Flush with cash, Allogene tackles the production conundrum

In the seven months since its founding the company has attracted $793m of financing. Now it must execute.

Last month’s turmoil on the public markets has wiped out the gains made by biotech over the past year, so Allogene must count itself pretty lucky. The group got its $324m flotation away on October 11, just as the markets turned sour.

Its financial strength could help the group’s portfolio of allogeneic CAR-T therapies, derived from Pfizer’s side of an alliance with Cellectis, progress faster than it has so far. But, as if to stress that it will not be plain sailing all the way, Allogene revealed this week that a manufacturing hitch would hit recruitment into trials of the most advanced asset, UCART19.

“A few days ago we were informed that [Servier was] encountering some manufacturing difficulties,” Allogene’s chief executive, David Chang, told the Jefferies healthcare conference in London on Wednesday. Servier is Cellectis’s partner for UCART19, and is running two studies – one in paediatric and the other in adult ALL.

Beyond stating that recruitment into these would be limited, Mr Chang would not comment on the precise reasons behind the snafu. Last year Servier signed a deal with the Orgenesis subsidiary Masthercell to develop an allogeneic CAR-T manufacturing process, but an Allogene spokesperson said the problems did not concern this.

Off the shelf

The currently available CAR-T therapies Kymriah and Yescarta are autologous, meaning that they use the patient’s own cells to generate a CAR-T product. Allogeneic CAR-T holds the promise of a more convenient, off-the-shelf approach, but is fraught with difficulties such as the serious risk of graft-versus-host disease and the inconvenience of host-versus-graft.

Allogene combats the former by editing out T cells’ endogenous T-cell receptors using the Talen technology that Cellectis brought to the deal (Allogene spells out its interest in Cellectis, September 17, 2018). The latter can to some extent be circumvented by lymphodepleting patients with the anti-CD52 MAb Campath – a process to which the CAR-T cells are immune because they are CD52-edited.

Interestingly, Allogene is free to pursue alternative methods of gene editing, but for now sees no need to switch from Talen to an alternative such as Crispr, Mr Chang told Vantage. One disadvantage of the current method is that the donor-derived T cells undergo a two-stage process, first lentiviral transfection to express the CAR and then electroporation to delete the genetic elements using Talen.

Mr Chang also said Allogene felt no need to license in additional CAR-T targets, but that it might seek technology deals. The rest of its pipeline includes ALLO-819 and ALLO-715, assets targeting Flt3 and BCMA respectively and being profiled at Ash next month, and ALLO-647, an anti-CD52 alternative to Campath, which is no longer easily available for leukaemia.

The Kite team

Allogene owes much of its success to the fact that its leadership team, including Mr Chang and its chairman, Arie Belldegrun, succeeded in selling their previous CAR-T business, Kite Pharma, to Gilead for $11.9bn.

This has helped dispel worries over the slow progress of Cellectis’s assets, and over the lack of clarity surrounding two patient deaths in a UCART19 adult ALL trial; this week Allogene characterised these as being due to sepsis and post-transplant cytopenia.

Of course, Allogene is not alone in pursuing allogeneic cell therapy. Fate Therapeutics, which presented at the Jefferies meeting on Thursday, is working on off-the-shelf CAR-T projects derived from a single pluripotent stem cell.

And recently the autologous players Celyad and Autolus suggested alternative methods of silencing endogenous T-cell receptors to generate off-the-shelf CAR-T cells, using shRNAs and an anti-TCR ScFv fused to a KDEL endoplasmic reticulum-retention domain respectively.

Autolus is, like Allogene, a beneficiary of now distant-seeming biotech enthusiasm, having floated in June. Its own presentation at Jefferies was preceded by extreme share price volatility, a 68% three-day climb being followed by a 26% fall and then an 11% increase.

While Autolus is somewhat less well capitalised than Allogene it still has ambitious plans, telling the conference that within three years it would switch from contract manufacturing at Cell Therapy Catapult to its own UK facility and then to a commercial US plant; this would take production capacity up from the current 300 to some 5,000 CAR-T therapies a year.

For its part Allogene also still uses contract manufacturing, but plans to build a facility of its own in the Bay Area to prepare for commercial launch, with a decision on the specifics to be made in the next few months, said Mr Chang.

He stressed that improving the manufacturing process was a major aim, but accepted that whether this actually reduced costs to patients – a key selling point of the allogeneic idea – was unclear.

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