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On 14 December 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Alofisel, intended for the treatment of complex perianal fistulas in patients with Crohn’s disease. As Alofisel is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. Alofisel was designated as an orphan medicinal product on 8 October 2009. The applicant for this medicinal product is Tigenix, S.A.U.
Alofisel will be available as a suspension for injection (5 million cells/ml). The active substance of Alofisel is darvadstrocel. Darvadstrocel contains expanded adipose stem cells which, once activated, impair proliferation of lymphocytes and reduce the release of pro-inflammatory cytokines at inflammation sites. This immunoregulatory activity reduces inflammation and may allow the tissues around the fistula tract to heal.
The benefits with Alofisel are its ability to improve the healing process of complex perianal fistulas in patients with Crohn’s disease. The most commonly reported side effects include anal abscess and fistula, as well as procedural pain and proctalgia.
The full indication is: “Alofisel is indicated 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, see section 4.2.”
It is proposed that Alofisel be administered by specialist physicians experienced in the diagnosis and treatment of conditions for which Alofisel is indicated.
Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
|INN or common name||darvadstrocel|
|Therapeutic area||Rectal Fistula|
|Date opinion adopted||14/12/2017|
|Company name||Tigenix, S.A.U.|
|Application type||Initial authorisation|
Cx601 is a local administration of expanded adipose-derived stem cells (eASCs) for the treatment of complex perianal fistulas in Crohn’s disease patients. The treatment is administered as a single dose and has been proven to have long-term efficacy in the healing of complex perianal fistulas in Crohn’s disease patients (ADMIRE-CD study completed in 2015 with positive 2 year follow-up data). The 24-week results of this trial were published in The Lancet in July 2016.
Cx601 has been designated as an orphan drug by the EMA and SwissMedic, in Switzerland.
On 4th July 2016, Takeda Pharmaceuticals acquired an exclusive right to develop and commercialize Cx601 for complex perianal fistulas in Crohn’s disease patients outside of the U.S. Takeda is a leading pharmaceutical company in the gastroenterology space. TiGenix retains full rights to the product in the US as well as to the development of Cx601 in other indications.
- DeveloperLa Fundacion para la Investigacion Biomedica del Hospital Universitario La Paz; Takeda; TiGenix
- ClassStem cell therapies
- Mechanism of ActionCell replacements
- Orphan Drug StatusYes – Rectal fistula
- New Molecular EntityNo
Highest Development Phases
- PreregistrationRectal fistula
- No development reportedRectovaginal fistula
Most Recent Events
- 15 Dec 2017Committee for Medicinal Products for Human Use (CHMP) and Committee for Advanced Therapies (CAT) recommend approval for darvadstrocel for Rectal fistula in European Union
- 14 Dec 2017TiGenix in-licenses patents related to adipose-derived mesenchymal stem cells from Mesoblast
- 16 Nov 2017Cx 601 is now called darvadstrocel
New medicine to treat perianal fistulas in patients with Crohn’s disease
Alofisel is the tenth advanced therapy recommended for marketing authorisation
The European Medicines Agency (EMA) has recommended granting a marketing authorisation in the European Union (EU) for a new advanced therapy medicinal product (ATMP) for the treatment of complex perianal fistulas in patients with Crohn’s disease. Alofisel is the tenth ATMP that has received a positive opinion from the Agency’s Committee for Medicinal Products for Human Use (CHMP).
Crohn’s disease is a long-term condition that causes inflammation of the digestive system or gut. Apart from affecting the lining of the bowel, inflammation may also go deeper into the bowel wall. Perianal fistulas are common complications of Crohn’s disease and occur when an abnormal passageway develops between the rectum and the outside of the body. These can lead to incontinence (a lack of control over the opening of the bowels) and sepsis (blood infection). Complex fistulas are known to be more treatment resistant than simple fistulas. There is currently no cure for Crohn’s disease, so the aim of treatment is to stop the inflammatory process, relieve symptoms and avoid surgery wherever possible. Crohn’s disease can affect people of all ages, with a higher incidence in the younger population.
The active substance of Alofisel is darvadstrocel. Darvadstrocel contains expanded adipose stem cells which, once activated, impair proliferation of lymphocytes and reduce the release of pro-inflammatory cytokines at inflammation sites. This immunoregulatory activity reduces inflammation and may allow the tissues around the fistula tract to heal.
The benefits of Alofisel were studied in a main phase III clinical trial involving 212 patients. After 24 weeks of treatment, half of the patients treated with Alofisel (49.5%) were in remission, compared to a third of the patients under placebo. An extended ongoing follow-up study, which will cover a period of up to 104 weeks of treatment, has supported this result to date.
Although there is a moderate difference between the treatment groups, the effect is considered to be clinically meaningful when other treatment options for fistulas have failed. The most common side effects observed include anal abscess and fistula, as well as procedural pain and proctalgia.
Alofisel was assessed by the Committee for Advanced Therapies (CAT), EMA’s specialised scientific committee for ATMPs, such as gene or cell therapies. At its December 2017 meeting, the CAT recommended a positive opinion for Alofisel to the CHMP. The CHMP agreed with the CAT’s recommendation and adopted a positive opinion for the authorisation of Alofisel across the EU at its 11-14 December 2017 meeting.
Because complex perianal fistulas are rare, Alofisel was granted an orphan designation. As always at time of approval, this orphan designation will now be reviewed by EMA’s Committee for Orphan Medicinal Products (COMP) to determine whether the information available to date allows maintaining Alofisel’s orphan status and granting this medicine ten years of market exclusivity.
The opinion adopted by the CHMP is an intermediary step on Alofisel’s path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of this medicine in the context of the national health system of that country.
- First allogeneic stem cell therapy to receive positive CHMP opinion in Europe
- Cx601 offers potential new treatment option for patients who do not respond to current available therapies and are subject to numerous invasive surgeries1
Takeda Pharmaceutical Company Limited (TSE: 4502) (“Takeda”) and TiGenix NV (Euronext Brussels and NASDAQ: TIG) (“TiGenix”) today announced that 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 adopted a positive opinion recommending a marketing authorization (MA) for investigational compound Cx601 (darvadstrocel). Cx601 is expected to be indicated 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.2 This recommendation marks the first allogeneic stem cell therapy to receive a positive CHMP opinion in Europe.
“Following today’s news, physicians and surgeons in Europe can look forward to offering these Crohn’s disease patients a novel and minimally invasive alternative treatment option in the future, which in clinical trials achieved higher combined remission and lower relapse rates* than the current standard of care,” said Professor Julian Panés, Head of the Gastroenterology Department at the Hospital Clinic of Barcelona (Spain) and President of the European Crohn’s and Colitis Organisation (ECCO). “Perianal fistulas are estimated to affect up to 28% of patients in the first two decades after Crohn’s disease diagnosis and Cx601 offers new hope for those suffering from this severe and debilitating condition.”
Cx601 was assessed by the CAT, the EMA’s specialized scientific committee for Advanced Therapy Medicinal Products (ATMP), such as gene or cell therapies. The positive CHMP opinion was based on results from TiGenix’s Phase III ADMIRE-CD pivotal trial. The ADMIRE-CD trial is a randomized, double-blind, controlled, Phase III trial designed to investigate the efficacy and safety of investigational compound Cx601.3 24-week results were published in The Lancet and showed that Cx601 achieved statistically significant superiority versus the control group in the primary efficacy endpoint of combined remission.**,1 In addition, the rates and types of treatment related adverse events (non-serious and serious) and number of discontinuations due to adverse events were comparable between Cx601 and control arms, the most common of which were anal abscess and proctalgia.1Further follow-up data indicated that Cx601 maintained long-term remission of treatment refractory complex perianal fistulas in patients with Crohn’s disease over 52 weeks.4
Dr. María Pascual, VP Regulatory Affairs and Corporate Quality at TiGenix, said, “We believe that this first approval recommendation for an allogeneic stem cell therapy in Europe reflects the maturity of our technology and its potential to offer new approaches for difficult to treat conditions. We have worked closely with the EMA and provided a robust data package from a well-designed clinical trial with challenging endpoints. In parallel, we will continue working hard to obtain regulatory approval in the U.S. and to develop Cx601 for additional indications, to fulfil our aim of allowing patients to benefit from the full potential of Cx601 across multiple geographies and diseases.”
The opinion will now be referred to the European Commission with a decision anticipated in the coming months. An MA will allow Cx601 to be marketed in all 28 member states of the EU, plus Norway, Iceland and Lichtenstein.
Cx601 has been licensed to Takeda for the exclusive development and commercialization outside of the U.S. Receipt of the MA will trigger a milestone payment from Takeda to TiGenix of €15 million. The companies have been working closely together to advance preparations for commercialization, with a potential start of the commercial launch by Takeda anticipated after MA is transferred from TiGenix to Takeda.
“Today’s positive CHMP opinion is a crucial step to bringing a new treatment option to patients with complex perianal fistulas in Crohn’s disease,” said Dr. Asit Parikh, Head of Takeda’s Gastroenterology Therapeutic Area Unit. “We would like to thank the scientific community and patients involved in the ADMIRE-CD trial for their support in helping us reach this important milestone. We remain committed to delivering innovative, therapeutic options for patients suffering from gastrointestinal disorders.”
Complex perianal fistulas are considered one of the most disabling complications of Crohn’s disease5 and can cause intense pain6 and swelling, infection and incontinence.1 Despite available therapies and surgical advancements, they currently remain challenging for clinicians to treat7 and have a significant negative impact on patient quality of life.6
* Relapse defined as reopening of any of the treated external openings with active drainage as clinically assessed, or development of perianal collection ≥2cm of the treated perianal fistula confirmed by centrally blinded pelvic MRI assessment in patients with clinical remission at any previous visit
** 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 pelvic MRI
TiGenix NV (Euronext Brussels and NASDAQ: TIG) is an advanced biopharmaceutical company developing novel therapies for serious medical conditions by exploiting the anti-inflammatory properties of allogeneic, or donor-derived, stem cells.
TiGenix´ lead product, Cx601, has successfully completed a European Phase III clinical trial for the treatment of complex perianal fistulas – a severe, debilitating complication of Crohn’s disease. Cx601 has been filed for regulatory approval in Europe and a global Phase III trial intended to support a future U.S. Biologic License Application (BLA) started in 2017. TiGenix has entered into a licensing agreement with Takeda, a global pharmaceutical company active in gastroenterology, under which Takeda acquired the exclusive right to develop and commercialize Cx601 for complex perianal fistulas outside the U.S. TiGenix’ second adipose-derived product, Cx611, is undergoing a Phase I/II trial in severe sepsis – a major cause of mortality in the developed world. Finally, AlloCSC-01, targeting acute ischemic heart disease, has demonstrated positive results in a Phase I/II trial in acute myocardial infarction (AMI). TiGenix is headquartered in Leuven (Belgium) and has operations in Madrid (Spain) and Cambridge, MA (USA). For more information, please visit http://www.tigenix.com.
Cx601 is a local administration of allogeneic (or donor derived) expanded adipose-derived stem cells (eASCs) for the treatment of complex perianal fistulas in adult Crohn’s disease patients that have previously shown an inadequate response to at least one conventional therapy or biologic therapy. Crohn’s disease is a chronic inflammatory disease of the intestine and complex perianal fistulas are a severe and debilitating complication for which there is currently no effective treatment. Cx601 was granted orphan drug designation by the European Commission in 2009 and by the U.S Food and Drug Administration (FDA) in 2017. TiGenix completed a European Phase III clinical trial (ADMIRE-CD) in August 2015 in which both the primary endpoint and the safety and efficacy profile were met, with patients receiving Cx601 showing a 44% greater probability of achieving combined remission compared to control (placebo).1 A follow-up analysis was completed at 52 weeks4 and 104 weeks post-treatment, confirming the sustained efficacy and safety profile of the product. The 24-week results of the Phase III ADMIRE-CD trial were published in The Lancet in July 2016.1 Based on the positive 24 weeks Phase III study results, TiGenix submitted a Marketing Authorization Application to the European Medicines Agency (EMA). A global Phase III clinical trial (ADMIRE-CD II) intended to support a future U.S. Biologic License Application (BLA) started in 2017, based on a trial protocol that has been agreed with the FDA through a special protocol assessment procedure (SPA) (clinicaltrials.gov; NCT03279081). ADMIRE-CD II is a randomized, double-blind, placebo-controlled study designed to confirm the efficacy and safety of a single administration of Cx601 for the treatment of complex perianal fistulas in Crohn’s disease patients. In July 2016, TiGenix entered into a licensing agreement with Takeda, a global pharmaceutical company active in gastroenterology, under which Takeda acquired exclusive rights to develop and commercialize Cx601 for complex perianal fistulas in Crohn’s patients outside of the U.S.
This press release may contain forward-looking statements and estimates with respect to the anticipated future performance of TiGenix and the market in which it operates. Certain of these statements, forecasts and estimates can be recognised by the use of words such as, without limitation, “believes”, “anticipates”, “expects”, “intends”, “plans”, “seeks”, “estimates”, “may”, “will” and “continue” and similar expressions. They include all matters that are not historical facts. Such statements, forecasts and estimates are based on various assumptions and assessments of known and unknown risks, uncertainties and other factors, which were deemed reasonable when made but may or may not prove to be correct. Actual events are difficult to predict and may depend upon factors that are beyond the Company’s control. Therefore, actual results, the financial condition, performance or achievements of TiGenix, or industry results, may turn out to be materially different from any future results, performance or achievements expressed or implied by such statements, forecasts and estimates. Given these uncertainties, no representations are made as to the accuracy or fairness of such forward-looking statements, forecasts and estimates. Furthermore, forward-looking statements, forecasts and estimates only speak as of the date of the publication of this press release. TiGenix disclaims any obligation to update any such forward-looking statement, forecast or estimates to reflect any change in the Company’s expectations with regard thereto, or any change in events, conditions or circumstances on which any such statement, forecast or estimate is based, except to the extent required by Belgian law.
1 Panés J, García-Olmo D, Van Assche G, et al., Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomized, double-blind controlled trial. The Lancet. 2016; 388(10051): 1281-1290.
2 European Medicines Agency. Available at: http://www.ema.europa.eu/ema/. Accessed December 15, 2017.
3 Clinicaltrials.gov. Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn’s Disease (ADMIRE-CD). Available at: https://clinicaltrials.gov/ct2/show/NCT01541579?term=cx601 &rank=2. Published February 2012. Accessed December 15, 2017.
4 Panés J, García-Olmo D, Van Assche G, et al., Long-term efficacy and safety of Cx601, allogeneic expanded adipose-derived mesenchymal stem cells, for complex perianal fistulas in Crohn’s Disease: 52-week results of a phase III randomized controlled trial. ECCO 2017; Barcelona: Abstract OP009.
5 Marzo M, Felice C, Pugliese D, et al., Management of perianal fistulas in Crohn’s disease: An up-to-date review. World J Gastroenterol. 2015; 21(5): 1394-1395.
6 Mahadev S, Young JM, Selby W, et al., Quality of life in perianal Crohn’s disease: what do patients consider important? Dis Colon Rectum. 2011; 54(5): 579-585.
7 Geltzeiler C, Wieghard N and Tsikitis V. Recent developments in the surgical management of perianal fistula for Crohn’s disease. Ann Gastroenterol. 2014; 27(4): 320-330.
- The applicant for Alofisel is Tigenix, S.A.U.
- AGA technical review on perianal Crohn’s disease 2003; 125(5):1508-1530
- TiGenix company presentation, June 2017 (http://tigenix.com/wp-content/themes/tigenix/images/TiGenix_Corporate_Presentation.pdf , accessed on June 22nd, 2017).
- Panes J et al. Long-term efficacy and safety of Cx601, allogeneic expanded adipose-derived mesenchymal stem cells, for complex perianal fistulas in Crohn’s disease: 52-week results of a Phase III randomized controlled trial. The 12th Congress of ECCO, February 15-18, 2017, Barcelona, Spain
- Cohen RD et al, 2008. Effects of fistula on healthcare costs and utilization for patients with Crohn’s disease treated in a managed care environment.
- Gene therapy: understanding the science, assessing the evidence, and paying for the value: a report from the 2016 ICER membership policy summit. March 2017.
- Chaparro M. et al., 2013 Health care costs of complex perianal fistula in Crohn’s disease.
- Takeda’s press release, January 5, 2018.
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