If the bullish forecasts of Juno and Kite Pharma are to be believed then this time next year the industry will be bracing itself for the imminent commercial launch of the first CAR-T product.
Such an exciting prospect is not without its daunting aspects, and perhaps the most immediately pressing is companies’ need to have in place efficient and reliable manufacturing capacity. But judging by comments at last week’s Adopt Summit in London – from potential applicants and the regulator alike – we are still some way off overcoming this major obstacle.
Paula Salmikangas, chair of the European regulator’s CAT – the committee for advanced therapies, which will oversee CAR-T approvals – said, “What worries me is the heavy, evolving nature of the science.” This relates both to the addition and deletion of genetic material in cells, and manufacturing constraints and inter-patient comparability issues that might not become obvious until launch.
GlaxoSmithKline’s head of cellular therapy, Cedrik Britten, said automation was the critical step that could make production far more efficient. He also floated the possibility of partnerships between developers and service companies, and said it largely came down to how the industry wanted to make money.
The three most advanced groups seem pretty sure: Juno and Kite have invested huge amounts to build their own commercial production plants, while Novartis bought an existing facility from Dendreon (Juno and Kite fight it out to be first to market, March 1, 2016).
No doubt the disaster of Dendreon’s Provenge, the first US approved autologous cell product, is still fresh in many people’s minds. Still, a horrendously complex manufacturing process was only part of Provenge’s problem – a meagre benefit, the advent of two new efficacious small molecules, and Dendreon’s crippling debt pile were at least as important.
At least the EMA has its procedural ducks in a row; Ms Salmikangas outlined her committee’s initial role in the scientific assessment of CAR-T therapies, which will be classified as advanced-therapy medicinal products.
Her advice to applicants was to “start from the basics: a robust product, with robust manufacturing”, and remember that if the production process changed then the cells would change too. She also stressed the need for early contact with the regulator, whether the applicant was a large or a small company.
Manufacturing efficiency feeds straight into the pricing debate. Glaxo’s Mr Britten appeared to confirm critics’ worst fears by suggesting that the $178,000 per patient per year price tag of Amgen’s Blincyto was a “range from which we can think about an increase”.
The Weizmann Institute’s Professor Zelig Eshhar, one of the founding fathers of CAR-T therapy, said as well as making the procedure safer it was vital to make it “handy and cheaper”. One approach might be to go down the allogeneic route, whereby an off-the shelf product is ready for use without the complexities of an autologous therapy.
Until recently Cellectis was the allogeneic CAR-T player to watch, but this is no longer the case, as demonstrated by the patent issued to Celyad last week covering TCR-deficient CAR-T cells – the same scientific approach that Cellectis uses.
Thus, in a field where litigation is hardly a novel prospect, a patent battle between Cellectis and Celyad could be on the cards. Novartis is also making early progress on a TCR-deficient universal CAR product, in its case through the use of Crispr/Cas.
Of course, allogeneic cell products have their own issues, which Johnson & Johnson’s scientific director Sicco Popma summarised as the “selection” problem. In other words, with allogeneic therapy the cells’ origin is critical: “What is the cell source I can use for every patient? Who can provide it?” asked Mr Popma.
This is distinct from autologous CARs’ “optimisation” problem – the need to improve persistence, for instance by isolating a very specific subset of a patient’s cells for expansion – and manufacturing. That said, TxCell's chief executive, Stéphane Boissel, reckons that production is a near-term problem that will soon be overcome.
“My vision is that in 10 years manufacturing cell therapies will be a commodity,” he said. “But we are not yet there.”