“I don’t think we had any real safety issue” with giving two doses in an earlier trial, Kiadis Pharma NV CEO Manfred Rüdiger told BioWorld Today, but Canadian phase III testing of ATIR101 (Allodepleted T-cell ImmunotheRapeutics) will deploy a single dose of the treatment, designed to provide safe donor lymphocyte infusion from a partially matched family member without the risk of causing graft-vs.-host-disease (GVHD) in hematopoietic stem cell transplant (HSCT) patients with leukemia.

“The perception in the market was that we ran into trouble because we had two cases of GVHD, which we didn’t see in the previous trials,” Rüdiger said. “However, the GVHD we saw was nothing that isn’t total daily clinical practice for every transplant doctor, even in a fully matched setting. We decided to not continue with it because we didn’t expect too much upside, and we didn’t want to expose more patients to risk, which they are typically exposed to” in standard-of-care treatment.

With ATIR101, T cells that would cause GVHD are eliminated from the donor lymphocytes using Kiadis’ photodepletion technology, which minimizes the risk of GVHD and eliminates the need for prophylactic immune suppression. The method also delivers potential cancer-killing T cells from the donor that could do away with residual disease and help prevent relapse known as the graft-vs.-leukemia effect. Administered as an adjunctive immuno-therapeutic on top of HSCT, ATIR101 provides the patient with functional, mature immune cells, possibly making curative HSCT a viable option to many more patients. The company estimated that about 35 percent of patients who are eligible and in urgent need of HSCT will not find a matching donor in time, whereas a haploidentical family donor will be available to more than 95 percent of patients.

T cells in ATIR101 have been shown to help fight infections until the immune system has fully re-grown from stem cells in the transplanted graft. The phase III trial in Canada will enroll about 195 patients with acute leukemia, randomized 1-to-1 to receive a haploidentical allogeneic HSCT using a single dose of ATIR101 or post-transplant cyclophosphamide, a method also known as the Baltimore protocol. The trial design has been submitted for approval and is being evaluated by the FDA and European regulatory gatekeepers as well. If they approve, the study will start adding centers in those territories.

The photodepletion approach is “based on a small-molecule rhodamine derivative, which we code-named TH9402, which is specifically retained in immune cells that have become activated,” Rüdiger said. “In our case, it’s immune cells activated against the patient tissue, the ones that are causing GVHD. The trick really is that, in activated immune cells, the multidrug-resistance pump, which is also responsible for resistances against chemotherapy, is inactivated; therefore this small molecule gets trapped in those immune cells that would later cause trouble in the patients.” Chemists who invented the method “were smart guys, obviously,” he said. “They engineered this molecule such that it becomes toxic upon exposure to green light – low-energy, visible light which will not do any harm to DNA for instance. So when we have the drug retained, we switch the light on, it renders the drug toxic and kills off all immune cells which are active.”

Kiadis plans “traditionally have always started the clinical trials in Canada, because that’s where the invention originally comes from,” Rüdiger said – specifically, the University of Montreal. CTI Clinical Trial and Consulting Services Inc., of Cincinnati, has been signed up to help the clinical aspect of the phase III program, and Basking Ridge, N.J.-based Caladrius Biosciences Inc. subsidiary PCT LLC will manufacture ATIR101 for the U.S. and Canada, while the German Red Cross Blood Donor Service in Baden-Wuerttemberg-Hessen will remain the manufacturer in Europe. All 15 study centers that participated in the company’s phase II trials with the product have confirmed their plans to take part in the phase III effort. Kiadis is aligning more sites with the aim of having more than 40 sites in North America and Europe on board.

TO RAISE MORE MONEY LATER

The market “may have overestimated” revenue benefits from using two doses rather than one, in the view of Edison analyst Juan Pedro Serrate. “We see no impact on our valuation or forecasts following this news, as the market opportunity we forecast is predicated on a single dose of ATIR101,” he wrote in a report. “Furthermore, safety has already been established for the single dose in previous studies. This second dose trial was purely to see if a second dose strategy could improve patient outcomes.”

When an independent data monitoring committee (IDMC) recommended against continued repeat dosing of the treatment because of the GVHD incidents, Roth Capital Partners analyst Mark Breidenbach – like Serrate – wasn’t put off. “We believe the IDMC decision should not impact the timing or likelihood of success of the planned phase III study of ATIR-101, a major value driver for the company,” he said in a report.

An ongoing phase II study with single-dose ATIR101 has treated five patients, of which three were infused more than 120 to 150 days ago. None has shown any symptoms of severe GVHD, and none has received any prophylactic immunosuppression, Kiadis said. The company’s preparations are going nicely for submitting the marketing authorization application to the EMA in blood cancers, too, and that submission will be based on single-dose phase II findings that proved the product safe and resulted in statistically significant benefits on overall survival (OS) and reducing death from GVHD and infections, compared to an observational control group of patients having received a similar T-cell depleted stem cell transplant from a haploidentical family member but without the addition of ATIR101. Kiadis already has an advanced therapy medicinal product certificate from the EMA, affirming the manufacturing quality and preclinical data.

Further back in the pipeline is phase I/II-stage ATIR201 for thalassemia, which won the nod from the national authority in the U.K., the Medicines and Healthcare products Regulatory Agency, as well as approval from the ethics committees of the Royal Manchester Children’s Hospital and the Birmingham Children’s Hospital. The ethics committee of the University of Regensburg in Germany agreed. Kiadis expects the first clinical trial data to become available in the second half of this year.

“The approach is fundamentally the same,” Rüdiger said. “The idea was to put a flag into the ground” with the stem cell transplant approach, as gene therapies were coming down the pike for thalassemia and sickle-cell disease. Since the disorders are bone marrow-oriented, Kiadis’ method “would be a way to cure the disease for life without the need to have a targeted gene therapy,” creating a “longer-lasting effect for a much cheaper price” in pediatric to adolescent patients.

Rüdiger said the company will eventually need to raise more money to complete its experiments. When the company went public a year and a half ago on the Euronext market, “the clinical program was already progressing very nicely. [Kiadis’] strategy was to raise enough to get beyond phase II readout” and then, “hopefully in better markets,” to raise more. The IPO happened “around the great crisis in Europe,” with “very high political instability at the time, which since then has not changed and is now the same elsewhere,” he noted. Down the road, “we don’t want to overfinance, because we do assume that we will start generating revenues [from ATIR101] in 2018. But realistically, even if you start selling, many health care payers or national authorities will not pay the bills immediately. Depending on the country you’re in, this can be quite a few months if not up to a year before the cash flows hit your account.” This means the timing of any fundraising will have to be determined later, he said. (See BioWorld Today, June 4, 2015.)