For all the progress made in developing novel treatments for cancer, many of the haematological malignancies like leukaemia still have few hopes beyond cytotoxic agents. High-dose chemotherapy plus stem-cell transplants can improve survival, but for those without a donor match the options are limited owing to the danger of graft vs host disease.
The private Dutch company Kiadis Pharma hopes to expand the population eligible for this treatment regimen by attenuating the body’s immune response to haploidentical, or partially matched, stem cells from a family member other than a sibling. “We’re working on making these donors acceptable for transplant by manipulating their white blood cells,” its chief executive, Manfred Rüdiger, tells EP Vantage.
No hope, new hope
It is a significant opportunity, according to Mr Rüdiger. Of 151,000 haematological cancer patients treated with chemotherapy every year in the US and Europe, 47,000 are eligible for stem cell transplantations, but 22,000 cannot find a matched donor.
Stem cell transplantation is necessary to rebuild the hematopoietic system after it is destroyed by chemotherapy. Autologous transplantation can be used, but the danger is reintroducing cancerous cells back into the patient and causing a relapse. The typical donor is a sibling because the similar human leukocyte antigens in closely related people reduce the chance of immune reactions; matches can be found in tissue banks, but patients’ chances of finding a match can depend on ethnicity, with Caucasians having about a 50% chance of a match and others much lower, Mr Rüdiger says.
Haploidentical transplants depleted of T-cells have been attempted, but outcomes have been very poor. On the other hand, attempting this with active T-cells risks triggering severe and fatal immune response.
Kiadis has taken the approach of turning off the immune response to haploidentical stem cells. Leukocytes from the donor and patient are mixed ex vivo to trigger graft vs host disease. They are then impregnated with a compound, codenamed TH9402, which accumulates in activated T-cells.
When exposed to light the compound becomes toxic to these cells, leaving only non-activated cells that will not trigger transplant rejection, which can be reinfused into the patient. Kiadis has dubbed this product Atir.
Kiadis this week reported follow-up from a 19-patient phase I/II trial of Atir that found that six of nine subjects in a middle dosage range were still alive at five years; the three deaths were from relapses, not immune reactions.
A phase II study is under way in up to 23 patients with acute myeloid and chronic lymphocytic leukaemia and myelodysplastic syndrome – a group representing 80% of all allogeneic transplants – with data expected in the first half of 2014. The primary endpoint is transplant-related mortality at six months; Mr Rüdiger says the EMA has told Kiadis that this would be an approvable endpoint. The US is likely to want one-year overall survival.
"Biotechs think they can shortcut"
The Netherlands group is not expecting to submit to the regulators after the data read out. “Not on the basis of phase II,” Mr Rüdiger says.
“All biotech companies think they can shortcut. I don’t even want to embark on that discussion,” he says. “Our development plan foresees a pivotal study. We feel invited to submit earlier if the data are as black and white as in the phase I. But we are living in the real world.”
Having raised €17m since November 2012, Mr Rüdiger believes the company is well financed until the end of phase II, at which point it will seek a licensing deal. He says a phase III trial would cost about €15-20m, depending on the effect size seen in the phase II trial; however, Kiadis does not intend to conduct it.
While stem cell transplantation is well established as a treatment for haematological cancers, Mr Rüdiger recognises that the shadow of cell-based therapies can make for hard going in the licensing game. However, should phase II data be strong, he believes a deal could be signed in 2014 or early 2015. He is encouraged by big pharma’s continuing interest in cell therapies, however, and says the end market – the physicians treating these patients – should be excited by the promise of Atir.
“The group of people having absolutely no difficulties with such a product is physicians and haematologists. They are transplanting patients; for them this is just another transplant. But [Atir] allows them to treat the 30-50% of people for whom they can’t do anything,” he says.
“For pharma it’s an unusual distribution way, it’s an unusual kind of manufacturing, it’s a different business model. But’s it’s also a huge market opportunity. It’s an option to show that they’re really pursuing innovative approaches to the benefit of patients and still be commercially attractive. Therefore I don’t see any difficulties.”