cell-based products, and a modified T-cell receptor construct targeting neoantigens for solid tumours. Perhaps before running Ziopharm should learn how to walk.

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