Industry Trend Analysis - Multiple Blockbuster IBD Market Is On The Horizon - APR 2017

BMI View: With no drugs yet providing cures for ulcerative colitis or Crohn's disease, inflammatory bowel disease remains a therapy area with blockbuster potential for any drugs that can tackle these conditions effectively. Products under development include biosimilars and innovative products, and as understanding of IBD increases, so too this market will develop. With Entyvio already marketed, Takeda Pharmaceutical is in a strong position to capitalise on IBD; its development agreement with TiGenix highlights the firm's focus on dominating this area of unmet need.

The recent 12th Congress of the European Crohn's and Colitis Organisation (ECCO) has provided an insight into some of the inflammatory bowel disease (IBD) drug developments currently taking place. During the conference, both Takeda Pharmaceutical and its partner, TiGenix, and Celltrion Healthcare announced Phase III results, whilst Takeda also unveiled long-term study data for vedolizumab for Crohn's disease (CD) and ulcerative colitis (UC).

IBD, including CD and UC, affects an estimated 2.5mn to 3mn patients in Europe, and the direct healthcare costs of IBD are estimated to be between EUR4.6bn (USD4.9bn) and EUR5.6bn (USD5.9bn) per year. CD is thought to affect up to 1.6mn in Europe, or around three people per 1,000, whilst UC affects around five people per 1,000. There are no cures for CD or UC, and existing drugs tend to manage symptoms. However, in a report issued in 2016, the Pharmaceutical Research and Manufacturers of America (PhRMA) reported that there are 58 drugs under development for IBD, including for both CD and UC.

The data show that for UC drugs under development, testing is evenly split between Phase I, Phase II and Phase III. For CD drugs, however, there is a spike of drugs currently in Phase II testing, with fewer in Phase I and fewer again in Phase III. The data include drugs that have already been approved for other indications, and some drugs that are in different stages of testing for both UC and CD.

PhRMA Data Suggests Healthy CD/UC Pipeline
IBD Projects Under Development
Source: PhRMA, BMI

There are around 44 companies listed in PhRMA's report that are working on IBD drugs. These include Pfizer, with five projects underway, including two Phase I CD programmes, one CD Phase II programme, one IBD Phase I programme and one Phase III UC programme. AbbVie also has five projects underway, including one in collaboration with Boehringer Ingelheim, a Phase II programme for UC. Celgene has five projects underway, including two Phase II UC programmes, one Phase III UC programme, one Phase II CD programme and one Phase III CD programme.

Biosimilar Developments Show Confidence In Existing Biologics

The PhRMA data do include a couple of biosimilars under development, but do not include any from Celltrion. However, at the ECCO conference, Celltrion reported the primary outcome from its pivotal randomised controlled trial of CT-P13, the firm's biosimilar version of infliximab, in CD. This reflects the growing importance of biosimilars in autoimmune treatments. Infliximab, the original version of which is marketed by Janssen Biotech ( Johnson & Johnson) as Remicade, is now available in the EU and US as a biosimilar treatment, primarily for rheumatoid arthritis, and in the EU is amongst the older biosimilar products to be marketed. Celltrion's infliximab was approved by the EC in September 2013, where it is marketed by Hospira (Pfizer) as Inflectra and by Egis as Flammegis. It was the first biosimilar infliximab to be approved in the EU, and has recently been launched by Pfizer in the US. The Phase III trial was funded equally by Celltrion and Pfizer.

In the results reported at ECCO, Celltrion noted that CT-P13 had comparable safety and efficacy in patients with moderate-to-severe CD to reference infliximab. The Phase III randomised control trial in 220 patients with CD examined whether CT-P13 is comparable to reference infliximab as determined by the Crohn's Disease Activity Index (CDAI). According to the six-week and 30-week data, similar clinical remission, CDAI-70 and CDAI-100 response rates were observed in both CT-P13 and reference infliximab treatment groups. This was the first randomised control trial to examine the use of a biosimilar in IBD.

Celltrion also presented data from two observational studies. The first study evaluated the efficacy and safety of CT-P13 in 74 paediatric patients with CD (naive patients: 26, switch patients: 25) or UC (naive patients: 16, switch patients: 7). The data showed that CT-P13 is effective in both treatment-naive and switch paediatric patients over 30 weeks and is well-tolerated. The second study examined 204 CD patients (fistulising CD: 24, CD patients: 180) in South Korea from July 2012 to 2016. CT-P13 was found to be clinically consistent to reference infliximab and well tolerated up to six months in patients with moderate-to-severe CD and those with fistulising CD.

Celltrion also used the forum of the conference to highlight CT-P13's health savings in Europe. According to the firm, real-world cost savings associated with the use of CT-P13 across all indications were studied in five European countries from the beginning of 2015 to H116. According to the data presented at ECCO, total cost savings observed for Germany, Italy, Spain and the UK amounted to EUR32.4mn (USD34.3mn) and the findings suggest that this could allow an additional 5,428 patients a year access to this biologic therapy. Significantly, the firm noted that there were no cost savings in France, as the price of biosimilar and reference infliximab were the same. Despite this, use of CT-P13 has gradually increased in France, suggesting that physician and patient acceptance of biosimilars is growing, even when cost differences are not a primary driver.

Cx601 On Course To Target Perianal Fistulas In CD Patients

At the meeting, Takeda and TiGenix announced new data from the Phase III ADMIRE-CD trial, which indicated that the investigational compound, Cx601, a suspension of allogeneic expanded adipose-derived stem cells (eASCs), maintained long-term remission of treatment refractory complex perianal fistulas in patients with CD over 52 weeks. The ADMIRE-CD trial is a randomised, double-blind, controlled, Phase III study, designed to investigate the efficacy and safety of the Cx601 for the treatment of complex perianal fistulas in patients with CD. Patients were randomised to a single administration of Cx601 cells or placebo, both added to standard of care. A significantly greater proportion of patients in the Cx601 group versus 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 (AEs, non-serious and serious) and discontinuations resulting from AEs were indicated to be similar in both groups (Cx601: 20.4%; control: 26.5%). TiGenix stressed that the definition of combined remission used in ADMIRE-CD, which includes both clinical and radiological assessment by MRI, is more stringent than the criteria commonly used in previous large-scale, randomised trials evaluating perianal fistulas in CD, based only on clinical assessment.

A global pivotal Phase III trial for US registration with Cx601 for the treatment of complex perianal fistulas is expected to be initiated by TiGenix in 2017. In the US, TiGenix intends to apply for fast track designation from the FDA. In 2009, the EC granted Cx601 orphan designation for the treatment of anal fistulas, recognising the debilitating nature of the disease and the lack of treatment options; this will give the product ten years' market exclusivity from the date of marketing authorisation.

In December 2016, Takeda exercised the option granted under a licensing agreement between it and TiGenix to make a EUR10mn (USD10.4mn) equity investment in TiGenix. On July 4 2016, Takeda and TiGenix entered into an exclusive ex-US licence, development and commercialisation agreement for Cx601 for the treatment of complex perianal fistulas in patients with CD. The licensing agreement also provided for Takeda to make an equity investment of EUR10mn in the share capital of TiGenix within the 12 months following the date of the licensing agreement.

TiGenix noted in its most recent annual report that the burden of perianal fistulas in CD is high, both to the individual patient and to the healthcare provider. In 2010, the firm commissioned a study by IMS which concluded that the total median cost of treatment of a patient with complex perianal fistulas resulting from CD was around EUR34,000 (USD37,441) per patient, of which around EUR20,000 (USD22,025) was spent on pharmaceutical treatment. With a target population of around 50,000 in Europe and 50,000 in the US, and assuming a sales price roughly equivalent to the median cost of pharmaceutical treatment used to treat fistulising CD, TiGenix estimates that Cx601's target market is around EUR2bn (USD2.2bn) for Europe and the US combined. Whilst there are other products in development that will compete with Cx601, should the drug candidate reach the market ahead of competitors, it will corner a blockbuster opportunity.

Entyvio Prospects Are Healthy

Takeda also used the meeting to announce interim findings from the ongoing, open-label GEMINI long-term safety (LTS) study. Data presented from two five-year interim analyses of effectiveness and safety in patients with moderate-to-severely active UC and CD indicated that long-term treatment of vedolizumab in responders was associated with long-term clinical response and remission in addition to health-related quality of life (HRQL) improvements for patients over a five-year period.

The LTS study is an ongoing open-label prospective study investigating the long-term safety of vedolizumab in moderate-to-severely active IBD. In total, 146 patients with CD were enrolled from GEMINI II and 154 patients with UC were enrolled from GEMINI I. The interim analysis reports clinical effectiveness evaluated at five years. Takeda reported that 58 patients with CD and 54 patients with UC had discontinued therapy before the data cut-off, (11 [19%] and 19 [35%] patients discontinuing respectively because of lack of benefit). Twenty-seven CD patients and 37 UC patients had not reached the five-year assessment time point in the study. According to Takeda, 61 patients with CD and 63 patients with UC were evaluated in the analysis.

Patients with CD were assessed for clinical response (decrease in Harvey-Bradshaw Index [HBI] of >=3 points from baseline). Clinical remission was defined as HBI <=4. Patients with UC were assessed for clinical response (decrease in partial Mayo Score [PMS] of >=2 points and >=25% change from baseline, with an accompanying decrease in rectal bleeding subscore of >=1 point from baseline or absolute rectal bleeding subscore of <=1 point). Clinical remission was defined as PMS of <=2 with no individual subscore >1.

This interim analysis showed that for the 63 observed patients with moderate-to-severely active UC, 98% experienced clinical response, and 90% were in clinical remission after five years of continued vedolizumab treatment. For the 61 observed patients with moderate-to-severely active CD, 95% experienced clinical response and 89% were in clinical remission after five years of continued vedolizumab treatment. Long-term use of vedolizumab was also associated with improvements in HRQL, which was measured by IBD Questionnaire (IBDQ) and Euro Quality of Life-5D visual analogue scale (EQ-5D VAS). The safety profile was consistent with that previously observed in a three-year interim analysis of the LTS study in patients with moderate to severely active UC and CD.

Additional data from a post-hoc analysis of GEMINI I reported that vedolizumab (n=620) was significantly more effective than placebo (n=149) at achieving sustained remission, defined as clinical remission (PMS <=2 points with no individual subscore >1 point) and rectal bleeding subscore equalling zero at weeks 26, 38 and 52, in patients with moderate-to-severely active UC who achieved remission at week 14. The analysis included patients enrolled in GEMINI I, who responded to two induction doses of vedolizumab and entered 46 weeks of maintenance therapy with either placebo or vedolizumab. Maintenance treatment with vedolizumab resulted in 60% of patients sustaining clinical remission from week 14 to week 52 compared with 37% who underwent placebo washout.

Vedoluzumab is marketed by Takeda as Entyvio, and was approved for both the treatment of UC and CD by the FDA and the EMA in 2014. In its FY16 annual report, Takeda noted that the product's launch has been a transformational event and represents a significant advance in understanding IBDs. Takeda reported Entyvio sales in FY16 worth JPY86.2bn (USD718.0mn), representing an increase of 210.1% over the JPY27.8bn reported for FY15. Takeda noted that since its launch in 2014, Entyvio sales have collectively exceeded USD1bn; with the current rate of annual growth, sales in FY17 alone will almost certainly also exceed USD1bn, propelling the drug into blockbuster status within three years of launch, underscoring the lucrative niche market it has so far targeted.

The data presented at ECCO represent just a small portion of the total number of CD and UC projects currently under development. Aside from PhRMA's data, also shows 296 open studies for CD and 259 for UC. Cures remain elusive, however, with many existing drugs and drugs under development focusing on managing symptoms, but as understanding of IBD increases, even drugs that serve only to manage symptoms, if they can provide significant improvements over existing therapies, can anticipate reaching blockbuster status. From the PhRMA data, a number of projects can be expected to reach marketing approval in the next five years, which will reinvigorate and increase knowledge of this currently underserved market.