Date: 2016-09-09
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 1st EBMT International Transplant Course
Company: MolMed (Italy)
Product: Zalmoxis® (investigational cell therapy product TK)
Action
mechanism: gene therapy/cell therapy. Zalmoxis® is atherapy based on genetically modified donor T lymphocytes to carry an inducible “suicide gene”. Administered to patients following HSCT from partially compatible donors (haploidentical HSCT), these cells foster an anti-leukaemia effect by eliminating post-transplant immunosuppression prophylaxis and inducing a rapid immune reconstitution. Furthermore, the suicide gene allows to readily control Graft versus Host Disease (GvHD), the most significant and serious adverse event in haploidentical transplantation, caused by the genetic disparity between patient and donor.
Disease: high-risk leukemia
Therapeutic area: Cancer - Oncology
Country: Italy, USA, France, Germany, Greece, Israel
Trial
details: TK008 is a pivotal randomised Phase III trial in adult patients affected by high-risk leukaemia undergoing transplant of haematopoietic stem cells collected from partially compatible (haplo-identical) family donors. The trial design has disease-free survival as the primary end-point - which includes both transplant-related mortality and disease relapse - evaluated on a patient population of 170 patients. The trial will compare the outcome of haplo-transplants with or without TK add-backs, with a 3:1 randomisation ratio in favour of the TK arm. Secondary end-points include overall survival, reduction of transplant-related mortality, safety and patients’ quality of life. With the aim to provide additional clinical benefit to patients and to significantly increase the potential participation of centres in the trial, the Company implemented in 2012 two important changes in the protocol design of Phase III trial TK008. The first consists in broadening the enrolment criteria to include patients in leukaemic relapse, in addition to those in disease remission; the second change provides for the introduction of a further treatment option in the control arm, based on the use of an unmanipulated transplant followed by cyclophosphamide administration during the post-transplantation period. (Trial identifier on ClinicalTrials.gov: NCT00914628).
Latest
news:
Conditional Marketing Authorisation (CMA) recently granted to Zalmoxis® have been presented at the 1st
EBMT International Transplant Course (Barcelona, Sept. 9 -11, 2016) during a symposium titled "A new era
of haplo-transplantation". On the 18th of August, the European Commission, following the CHMP recommendation issued on the 23rd of June, has granted a CMA for Zalmoxis® as adjunctive treatment in haploidentical haematopoietic stem-cell transplantation (HSCT) for adult patients with high-risk haematological malignancies.
The CMA decision is based on efficacy and safety data collected from patients enrolled in the Phase I/II trial
(TK007) and in the currently ongoing pivotal randomised Phase III trial (TK008). The Zalmoxis group comprised 30 patients from the TK007 trial and 15 patients from the experimental arm of the TK008 trial. The TK007 trial included patients with various types of high-risk haematologic malignancies, while the TK008 trial is enrolling patients with acute myeloid or lymphoblastic leukaemia in any complete remission or advanced-stage disease, or with secondary acute myeloid leukaemia. To support the European Authority assessment process, data of Zalmoxis-treated patients (n=37) have been compared with a 1-to-4 ratio to contemporaneous control patients (n=140) from the database of European Group for Blood and Marrow Transplantation (EBMT) Registry by a pair-matched analysis.
Outcomes of this pair-matched analysis, presented in Barcelona, showed a robust survival improvement
in Zalmoxis-treated patients, specifically driven by a reduction in mortality from both infection and GvHD (i.e.
in non-relapse mortality - NRM), which historically represent the main complications and causes of death after
haploidentical transplant. In fact, the 32% relative increase in overall survival in patients treated with Zalmoxis
compared with control patients (49% vs 37%) was mainly due to the halving in non-relapse mortality in
Zalmoxis-treated patients, as compared with controls (22% vs 43%). Among controls dying from non-relapse
causes, the majority (78%) indeed died for either infection (56%) or GvHD (22%), while the only adverse event
related to Zalmoxis treatment was GvHD, fully resolved by activating the suicide gene system with ganciclovir
treatment, without any GvHD-related death. In TK cells-treated patients, moreover, chronic GvHD was
extremely low in comparison with the control group (6% vs 25%). Therefore, the protective effects of TK cells
in controlling infection and GvHD mainly drove the decreased NRM in Zalmoxis group compared with control
patients.
This pair-matched analysis has clearly established the clinical benefit for Zalmoxis-treated patients compared
with contemporaneous EBMT controls, by means of clinically meaningful endpoints, such as overall survival,
non-relapse mortality and chronic GvHD. Furthermore, chronic GvHD reduction and acute and chronic GvHD
control by the suicide gene system has allowed Zalmoxis patients to benefit from long lasting and
immunosuppressive-free survival. So far, there were neither an approved therapy nor a widely accepted
standard of care able to overcome opportunistic infections and GvHD, the two problems that continue to
account for most of the non-relapse deaths, as well as to increase survival rates after haploidentical HSCT.
* On December 9, 2014, MolMed presented new data from three studies on the experimental TK cell therapy in patients with acute leukemia at high risk of relapse who underwent transplantation from a partially compatible donor (haploidentical) at the 56th annual meeting of the American Society of Hematology (ASH)). The results showed high survival rates, dose-related antileukemic activity and long-term efficiency in the control of GvHD (graft-versus-host disease). Results presented at the ASH meeting on a pooled analysis of the Phase II TK007 and Phase III TK008 trials confirmed the potent anti-leukemic effect of the TK cell therapy related to dose with strong statistical significance (p<0.001), as evidenced by the absence of leukemia relapse at 4 years after transplantation in those patients who received the highest dose of TK cells.
Claudio Bordignon, Chairman and CEO of MolMed, comments: "We are delighted by the new phase III data on the TK cell therapy confirming the high disease-free survival rates, the primary phase III trial endpoint and the scientific basis for the request of Conditional Marketing Authorization from the European regulatory authority. In addition, the long-term analyses have clearly demonstrated the ability of TK cells in inducing a dose-dependent anti-leukemic activity and in fully controlling a hard-to-treat complication such as GvHD." An application for conditional approval of the TK cell therapy has been filed in March 2014 in EU and the European Medicines Agency has validated the submission of the registration dossier.
* On December 9, 2013, MolMed has announced the presentation of the long term assessment of the immune-reconstitution and the related clinical benefit induced by its investigational cell therapy TK at the 55th Annual Meeting of the American Society of Hematology (ASH), taking place in New Orleans . Dr. Giacomo Oliveira from the San Raffaele Scientific Institute (Milan, Italy) gave an oral presentation entitled “Long-term immunological profile and T cell dynamics in patients treated with allogeneic transplantation and TK-cells for hematological malignancies”. Results show that in the majority of patients (90%) TK cells are still present, functional and susceptible to ganciclovir up to 14 years after the treatment, confirming the validity of the TK approach in inducing a long-term and complete immune reconstitution in patients suffering from high risk acute leukemia, without losing the ability to control GvHD. Moreover, immune-reconstitution observed in study subjects was characterized by full functionality of T cells and Natural Killer cells, key components of the anti-leukemic immune response. The overall analysis was performed on 14 patients who underwent the TK treatment between 1995 and 2010 (median follow-up 9 years, range 3-18), all currently in complete remission and disease-free. Notably, no adverse events correlated to the use of TK cells were ever reported during the follow-up period. Graft versus Host Disease (GvHD) was reported in 5 patients and was rapidly and completely controlled thanks to the TK technology without the need of post-transplant high-dose immunosuppression.