DUBLIN – Xenikos BV aims to move its T-Guard cocktail of two antibody-drug conjugates into a pivotal phase III trial in acute graft-vs.-host disease (aGVHD) early next year, on the back of data from an open-label phase I/II trial, in which 12 of 18 treated patients (67 percent) remained alive at six months.

The intent-to-treat (ITT) six-month overall survival (OS) rate is a little lower – at 60 percent – as the study recruited two other participants who did not receive the therapy. The therapy attained a complete response rate of 50 percent for the ITT cohort and a clinical response rate of 60 percent. On a per-protocol basis, the equivalent numbers are 67 percent and 56 percent, respectively, Xenikos reported Sunday at the American Society of Hematology Annual Meeting in Atlanta.

The data compare favorably with historical control data from the two transplant centers in which the study was performed. Immediately prior to the T-Guard regimen, patients received either the TNF-alpha inhibitor Remicade (infliximab) (n=21) or a combination of inolimomab (an investigational interleukin-2 receptor inhibitor) and another TNF-alpha inhibitor, Enbrel (etanercept), (N=21). The pooled overall response rate and six-month OS rates were 52 percent and 29 percent, respectively.

"This phase I/II data is obviously preliminary, but I believe it's a good start," Mohamad Mohty, professor of hematology at the Saint-Antoine Hospital and University Pierre & Marie Curie in Paris, told BioWorld. Mohty, who is also president of the European Society for Blood and Marrow Transplantation, was not a clinical investigator on the trial, but he is working with Xenikos as a scientific advisor on the program.

"We do have a very nice complete response rate at day 28, and this translates to a survival advantage compared to historical controls," he said.

T-Guard became available on a named-patient basis in the Netherlands earlier this year. "So far we have treated four patients, and three of them have been sent home with complete remissions," Ypke van Oosterhout, founder and CEO of Nijmegen, the Netherlands-based Xenikos, told BioWorld.

The upcoming pivotal trial will, unlike the present study, have a comparator arm, which will probably comprise physician's choice. "It will be a large study," van Oosterhout said. "We will be meeting the FDA in the first week of January, to discuss the protocol and adjust it a little, if necessary. In essence, we're ready to go."

The company aims to begin dosing patients before the end of the first quarter. The study, which will involve U.S. and European bone marrow transplant centers, will take about three years to complete, he said. It will have an OS primary endpoint, but the company aims to file for approval based on interim survival and response data. It is currently seeking a development partner for the program.

T-Guard is an immunotoxin. It comprises a mix of CD3- and CD7-directed antibodies, each of which is tethered to the A chain of the ricin toxin. The latter has been crippled, van Oosterhout said, as it normally requires the lectin (carbohydrate-binding) activity of the B chain in order to gain cell entry. In the context of T-Guard, the toxic (ribosome-inactivating) A chain only gains cell entry, through antibody internalization, to cells expressing CD3 or CD7, namely T cells and natural killer cells present in the graft.

The occurrence of aGVHD is increasing in line with the growth in the uptake of allogeneic hematopoietic stem cell transplant (aHSCT) procedures. About 20,000 were performed in Europe in 2016, and a similar number were performed in North America, said Mohty. The procedure is becoming more widely adopted globally as well, for treating patients with hematologic malignancies.

"For a great number of patients, the only curative treatment is still allogeneic stem cell transplantation," he said.

A good start

Although aHSCT is becoming safer, the risk of aGVHD developing is unchanged – so too is the available treatment. "We haven't seen much improvement in the field," Mohty said. "We've been using the same treatment for over 40 years, which is corticosteroids."

About 30 to 40 percent of patients who develop aGVHD disease become refractory to steroids, however, and there is currently no approved therapy available for them.

Current standard of care involves the off-label use of immunosuppressive antibody therapies over long time periods. That inevitably increases the risk of infection, whereas T-Guard is administered as a short-term therapy. In the phase I/II trial, patients received four four-hour infusions every two days. "We are in and out," van Oosterhout said. "We seem to be more targeted than other therapies, in that we preferentially – not exclusively – target activated T cells."

Moreover, patients' immune systems recovered rapidly, with diverse T-cell repertoires.

The general approach Xenikos is pursuing has a long history. More than 20 years ago, Berkeley, Calif.-based Xoma Corp. developed CD5 Plus, comprising an anti-CD5 antibody linked to the ricin toxin A chain. It failed to show efficacy in a phase III trial, however.

There have been about a dozen phase III failures in recent years, Mohty said. One recent casualty was inolimomab, a CD25-directed antibody, which Dublin-based Jazz Pharmaceuticals Corp. gained through its acquisition of Eusa Pharma Inc., of Langhorne, Penn.

"Not all of them failed because they were not effective," he said. But even if patients do go into remission, relapse or infection can occur and can affect survival rates. In that context, the T-Guard data represent a good start – but no more than that. "We need to be very cautious about this, because it's only phase I/II data, and it's a very small number of patients," he said.

Phase III trials of several other therapies are ongoing, including MSC-100-IV, a stem cell therapy that Mesoblast Ltd., of Melbourne, Australia, is evaluating in a single-arm, open-label study in 60 patients. Its partner in Japan, Ashiya-based JCR Pharmaceuticals Co. Ltd., has already received approval in aGVHD for that therapy, which it markets as Temcell. Basel, Switzerland-based Novartis AG and partner Incyte Corp., of Wilmington, Del., are also in phase III with JAK 1/2 inhibitor Jakafi (Jakavi; ruxolitinib), which is already approved for treating myelofibrosis.

The adjacent area of chronic GVHD notched up its first approval in August. Abbvie Inc., of North Chicago, won FDA approval for the Bruton's tyrosine kinase inhibitor Imbruvica (ibrutinib) in August on the basis of an open-label study in 42 patients, nine (21 percent) of whom were complete responders and 19 (45 percent) of whom were partial responders. At 20 weeks, 20 patients (48 percent) had maintained their responses.

Whether those outcomes were good enough to influence clinical practice is very much an open question for now. "No one involved in the field could believe this approval based on this small [patient] series," Mohty said. "I personally think the data are relatively weak," he added. "The whole community was very skeptical."