dm+d

Unassigned

New Medicines

AlofiselComplex perianal fistulas in adults with Crohn's disease

Information

Alofisel
New molecular entity
Takeda Pharmaceuticals
TiGenix

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Phase III Clinical Trials
Yes
May 21Takeda will need to assess the data from ADMIRE-II when it reads out to determine whether it is sufficient to overcome the uncertainty identified at the last NICE appraisal. Timeline for possible UK availability is uncertain for now [25].
Jul 20Takeda is planning to make this available in the UK and presumably re-submit to NICE with data from PIII ADMIRE-CD-II which are due in 2022 [23].
Jan 19Darvadstrocel will not be made commercially available in the UK until it has received NICE/SMC approval [21].
Jun 18The NHS list price of darvadstrocel is £54,000.00 per treatment (4 vials). However, it is not yet commercially available and there is currently no launch date [20].
Mar 18Approved in EU for the treatment of complex perianal fistulas in adult patients with nonactive/mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response to at least one conventional or biologic therapy. Alofisel should be used after conditioning of fistula [19].
Dec 17EU positive opinion: the indication will be "for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response to at least one conventional or biologic therapy. Alofisel should be used after conditioning of fistula". It is proposed that it should be administered only by relevant specialists [16].
Jun 17Takeda Pharma is positioning itself to take over stem cell production of Cx601 in Europe from its partner TiGenix by 2021. The drug is currently being produced by TiGenix at its Madrid facility, but Takeda has not said whether this will continue, or whether production will transfer to an alternative location. TiGenix currently has US rights to the compound, and has said it is in discussions with the FDA to work toward garnering marketing approval [14].
Mar 17The licensing authority raised issues which the company hope will be addressed by August 2017, delaying potential EU approval to the end of the year [15].
Mar 17Company announces that it has received the formal Day 180 List of Outstanding Issues from the EMA and entered the clock-stop period of the authorisation timeline. The company is confident that it can provide appropriate responses to the issues raised and still expects to receive EU Marketing Authorisation in 2017 [13].
Jul 16TiGenix enters an exclusive licensing agreement with Takeda Pharmaceuticals for development and commercialisation of Cx601 outside the US. Takeda have made upfront payment and will make a first milestone payment when the EU MAA is granted: these will allow initiation of a PIII trial in the US, which is expected to account for 50% of the global market [12].
Mar 16Filed in EU [9].
Sep 15TiGenix suggest that positive data from the ADMIRE-CD trial will allow for European filing in the Q1 of 2016 and moving forward in the US with the SPA-approved pivotal study [8].
Jun 15TiGenix begins process for Marketing Authorisation Application for Cx601 in the treatment of complex perianal fistulas in patients with Crohn´s disease. TiGenix announced that it has submitted a letter of intent to file, and a request for the assignment of Rapporteur/Co-Rapporteur to the EMA as part of the process. In parallel, TiGenix has submitted the request in order to be eligible for the centralised procedure for the approval of medicinal products in the EU which Cx601 falls within the mandatory scope of because it is an Advanced Therapy Medicinal Product and an Orphan-designated product [6].
Mar 15Completion date for ADMIRE-CD study has moved to Jan 2016 [5].
Apr 14Results from the PIII ADMIRE-CD trial are expected H1 2015 [4].
Mar 13Final data from ADMIRE-CD trial are expected in 2014. The EMA indicated that this trial might be sufficient to support an EU licence application [3].

Category

Cell replacements, a suspension of expanded allogeneic stem cells from adipose tissue of donors
The estimated prevalence of Crohn’s disease in England is 164 to 182 per 100,000 people, with an incidence of 4,500. About 20% will develop a perianal fistula, and 30% of these have recurrent fistulas.
Complex perianal fistulas in adults with Crohn's disease
Intralesional

Further information

Yes
January 2019

Trial or other data

May 21PIII ADMIRE-CD-II study is still recruiting and is now due to finish collecting primary outcome data in Aug 22 [24].
Jul 20PIII ADMIRE-CD-II study is recruiting (NCT03279081). The study began in Sep 2017 and its purpose is to evaluate the combined remission of complex perianal fistulas, defined as the clinical assessment at Week 24 of closure of all treated external openings that were draining at baseline despite gentle finger compression, and absence of collections greater than (>) 2 centimeter (cm) (in at least 2 dimensions) confirmed by blinded central magnetic resonance imaging (MRI) assessment at Week 24. 554 adults are being recruited in countries including the US, EU & UK. Collection of primary outcome data is due to complete Mar 22 [22].
Jan 19NICE does not recommend darvadstrocel for use. The additional evidence submitted after consultation did not clarify the uncertainties around long-term benefits of darvadstrocel. The committee considered that further research in this area would be beneficial [21].
Jan 18Final results of the PIII ADMIRE-CD trial (52-week data) published in Gastroenterology. The data show that Cx601 maintained long-term remission of treatment refractory complex perianal fistulas in pts with Crohn´s disease [18].
Sep 16Results of ADMIRE-CD trial published in The Lancet. RCT (n=212) found a significantly greater proportion of patients treated with allogeneic, expanded, adipose-derived stem cells achieved combined remission at week 24 vs. placebo (50% vs. 34%, p=0.024) [11].
Mar 16TiGenix announces 52-week data from the ADMIRE-CD trial. A single injection of Cx601 was statistically superior to placebo in achieving combined remission at week 52 in the treatment of complex perianal fistulas in Crohn´s disease patients with inadequate response to previous therapies, including anti-TNFs. 54.2% of patients treated with Cx601 achieved combined remission at week 52 compared to 37.1% in the placebo arm. 75.0% of Cx601 treated patients who achieved combined remission at week 24 remained in combined remission at week 52 compared to only 55.9% in the placebo arm [10].
Sep 15Cx601 met the primary endpoint in the PIII ADMIRE-CD trial of complex perianal fistula in pts with Crohn´s Disease. Cx601 is a suspension of allogeneic expanded adipose-derived stem cells (eASC) injected intra-lesionally. A single injection of Cx601 was statistically superior to placebo in achieving combined remission at wk 24, in pts with inadequate response to previous therapies, including anti-TNFs. A higher number of Cx601-treated pts had their fistulas closed by week 6 The study results confirm the favourable safety and tolerability profile of Cx601 [8].
Aug 15The FDA has endorsed Special Protocol Assessment for the Cx601 Phase III Registration Trial in the US. The randomised, double-blind phase III trial (n=224) will evaluate the efficacy and safety of Cx 601 in the treatment of perianal fistulas in patients with Crohn´s disease. Data from the phase III ADMIRE-CD trial and this trial will support the company´s planned BLA submission [7].
Jun 15Cx601 is currently completing the pivotal PIII randomised, double-blind, placebo-controlled Phase III trial in Europe and Israel, which is intended to support filing. Recruitment of the whole sample of patients was completed in the fourth quarter of 2014. Results are expected during Q3 of 2015 with intention to submit a request for MA with the EMA in early 2016 [6].
Jul 12The first pt enrolled in the ADMIRE-CD trial. The ADMIRE-CD (Adipose Derived Mesenchymal stem cells for Induction of REmission in perianal fistulising Crohn´s Disease) PIII trial 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. The objective is to demonstrate safety and efficacy, which is defined as closure and/or remission after 24 weeks [1].

Evidence based evaluations