The EU’s already considerable lead over the US in haematopoietic stem cell transplantation (HSCT) looks set to widen over the next few weeks, with two notable developments in this space.
The first is the formal EU approval for Zalmoxis, a novel engineered T-cell product for use with HSCT that incorporates a “suicide gene” to allow doctors to manage the risk of acute graft vs host disease, a serious complication. The second is yesterday's outcome of Bellicum’s (NASDAQ:BLCM) regulatory interactions with the EMA for BPX-501, a similar engineered product for use with halpoidentical HSCT, giving BPX-501a clear pathway for the first time.
Zalmoxis has been developed by the little-known Italian biotech MolMed, one of three companies – the others being Bellicum and Kiadis Pharma – known to be working on engineered T-cell products to improve the outcomes with haploidentical or partial matched HSCT.
Patients undergoing HSCT are at high risk of serious bacterial, viral and fungal infections until the immune system has been reconstituted from the transplant, which can take up to one year. They could receive T cells from their donor to help fight infections, but this would put them at high risk of GvHD, which can only be managed by immune-suppression. The risk of GvHD limits the procedure to only the most serious malignancies.
Both Zalmoxis and BPX-501 comprise T cells that have been engineered to include genes that render them sensitive to other agents – ganciclovir or valaciclovir for Zalmoxis and rimiducid for BPX-501. These agents can therefore be administered to trigger destruction of teh T cells if acute GvHD occurs.
The donor T cells allow recipients to fight infections while their system is being reconstituted, and are thought to have an anti-leukaemic effect. Some data suggest that Zalmoxis can improve long-term outcomes: for example, a study in 45 patients showed a one-year survival rate of 49%, compared with one-year survival of 37% from a database of 140 matched HSCT controls.
In June MolMed received a CHMP positive opinion recommending conditional approval, and expects formal approvals to come through by September. As a potential first for such a product, this should mark a significant advance in the HSCT field, but it is not the first one where the EU regulator has taken a lead over its US counterpart.
Bellicum yesterday said the EMA would allow a regulatory submission for BPX-501 based on data from the European arm of its BP-004 trial with six-month follow-up data. BPS-004 is a single-arm, open-label study, recruiting 180 paediatric patients undergoing T-cell depleted HSCT for haematological disorders.
Bellicum said the EMA had accepted that a review and approval under exceptional circumstances could be suitable, given that a randomized trial might not be feasible in the paediatric setting. Bellicum is holding similar interactions with US regulators, although it is thought that the FDA is unlikely to be as accommodating as the EMA.
Meanwhile, Kiadis is developing its T-cell product, ATIR101, engineered to remove the cells that cause GvHD, thus eliminating the need for prophylactic immune-suppression. It is conducting a 15-patient phase II study due to read out in March.
Bellicum remains the company to watch in the field, since it has a largest clinical program by some margin. Three studies are under way involving nearly 240 patients, and a further three are planned with another 70 volunteers.
Bellicum is also alone among the three companies in developing BPX-501 for non-haematological indications, which could massively expand the market opportunity. HSCT is a viable option for haemoglobinopathies and other inherited conditions, but haplo-identical HSCT cannot be used because of the risk of GvHD in these patients.
HSCT is one of the fastest-growing medical procedures and is one where, unusually, the EU has a lead over the US. Around 15,000 such procedures are conducted in Europe each year, compared with 7,500 in the US. There were an estimated 1,300 haplo-identical HSCT procedures in the EU in 2014, a number that is thought to be growing at around 30% per year.
MolMed estimates that 11,000 persons in the EU could be candidates for allogeneic transplant, but lack a fully compatible donor. Thanks to the ability to manage teh risk of GvHD those patients – at least those in the EU – might soon have a new option.