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Clinical Trials

Date: 2017-02-17

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 12th Congress of the European Crohn's and Colitis Organisation (ECCO)

Company: Tigenix (Belgium)

Product: Cx601 (adipose derived allogeneic stem cell therapy)

Action mechanism:

Cell therapy. Cx601 is a suspension of expanded allogeneic adult stem cell product derived from human adipose (fat) tissue (expanded Adipose derived Stem Cells or eASCs) that is delivered locally in the fistula through intra-lesional injection.

In July 2015, Takeda Pharmaceutical and TiGenix  have entered into an exclusive ex-U.S. license, development and commercialization agreement for Cx601.

In March 2016, TiGenix announced that it submitted the Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Cx601.  If granted, Takeda will become the Marketing Authorization holder and will be responsible for all commercialization and regulatory activities.

Disease: perianal fistulas in Crohn's disease patients

Therapeutic area: Autoimmune diseases - Inflammatory diseases - Digestive diseases

Country: Austria, Belgium, France, Germany, Israel, Italy, The Netherlands, Spain

Trial details:

The ADMIRE-CD (Adipose Derived Mesenchymal stem cells for Induction of REmission in perianal fistulising Crohn's disease) Phase III trial has been designed in accordance with EMA requirements. It is a randomized, double-blind, placebo controlled international trial conducted in 46 centers, across 8 countries. Approximately 200 patients are to be enrolled. Key inclusion criteria are up to 2 internal openings and up to 3 external openings, and non-active luminal Crohn's disease. Patients included had an inadequate response to previous therapies, including anti-TNFs.  The objective is to demonstrate safety and efficacy, which is defined as closure and/or remission after 24 weeks. (NCT01541579)

 

Latest news:

* On February 17, 2017, Takeda Pharmaceutical and TiGenix announced new data from the Phase 3 ADMIRE-CD clinical trial, which indicated that investigational compound Cx601 maintained long-term remission of treatment refractory complex perianal fistulas in patients with Crohn's disease over 52 weeks. Results were presented at the 12th Congress of the European Crohn's and Colitis Organisation (ECCO).
 A significantly greater proportion of patients in the Cx601 group versus in the control group achieved clinical and radiological combined remission (56.3% and 38.6%; p=0.010), and clinical remission (59.2% and 41.6%; p=0.013) at week 52 in the modified intention-to-treat population (mITT). Of those mITT patients who had shown combined remission at week 24, a greater number in the Cx601 group versus the control group reported no relapse at week 52 (75.0% and 55.9%). The rates and types of treatment related adverse events (non-serious and serious) and discontinuations due to adverse events were indicated to be similar in both groups (Cx601: 20.4%; control: 26.5%).
In March 2016, TiGenix announced that it submitted the Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Cx601, and a decision by the EMA is expected in 2017. A global pivotal Phase 3 trial for US registration with Cx601 for the treatment of complex perianal fistulas is expected to be initiated by TiGenix in 2017. In the U.S., TiGenix intends to apply for fast track designation from the FDA.

*  On August 2, 2016, Takeda Pharmaceutical and TiGenix announced that the 24-week results of the Phase 3 ADMIRE-CD trial investigating Cx601 have been published in The Lancet. The trial has been designed to investigate the efficacy and safety of a single treatment of Cx601 for the treatment of complex perianal fistulas in Crohn's disease patients. A significantly greater proportion of patients in the Cx601 group versus the placebo group achieved the primary endpoint of combined remission (defined as clinical assessment of closure of all treated external openings draining at baseline, despite gentle finger compression, and absence of collections >2cm confirmed by MRI) at week 24 in the ITT population 53 (50%) of 107 vs 36 of 105 (34%), respectively (97.5% CI 0.2-30.3; p=0.024) and the mITT population 53 (51%) of 103 vs 36 (36%) of 101 (0.5-31.2; p=0.021). These results were confirmed in the per-protocol population and in additional supportive and sensitivity analyses. This definition of remission is more stringent than those commonly used in clinical trials on perianal fistulizing disease, as it includes both clinical and radiological assessment by MRI.  Treatment-emergent adverse events (non-serious and serious) and discontinuations due to adverse events were comparable between Cx601 and placebo arms.
In addition, severity of perianal Crohn's disease was assessed at baseline and all study visits with the Perianal Disease Activity Index (PDAI). In the mITT population, the PDAI score was similar in the Cx601 and the placebo groups at baseline. The improvement in PDAI with Cx601 was significantly greater than placebo at week 6, 12 and 18. In addition, the mean total PDAI score at week 24 with Cx601 (4.4) was close to the threshold for inactive perianal disease (PDAI<4) at which patients do not need medical or surgical treatment.
A pivotal Phase 3 trial for Cx601 for the treatment of complex perianal fistulas is expected to start in the United States in 2017. In the U.S., TiGenix intends to apply for fast track designation from the FDA.
* On May 18, 2016, TiGenix, an advanced biopharmaceutical company focused on developing and commercializing novel therapeutics from its proprietary platforms of allogeneic expanded stem cells, announced that the company will present the week 24  results from its Phase III ADMIRE-CD pivotal study of Cx601 at the 2016 Digestive Disease Week (DDW) in San Diego. These results will be presented by Professor Julian Panés, Head of the Gastroenterology Department, at the Hospital Clinic of Barcelona and Chairman of the TiGenix ADMIRE-CD Scientific Advisory Board in Europe, at the DDW session dedicated to Controlled Clinical Trials in Inflammatory Bowel Diseases on May 24, 2016.  In this double-blind, placebo controlled, randomized Phase III study, Cx601 met the primary endpoint of combined remission of complex perianal fistulas at week 24. As recently reported, Cx601 continued to show a sustained effect at week 52, while confirming the favorable safety and tolerability profile of the treatment. Combined remission is defined as the clinical assessment of the closure of all treated external openings draining at baseline combined with the absence of collection >2 of the treated perianal fistulas confirmed by central blinded MRI, and it is a more stringent definition of remission than the one commonly used in clinical trials on perianal fistulizing disease. TiGenix submitted a Marketing Authorization Application for Cx601 in first quarter of 2016 to the European Medicines Agency, and expects to begin marketing in European markets in the second half of 2017.

* On March 17, 2016, TiGenix announced the presentation of the 24 week results from the Phase III ADMIRE-CD pivotal trial of Cx601 for complex perianal fistulas in Crohn's disease patients, in a plenary session at the 11th Annual Congress of the European Crohn's and Colitis Organisation (ECCO) in Amsterdam, The Netherlands. As already reported, a single injection of Cx601 achieved statistically significant superiority vs. placebo in the primary efficacy endpoint of combined remission at week 24 (defined as clinical assessment of closure of all treated external openings draining at baseline, despite gentle finger compression, and absence of collections >2cm confirmed by MRI; p=0.024). This definition of remission is more stringent than those commonly used in clinical trials on perianal fistulizing disease, as it includes both clinical and radiological assessment by MRI. The abstract describing the 24-week results of Cx601 was selected as one of the thirty best abstracts deserving an oral presentation at the meeting's plenary session. The presentation was given by Prof. Dr. Julián Panés, Global Study Coordinator and Head of the Inflammatory Bowel Diseases Unit at the Hospital Clínic of Barcelona, on Thursday, March 17.

Prof. Panés described the consistency of the 24 week secondary endpoints which on the treated population showed improvements in both response (clinical closure of at least 50% of all treated external openings that were draining at baseline; p=0.039) and clinical remission (clinical closure of all treated external openings that were draining at baseline despite gentle finger compression; p=0.052). Furthermore, the PDAI score, an index that measures the severity of the disease, fell by more than 30% in the Cx601 group and maintained a statistically significant difference at 6, 12 and 18 weeks over placebo. Finally, Prof. Panés underlined the favorable safety and tolerability profile of the local treatment with Cx601, in contrast to the systemic immunosuppression of anti-TNF therapy and thiopurines, currently used in treating fistulizing Crohns disease.

* On March 7, 2016, TiGenix announced that a single injection of Cx601 was statistically superior to placebo in achieving combined remission at week 52 in the Phase III ADMIRE-CD trial in Crohn's disease patients with complex perianal fistulas with inadequate response to previous therapies, including anti-TNFs. The one-year data also confirm the favorable safety and tolerability profile of Cx601 already reported at week 24. In the ITT  population (n=212), Cx601 achieved statistical superiority (p=0.012) with 54.2% combined remission at week 52 compared to 37.1% in the placebo arm. In the mITT[3] population (n=204), the combined remission at week 52 was 56.3% and 38.6% for Cx601 and placebo respectively (p=0.010). Efficacy results were robust and consistent across all statistical analyses. The week 52 data also shows a higher rate of sustained closure in those patients treated with Cx601 and in combined remission at week 24 (75.0%) compared to patients in the placebo group (55.9%). Treatment-emergent adverse events (non-serious and serious) and discontinuations due to adverse events were comparable between Cx601 and placebo groups.

* On August 23, 2015, TiGenix, an advanced biopharmaceutical company focused on developing and commercialising novel therapeutics from its proprietary platforms of allogeneic expanded stem cells, announced that its lead compound Cx601 met the primary endpoint in the Phase III ADMIRE-CD trial in Crohn's disease patients with complex perianal fistulas. A single injection of Cx601 was statistically superior to placebo in achieving combined remission at week 24, in patients with inadequate response to previous therapies, including anti-TNFs. The study results confirm the favourable safety and tolerability profile of Cx601. In total, 289 patients were recruited across 50 active sites in 7 European countries and Israel. Patients included had an inadequate response to previous therapies, including anti-TNFs. Continuation of medical standard of care was allowed during the duration of the trial in both groups. The study primary endpoint was combined remission at week 24, defined as closure of all treated external openings draining at baseline despite gentle finger compression, and absence of collections >2cm confirmed by MRI. In the ITT[ population (n=212), Cx601 achieved statistically significant superiority (p<0.025) with 49.5% combined remission at week 24 compared to 34.3% in the placebo arm. In the mITT population (n=204), the combined remission rates at week 24 were 51.5% and 35.6% for Cx601 and placebo, respectively (p<0.025). These results translate into an observed relative risk of 1.44, meaning that patients receiving Cx601 had 44% more chances to achieve combined remission than placebo patients. Efficacy results were robust and consistent across all statistical populations. Treatment-emergent adverse events (non-serious and serious) and discontinuations due to adverse events were comparable between Cx601 and placebo arms. Full efficacy and safety results will be presented at the 11th Congress of ECCO (European Crohn's and Colitis Organisation). These positive data allow for European filing in the first quarter of 2016 and moving forward in the US with the SPA-approved pivotal study.

* On November 12, 2014, TiGenix announced that it has completed the patient recruitment for its Phase III trial of Cx601 in Europe for the treatment of complex perianal fistulas in Crohn's patients. The trial has recruited more than 278 patients across 51 centres in 7 European countries and Israel. The study's primary endpoint is remission of fistulous disease, defined as 100% healing of the tracts. The first complete analysis of results will be at 24 weeks, with a follow-up analysis to be performed at 52 weeks post-treatment. Evaluation of healing includes both clinical assessment and MRI confirmation (lack of abscesses larger than 2 cm²). This pivotal study is intended to allow filing for marketing authorisation in Europe, and to serve as a key supportive study in filing for approval in other territories, including the United States.

Following the positive feedback received at a meeting with the Center for Biologics Evaluation and Research within the FDA, TiGenix is moving ahead with the development of Cx601 for the United States market. The Company will start the process of technology transfer to a US-based contract manufacturing organization (CMO) later this year. Also by the end of this year, TiGenix will file a special protocol assessment (SPA) with the FDA in order to be able to file an investigational new drug (IND) application for a Phase III trial in the United States. That SPA file will be prepared by the company in cooperation with its US advisory board of North American clinical experts in gastroenterology and inflammatory bowel disease. The Phase III trial in the US, if successful, together with positive data from the European Phase III trial, would enable the Company to file a biologics license application (BLA) with the FDA.

* On July 10, 2012, Tigenix has announced the enrolment of the first patients in the ADMIRE-CD trial, its pivotal Phase III clinical trial with Cx601 in perianal fistulas in Crohn's disease patients at Hospital Clínic, Barcelona, Spain. The main objectives of the study are to demonstrate safety and superior efficacy over placebo in perianal fistulas in Crohn's disease patients after failure with their previous treatment  and to confirm the strong safety and efficacy results from the Phase II trial completed in 2011.  Final results of ADMIRE-CD are expected towards the end of 2014. TiGenix has received a € 5M soft loan from Madrid Network to support funding of the Phase III trial.

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