Type of information: Product launch
Product name: Zalmoxis® - TK cell therapy
Compound: TK cell therapy
Therapeutic area: Transplantation
- cell therapy. Zalmoxis® is a cell therapy product, based on the use of genetically engineered donor T cells with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor (LNGFR) and the herpes simplex I virus thymidine kinase (HSV-TK Mut2). Zalmoxis® innovative therapy is based on genetically engineering donor immune system T cells 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. The suicide gene in the modified T cells makes them susceptible to ganciclovir or valganciclovir. If the patient develops graft-versus-host disease, ganciclovir/valganciclovir is given, which kills the modified T cells that have the suicide gene, so preventing further development of the disease.
- Zalmoxis® is administered following haploidentical haematopoietic stem-cell transplantation (HSCT) from
partially compatible donors to adult patients with leukaemia and other high-risk haematologic malignancies. It is administered from the 21st day post-transplantation and foresees up to a maximum of 4 infusions per patient based on the achievement of immune-reconstitution.
- Zalmoxis® is an advanced therapy medicinal product (ATMP).
Company: MolMed (Italy)
- adjunctive treatment in hematopoietic stem cell transplantation (HSCT) for patients affected by high risk leukaemia
- • On January 25, 2018, Dompé announcesd the submission of the medical dossier for Zalmoxis® to the Federal Joint Committee on 15 January 2018. With this, the company fulfilled an important prerequisite for the launch of the therapy in Germany. Zalmoxis® is developed and produced by MolMed. Per a Europe-wide licensing and distribution agreement, Dompé oversees the product’s promotion and marketing in Germany.
- Zalmoxis® can be now prescribed and reimbursed in Germany at a price valid for twelve months during which the additional benefits of this innovative therapy for patients will be assessed by the German authorities.
- • On December 13, 2017, MolMed announced that it obtained its first national marketing authorization for Zalmoxis®. The Board of Directors of AIFA (Agenzia Italiana del Farmaco) approved the agreement negotiated between AIFA’s Prices and Reimbursement Committee (CPR) and MolMed, in which the price and reimbursement for Zalmoxis® medicinal product were defined.
- The terms of the agreement provide for an ex-factory price, excluding VAT, of €149,000 per infusion, gross
of discounts foreseen by law and of selective reductions foreseen by AIFA Resolutions of 3 July 2006 and 27 September 2006. Furthermore the agreement also set a flat fee per patient and a safeguard clause on sales for the first 24 months. Given the nature of the product, it will be a hospital-only dispensed therapy.
- • On June 13, 2017, MolMed, according with the post authorisation procedure, submitted to the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), the application for an annual renewal of the Conditional Marketing Authorisation for Zalmoxis®. As expected, the CHMP recommended the renewal of the CMA granted to Zalmoxis®. The CHMP, on the basis of the evidence of compliance with the specific obligations submitted by the company, is of the opinion that the risk-benefit balance of Zalmoxis® remains favourable and therefore recommended the renewal of the conditional marketing authorisation. The CHMP has forwarded the opinion to the European Commission, who will grant the formal renewal.
- • On August 22, 2016, MolMed announced that the European Commission has granted a Conditional Marketing Authorisation (CMA) for Zalmoxis®, the first immunogene therapy, as patient-specific adjunctive treatment in haplo-identical haematopoietic stem-cell transplantation (HSCT) for adult patients with high-risk haematological malignancies. The CMA decision was based on cumulative efficacy and safety data collected from patients enrolled in the Phase I-II trial (TK007) and in the currently ongoing pivotal randomised Phase III study (TK008).
The Zalmoxis group comprised 30 patients from the TK007 trial and 15 patients from the experimental arm of the ongoing TK008 trial. The TK007 trial included patients with various types of high-risk hematologic 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 leukemia.
The data showed the ability of Zalmoxis in providing patients undergoing haploidentical transplantatio n with rapid immune reconstitution, anti-leukaemia effect and complete control of GvHD, in absence of any post transplantation immunosuppression. Overall, these effects led to a clinically meaningful increase in survival rates in Zalmoxis-treated patients, when compared to historical control patients from the database of European Group for Blood and Marrow Transplantation (EBMT) Society. Currently, there are neither approved therapy nor widely accepted standard of care able to overcome the two problems that continue to account for most of the non-relapse deaths, opportunistic infections and GVHD, as well as to increase survival rates after haploidentical HSCT. Importantly, the comparison with control patients confirmed that the survival improvement in Zalmoxis-treated patients was specifically driven by a reduction in mortality due to both infection and GvHD. Concerning safety, the only adverse event related to Zalmoxis treatment was GvHD, which fully resolved by the activation of the suicide gene system with ganciclovir treatment, without any GvHD- related death.
Following CE authorisation, patients found eligible will receive treatment with Zalmoxis through dedicated centres of excellence and TK cells will be manufactured at MolMed’s facilities, located at the San Raffaele Biotechnology Department (DIBIT) in Milan and at Open Zone scientific park in Bresso (Milan), where MolMed has recently completed a new manufacturing site, which will substantially increase the current production capacity, waiting for gradual AIFA authorisation by the end of 2016.
- • On June 23, 2016, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), in conjunction with the Committee for Advanced Therapies (CAT), has issued a positive opinion recommending conditional marketing authorisation for Zalmoxis®, the first immunogene therapy as patient-specific adjunctive treatment in haplo-identical haematopoietic stem-cell transplantation (HSCT) for adult patients with high-risk haematological malignancies. Zalmoxis® significantly increases long-term survival, regardless of disease status at transplant, thus making HSCT from partially compatible donors safer and more effective.
Zalmoxis® will be available as dispersion for infusion. Zalmoxis® showed that survival rate was 49% after one year with Zalmoxis®, compared with data from databases of 140 patients who had undergone haploidentical HSCT without Zalmoxis®, where survival rate was 37%.
The most common side effect was acute graft-versus-host disease.
The full indication is: "Zalmoxis® is indicated as adjunctive treatment in haploidentical haematopoietic stem cell transplantation (HSCT) of adult patients with high-risk haematological malignancies". It is proposed that
Zalmoxis be prescribed by physicians experienced in the haematopoietic stem cell transplantation for
- • On March 26, 2014, MolMed has announced that the European Medicines Agency has validated the submission of the Conditional Marketing Authorisation for TK, a novel proprietary investigational cell-gene therapy. The data review of the submitted dossier starts today. The company has also announced that the Company has been invited by the European Society for Blood and Marrow Transplantation (EMBT) to illustrate the scientific and regulatory path of TK which – with more than 120 patients treated so far - is the largest cell-gene therapy application ever performed. Claudio Bordignon, CEO and president of the Board, will give a presentation on the topic next Tuesday 1st of April during the plenary session of the 40th annual meeting of the EMBT, which will be held in Milan from March 30th to April 2nd
- • On March 7, 2014, MolMed has announced that the Company has filed to the European Medicines Agency an application for Conditional Marketing Authorisation for TK, its novel investigational cell-gene therapy. TK is an adjunctive treatment in hematopoietic stem cell transplantation (HSCT) for patients affected by high risk leukaemia. The Conditional Marketing Authorisation application is supported by cumulative efficacy and safety results obtained from a completed Phase I-II, multicentre trial (TK007). These data were included in presentations given at the 49th annual congress of the American Society of Clinical Oncology (ASCO) and at the 55th Annual Meeting of the American Society of Hematology (ASH) in 2013. Results show that TK can reduce transplant-related mortality and increase overall survival in high risk leukaemia patients transplanted from a mismatched HSCT donor. The application also includes initial data from the currently ongoing pivotal randomised Phase III study (TK008), which have been submitted to the next ASCO congress taking place in May in Chicago. The TK therapy was granted Orphan Drug Designation by the European Commission.
- • On February 3, 2014, MolMed has provided an update on the registration strategy for its gene therapy TK in Europe and in the US. With regard to the Conditional Approval procedure in EU, after two meetings with the national agencies from rapporteur and co-rapporteur member states designated by the European Medicines Agency (EMA), the Company confirms the expected filing date of the application in the first quarter of 2014.
- As far as the Breakthrough Therapy submission is concerned, the FDAhas not - at this time - granted the designation for the cell therapy TK as adjunctive treatment in hematopoietic stem cell transplantation (HSCT) for adult patients affected by high risk acute leukaemia. However, the FDA indicates that the Company can submit a new request once new clinical evidence becomes available. According to this suggestion, MolMed intends to re-apply for Breakthrough Therapy designation in the US since new evidence is now becoming available, including initial efficacy data from the ongoing Phase III clinical trial. These data will be submitted for presentation at next meeting of the American Society of Clinical Oncology (ASCO).
- Currently, a pivotal randomised Phase III trial in adult patients affected by high-risk leukaemia undergoing transplant of haematopoietic stem cells collected from partially compatible (haploidentical) family donors is ongoing. The TK008 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.
- • On November 21, 2013, Molmed has announced that this coming Monday, 25 November, the company will meet the EMA authorities in a pre-submission meeting to discuss the European registration plan in order to finalize the application for the conditional approval of its gene therapy TK. Molmed now expects to submit the final application in Q1 2014. The company will also expand its registration strategy with the submission to the FDA of a request for Breakthrough Therapy designation. This decision follows the recently announced start in the USA of patient's recruitment in the phase 3 clinical trial (TK008).
- • On January 13, 2014, MolMed has announced receipt of the official notification from the European Patent Office of the decision to grant a patent covering stable constitutive packaging cell lines for lentiviral vectors. The patent will formally be granted on the 12th of February 2014 when it will be published in the European Patent Bulletin. This new European patent (EP2480678) will be part of a proprietary patent family which comprises 13 patent applications covering constitutive stable packaging cell lines for lentiviral vectors filed in the most important pharmaceutical markets, including the United States, Japan, Canada, Australia and China.
The patent will provide protection until 2031 and will give right to market exclusivity in 40 European countries, including European Union member states, Eastern Europe countries, Switzerland and Turkey. MolMed further strengthens its patent portfolio on cell and gene therapy consisting of ten patent families, which includes 106 granted patents and 35 pending applications, covering genes for the treatment of genetic diseases and tumours, methods and technologies for hematopoietic stem cells and T cells manipulation, viral vectors production systems and packaging cell lines for the production of retroviral vectors and for stable and semi-stable production of lentiviral vetors.
- • On August 17, 2011, MolMed announced that the European Patent Office granted a key patent covering the gene forming the basis of TK, MolMed’s investigational cell therapy product currently in Phase III for the treatment of high-risk leukaemia. The new European composition of matter patent (EP1781789) is part of a large patent family owned by MolMed and covers a non-splicing variant of the HSV-TK gene, i.e. a variant that is transcribed in a stable and unmodifiable manner. The patent, affording patent protection until 2025 with the possibility of a 5-year term extension, guarantees market exclusivity in 29 designated countries within the European Patent Convention, including all major countries of the European Union, Switzerland and Turkey. Equivalent patent applications are pending in the United States, Japan and important emerging markets.
The new European patent strengthens the intellectual property position of MolMed on TK, consisting of 11 patent families - all granted patents in Europe - covering the following components of the TK technology: the retroviral vector carrying the HSV-TK gene for therapeutic use, the non-splicing variants of the gene, the marking and selection of transduced human cells and all relevant production processes, including the manufacturing of TK cells in a closed system. The overall TK intellectual property portfolio consists of a total of 137 granted patents and 16 pending applications.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE: 2014-03-07
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
UE authorization: 2016-08-22
Favourable opinion UE: 2016-06-23
Favourable opinion USA:
Orphan status USA:
Orphan status UE: 2003-09-17
Pediatric exclusivit _USA:
Pediatric exclusivity UE: