Takeda Pharmaceutical Company Limited (Takeda) and TiGenix NV (TiGenix) announced that the companies have entered into an exclusive ex-US license, development and commercialization agreement for Cx601, a suspension of allogeneic adipose-derived stem cells (eASC) injected intra-lesionally for the treatment of complex perianal fistulas in patients with Crohn’s disease.

TiGenix will receive an upfront cash payment of €25 million. TiGenix will be eligible to receive additional regulatory and sales milestone payments for up to a potential total of €355 million and double digit royalties on net sales by Takeda.

The first anticipated milestone payment is €15 million upon obtaining the Marketing Authorization of Cx601 in the European Economic Area (EEA). In addition, Takeda will make an equity investment of €10 million in the share capital of TiGenix within the next 12 months.

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract. People living with Crohn’s disease often experience complex perianal fistulas for which there are limited treatment options. Recognizing the debilitating nature of the disorder and the lack of treatment options, in 2009 the European Commission granted Cx601 orphan designation for the treatment of complex perianal fistulas. In March 2016, TiGenix announced that it submitted the Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Cx601. The filing was based on the 24 week results of the ADMIRE-CD phase 3 clinical trial. The company also recently announced top-line 52 week data confirming the efficacy and safety of a single injection of Cx601.

Following Marketing Authorization in the European Union, Takeda will become the marketing authorization holder and will be responsible for all commercialization and regulatory activities. Takeda will also be responsible for additional development activities of Cx601 for the indication of complex perianal fistulas in Crohn’s disease. TiGenix will retain the rights to develop Cx601 in new indications.

“In Europe approximately one million people suffer from Crohn’s disease, with rising incidence. As a leader in gastroenterology, Takeda aspires to bring innovative treatments to patients where unmet medical needs exist,” said Marc Princen, president of Europe and Canada, Takeda. “This collaboration and the addition of Cx601 to our portfolio highlights Takeda’s commitment to the development of treatments to improve the health of people living with gastroenterological disorders, leveraging our expertise in Inflammatory Bowel Disease and Crohn’s specifically.”

“TiGenix is pleased to partner with Takeda, a global pharmaceutical company with a strong track record and strong leadership position in gastroenterology. This agreement reduces the investment risks associated with building a pan-European marketing and selling infrastructure, and helps get this much-needed treatment option to patients and gives to Cx601 the best partner with the needed capabilities and resources to secure its commercial success” said Eduardo Bravo, CEO, TiGenix. "This agreement further provides TiGenix with the financial strength to move forward with the clinical development of Cx601 in the US, which represents approximately 50 per cent of the world’s Crohn’s market."

Cx601 is a suspension of allogeneic expanded adipose-derived stem cells (eASC) injected intra-lesionally. Cx601 is being developed for the treatment of complex perianal fistulas in Crohn’s disease patients. Crohn’s disease is a chronic inflammatory disease of the intestine and patients can suffer from complex perianal fistulas for which there is currently no effective treatment.

In 2009, the European Commission granted Cx601 orphan designation for the treatment of perianal fistulas, recognizing the debilitating nature of the disease and the lack of treatment options. Based on positive phase II results, TiGenix sought scientific advice from the European Medicines Agency (EMA) on the future development path of Cx601. TiGenix then initiated a randomized, double-blind, placebo-controlled phase III trial in Europe and Israel designed to comply with the requirements laid down by the EMA (the ADMIRE-CD trial).

‘Madrid Network’, an organization within the Autonomous Region of Madrid which helps companies to grow through high-technology innovation, issued a soft loan to help finance this Phase III study. The programne is funded by The Secretary of State for Research, Development and Innovation (Ministry of Economy and Competitiveness) within the framework of the INNTEGRA plan. The study’s primary endpoint was combined remission, defined as clinical assessment at week 24 of closure of all treated external openings draining at baseline despite gentle finger compression, and absence of collections >2cm confirmed by MRI.

In the ADMIRE-CD trial, the results of which were reported in August 2015, Cx601 achieved statistically significant superiority (p<0.025) on the primary endpoint with 49.5% combined remission at week 24 compared to 34.3% in the placebo arm in the ITT population. These results translate into a relative risk of 1.44, meaning that patients receiving Cx601 had a 44% greater probability of achieving 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.

The ADMIRE-CD trial has completed a follow-up analysis at 52 weeks post-treatment. Based on the positive 24 week phase III results, TiGenix has submitted a Marketing Authorization Application to the EMA in early 2016. TiGenix is preparing to develop Cx601 for the US market after having reached an agreement with the FDA through a special protocol assessment, or SPA, procedure on its proposed protocol on August 7, 2015.

TiGenix NV is an advanced biopharmaceutical company focused on developing and commercialising novel therapeutics from its proprietary platforms of allogeneic, or donor-derived, expanded stem cells.