As part of our ongoing response to requests for clinical trials tracking service, TrialSite News analyzes Crohn’s Disease studies worldwide. Crohn’s Disease is a type of inflammatory bowel disease (IBD) that may adversely impact any part of the gastrointestinal tract from mouth to anus. Symptoms range from mild to severe and can be life threatening. Those with the disease face a greater risk of bowel cancer. The cause is unknown, but it is believed that it could possibly originate from a combination of environmental, immune and bacterial factors in genetically susceptible individuals. As many as 700,000 patients struggle with Crohn’s disease in the United States. There is evidence that rates in African Americans are growing, and there appears that Ashkenazi Jews face elevated risk with Crohn’s. There are no medications or surgical procedures that can cure the disease. TrialSite News refers readers to the Crohn’s & Colitis Foundation, a patient advocacy and support group for more information.
In early 2018 the American College of Gastroenterology published “Management of Crohn’s Disease in Adults,” a comprehensive overview of Crohn’s disease standard of care. According to Mayo Clinic, the following are foundational Crohn’s disease treatments:
- Anti-Inflammatory Drugs
- Immune System Suppressors
- Other Medications used:
- Pain relivers
- Iron Supplements
- Vitamin B12 shots
- Calcium and Vitamin D supplements
- Nutrition Therapy
- Nearly half of those with Crohn’s disease will require at least one surgery. However, surgery does not cure Crohn’s disease.
- Clinical Trials
For a relevant summary of Crohn’s disease pipeline review, see a recent Irritable Bowel Syndrome (including Crohn’s disease) Pipeline review by Dr. James Lord, Benaroya Research Institute, Translational Immunology, Virginia Mason Medical Center (refer below to Celgene for summary of Mongersen).
In this article we review the current Crohn’s disease phase 3 biopharmaceutical company commercial pipeline as well as summarize a key literature review and our findings. Based on our search criteria of Clincialtrials.gov, there are 38 active commercial sponsor clinical trials. There are several sponsors reporting Crohn’s disease pipelines including:
- Abbvie (7)
- Takeda (7 with acquisition of TiGenix)
- Celgene (4)
- J&J (4)
- Shire (4)
- Several others with one or two trials including Roche & Valeant.
What follows is a summary of these sponsors studies including TrialSite News commentary.
One of America’s great pharmaceutical companies (result of spin off of Abbott Laboratories), AbbVie has risen to ninth largest by revenue worldwide at least according to Wikipedia. The company’s pipeline centers on oncology, immunology and others. It has seen tremendous success with Humira which we have covered in TrialSite News in relation to hidradenitis suppurativa (HS). Motley Fool has recently published the potential risks with the pipeline. As measured by total number of commercially-sponsored phase 3 trials, AbbVie leads the commercial sponsor effort to improve conditions for Crohn’s disease patients. What follows is a breakdown of their seven Crohn’s disease studies.
AbbVie is taking multiple approaches to addressing Crohn’s disease. Can larger doses of Humira help certain Crohn’s Disease patients? In one trial they are evaluating the efficacy and safety of Humira by studying higher vs. standard dosing regimens for induction and maintenance therapy in patients with moderately to severely active Chron’s Disease and evidence of mucosal ulceration. AbbVie has targeted 600 patients and has a completion date of 2020. But as discussed in TrialSite News, some patients have difficulty with Humira (Adalimumab).
What else is AbbVie considering? They have a treatment in the pipeline for not only Crohn’s disease, but also ulcerative colitis, atopic dermatitis and psoriatic arthritis and axial SpA called ABT-494 which is a JAK1 selective inhibitor. Known as Upadacitinib, it surfaces information in a clinical direction. In one trial, AbbVie seeks to evaluate the efficacy and safety of ABT-494 compared to placebo as induction therapy in patients with severely active Crohn’s disease. They are seeking 855 participants and have an estimated completion date of 2020. Another replica trial is reported in ClinicalTrials.gov where they seek an additional 300 patients but use seemingly the same trial protocol. In another ABT-494 trial, AbbVie invests in a multicenter study to evaluate the efficacy and safety of maintenance and long-term administration of Upadacitinib in Crohn’s disease patients who have completed studies M14-431 or M14-433. AbbVie also has an ABT-494 trial listed that has been organized as a multicenter study to evaluate the efficacy and safety of maintenance and long-term treatment administration of the orally administered Janus kinase 1 inhibitor in adult Crohn’s disease patients. They are planning for 738 patients and a completion date of 2023.
Another drug under AbbVie consideration is Risankizumab. Also known as BI-655066, Risankizumab is a humanized monoclonal antibody targeting interleukin 23A (IL-23A). Risankizumab is part of a collaboration between German biopharmaceutical company Boehringer Ingelheim and AbbVie. It is an experimental drug that has not been approved for the treatment of any medical conditions. The therapeutic potential of risankizumab was evaluated for the treatment of psoriasis in a preliminary phase 2 clinical trial. AbbVie is sponsoring a study to evaluate the efficacy and safety of Risankizumab in patients with Crohn’s disease who responded to induction treatment in M16-006 or M15-991, or completed M15-989 (later being a Abbvie and Boehringer Ingelheim collaboration).
The Risankizumab trial consists of three sub-studies with various inclusion/exclusion criteria. Another Risankizumab trial AbbVie has sponsored to study the efficacy and safety of the anti-IL-23 antibody versus a placebo during induction therapy in moderately to severely active Crohn’s disease patients. They protocol calls for 940 patients and a completion date of 2020. AbbVie is also studying Risankizumab in patients with moderate to severe Crohn’s disease who failed other prior biologic treatments. Finally, our review of ClincalTrials.gov uncovered a Risankizumab study targeting Crohn’s disease patients who responded to induction treatment.
In summary, AbbVie has more reported phase 3 Crohn’s disease clinical trials than any other sponsors based on the search criteria utilized by TrialSite News research team. The American biopharmaceutical sponsor is investigating a few different approaches including:
- Humira (Adalimumab)—market leading TNF-inhibiting, anti-inflammatory, biologic medication (cost as of 2017 approximately $4,370 per month)
- Upadacitinib (ABT-494)—a JAK1 selective inhibitor
- Risankizumab (BI-655066)—a humanized monoclonal antibody targeting interleukin 23 A
These reported studies have reported end dates from 2020 to 2023. AbbVie is clearly making big bets in the Immunotherapy therapeutic area which includes Crohn’s disease.
Ranked at 20th largest pharmaceutical company by revenue, Takeda originates in Japan. Headquartered in Japan, it is the largest pharmaceutical company in Asia. With over 30,000 employees, it focuses on metabolic disorders, gastroenterology, neurology, inflammation as well as oncology through an independent subsidiary—Takeda Oncology. Founded in 1781, it is one of the world’s oldest pharmaceutical companies. It first entered the United States via a joint venture with Abbott Laboratories. To this day it still has a large presence in Chicago where Abbot Laboratories (now AbbVie for pharma) operates. Takeda has made one of the biggest commitments to targeting Crohn’s disease treatments. We summarize the reported Crohn’s disease trials reported to ClinicalTrials.gov.
Takeda has developed a few different drugs for Crohn’s disease including Vedolizumab (MLN0002) and Darvadstrocel (Cx601). We start with Vedolizumab-based studies. With a trade name of Entyvio, it is a monoclonal antibody developed by Millennium Pharmaceuticals Inc. (a subsidiary of Takeda Pharmaceuticals) for the treatment of ulcerative colitis and Crohn’s disease. It binds to integrin α4β7 (LPAM-1, lymphocyte Peyer’s patch adhesion molecule; blocking the α4β7 integrin results in gut-selective anti-inflammatory activity. Takeda reports the following Vedolizumab studies,
In a study in China with 300 participants, Takeda is studying the safety and efficacy of Vedolizumab Intravenous (IV) infusion as induction treatment with Chinese participants with moderately to severely active Crohn’s disease. The study is planned to be completed in 2020. In another Vedoluzimab study, Takeda assesses the effect of Vedolizumab subcutaneous as maintenance treatment in participants with moderately to severely active Crohn’s disease who achieved clinical response following administration of Vedolizumab Intravenous induction therapy. With 644 participants, the study is scheduled to conclude in 2019. Takeda is evaluating Vedolizumab subcutaneous treatment in a long-term safety and tolerability trial with 692 planned participants to be completed in 2022. Moreover, Takeda is running a Vedolizuman study in Japan with 157 patients and a scheduled completion in 2019.
It was reported in January 2018 that Takeda was acquiring TiGenix and the acquisition was completed June 2018 for $627 million all cash deal. The TiGenix take cover is to give to Takeda full control over Cx601, a stem cell therapy that is closing in on European approval for Crohn’s disease. Takeda now has one phase 3 Cx601 trial listed to evaluate the efficacy for the treatment of complex perianal fistulas in adult patients with Crohn’s disease over 24 weeks. A small targeted study, the sponsor has targeted 20 patients and a completion date of 2022. A couple other trials are reported based on the TiGenix acquisition. For more information on perianal fistulas associated with Crohn’s disease, see “Modern Management of Perianal Fistulas in Crohn’s Disease: Future Directions.”
To conclude, Takeda’s Crohn’s disease treatments include Vedolizumab (developed by Millennium Pharmaceuticals which Takeda acquired) and Cx60 which comes with the TiGenix acquisition in 2018.
Celgene, founded in 1986, is an American biotechnology company that discovers, develops and commercializes medicines for cancer and inflammatory disorders. The company’s major product is Revlimid (lenalidomide), in combination with Dexamethasone for treatment of multiple myeloma patients. Celgene’s Crohn’s disease strategy centers on Ozanimod. An investigational immunomodulatory drug currently in phase 3 clinical trials, Celgene is targeting therapies for multiple sclerosis as well as ulcerative colitis. Celgene made a $710 million bet on Mongersen but lost. Due to this painful loss, Celgene is now banking on Ozanimod, an oral agonist of the sphingoine-1-phosphae subtype (S1P1) receptor, to make up the loss for Mongersen’s potential sales. Celgene bought Ozanimod as part of its 2015 $7.2 billion-dollar purchase of biotech venture Receptos. By 2018, the biotech media begins to question the results with even stock evangelist Jim Cramer questioning the wisdom of the acquisition.
What is the status of Ozanimod phase 3 trials for Crohn’s disease? In one multicenter study, Celgene seeks to understand the safety and efficacy in moderately to severely active Chron’s disease patients. With a target of 1200 patient the trial is scheduled to conclude in 2022. Celgene has three other reported Ozanimod trials scheduled to be concluded from 2020 to 2021.
Johnson & Johnson
Johnson & Johnson (J&J), one of the largest multinational companies, is conducting Crohn’s disease research via a couple of its affiliates including Janssen-Cilag Ltd and Janssen Research & Development LLC. The J&J targeted treatments include Guselkumab (Tremfya) and Ustekinumab (Stelara). First, a brief overview of each drug:
Guselkumab (Tremfya): Approved by the FDA to treat moderate to severe plaque psoriasis in adults, it is also being studied for use addressing psoriatic arthritis and Crohn’s disease. As reported in Wikipedia, side effects are significant. For example, because Guselkumab lowers the release of immune system signaling molecules, patients have a higher risk of getting infections from bacteria, viruses, and fungi. For this reason, patients must be screened for tuberculosis infection prior to treatment with guselkumab. The most common side effects for Guselkumab are upper respiratory tract infections, headache, injection site reactions, joint pain, diarrhea, stomach flu, fungal skin infections and herpes simplex infections. It is noteworthy that during the studies where side effects were tracked, patients who received a placebo experienced these side effects at rates just slightly lower than the patients who received Guselkumab, suggesting Guselkumab only marginally increases the risk of having an adverse effect. As Guselkumab is a new medicine, the long-term effects are not fully understood. As reported in GoodRx the drug costs around $10,000. Janssen Research & Development LLC (J&J affiliate) is presently sponsoring a trial to evaluate the efficacy and safety of Guselkumab for Crohn’s disease with up to 2,000 patients targeted for an endpoint of 2024.
Ustekinumab (Stelara) is a human monoclonal antibody currently approved to treat psoriasis and Crohn’s disease in 2016. Manufactured in the Netherlands, it is directed against interleukin 12 and interleukin 23—naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders. In some cases, serious side affects were reported by Centocor (J&J affiliate) maker of one medication based on Ustekinumab. Some examples include A) risk of infection and B) increase risk of certain types of cancer as well as C) risk of brain swelling of posterior reversible encephalopathy syndrome. Other risks include serious allergic reactions as well as more common side effects such as upper respiratory infection, headache and fatigue. Research results from clinical trials have evidenced that subcutaneous Ustekinumab has been generally well tolerated. Goodrx price estimates are $20,488.
J&J affiliates presently are running four phase 3 trials including the STARDUST trial sponsored by affiliate Janssen-Cilag, Ltd. to study treat to target versus routine care maintenance strategies in Crohn’s disease patients treated with Ustekinumab. The sponsor plans to complete the study in 2021 and targets 650 patients. Janssen Scientific Affairs is studying the safety and efficacy of Humira versus Ustekinumab in the SEAVUE trial. Targeting 350 patients and a completion date in 2020, the purpose of this study is to compare the efficacy of treatment with Ustekinumab or Adalimumab in biologic naive participants with moderately-to-severely active Crohn’s disease (CD) who have previously failed or were intolerant to conventional therapy (corticosteroids and/or immunomodulators, such as azathioprine, 6-mercaptopurine, or methotrexate), as measured by clinical remission at one year. In another Ustekinumab trial, Janssen Research & Development LLC (affiliate of J&J) the sponsor is evaluating the safety and efficacy of Ustekinumab maintenance therapy with patients with moderately to severely active Crohn’s disease. Known as the IM-UNIT trial, they have produced results of which some are reported in this report “Clinical Utility of Ustekinumab in Crohn’s disease” where the report’s authors concluded “the inhibition of the IL-12 and -23 pathways has been demonstrated to be an effective strategy in the management of Crohn’s disease.” They note, however, that discovering the “optimal treatment strategy and positioning of UST (Ustekinumab) in the Crohn’s disease management algorithm remain undefined and these decisions should be individualized and discussed with patients.”
A Jersey-registered, Irish-headquartered global specialty biopharmaceutical company, it originated in the United Kingdom with operational bases in the United States. Its primary products include Vyvanse (ADHD), Lialda (IBD/maintain remission with Crohn’s disease) and Adderall XR (ADHD, narcolepsy). Shire’s Crohn’s disease target rests on SHP647, an anti-inflammatory, monoclonal antibody.
Earlier this year regulators awarded orphan drug status to Shire’s SHP647 for the treatment of pediatric patients with moderately to severely active Crohn’s disease. This decision helped Shire qualify for access to several incentives designed to accelerate development of drugs for rare diseases including tax credits and qualified clinical testing. In the CARMEN CD 307 study, Shire is recruiting up to 983 patients and plans to evaluate the efficacy and safety of SHP647 as maintenance treatments in patients with moderate to severe Crohn’s disease. The trial is planned to end in 2022. CARMEN 306 is structured to include 1032 patients with a completion date of 2021 while CARMEN 305 also has a planned end date of 2021. Finally, Shire is running AIDA, a safety extension study of SHP647 in patients with moderate to severe ulcerative colitis or Crohn’s disease with a target of 2452 patient and a completion date of 2025.
Other Clinical Trials
Filgotinib (Gilead Sciences & Galapagos)
The result of a collaboration between American-based Gilead Sciences, one of the world’s largest biotech firms, and Galapagos, a Belgo-Dutch pharmaceutical research venture founded in 1999, Filgotinib 0634 is a drug which is currently under investigation for the treatment of rheumatoid arthritis and Crohn’s disease. A janus kinase inhibitor, it is considered a promising agent as it inhibits JAK1 selectively. For a summary see Wikipedia. One of the Gilead/Galapagos studies (Diversity1) is scheduled to conclude in 2019; another (DIVERSITYLTE) is planned for 2022 completion.
Rifaximin/Xifaxan (Valeant which acquired Salix Pharmaceuticals)
Most recently it was reported that Xifaxan (Rifaximin) exhibited positive impact on patients with moderate to severe Crohn’s disease.
Valeant is current conducting a couple of rifaximin phase 3 trials—both are scheduled to conclude in 2020.
PROCHYMA (Mesoblast which acquires developer Osiris)
A stem cell therapy developed by Osiris Therapeutics, it is the first such stem cell therapy approved by Canada. It is an allogenic stem therapy base on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. Read a summary of acquired Osiris description of PROCHYMA trials for Crohn’s disease.
Now Mesoblast is conducting a study to evaluate the safety in patients with active Crohn’s disease who are resistant to standard Crohn’s disease therapies. The sponsor is not actively recruiting and is planning on concluding the study in 2019. In another study being conducted at 56 research sites, including major academic medical centers (Protocol 603), Mesoblast is enrolling patients with moderate to severe Crohn’s disease who are intolerant to, or have previously failed therapy with at least one steroid and at least one immunosuppressant and a biologic monoclonal anti-body to tumor necrosis factor alpha. PROCHYMAL is delivered through a vein in the arm four times over two weeks, for approximately an hour each time.
Etrolizumab/rhuMAb Beta7 (Roche)
Etrolizumab is a biopharmaceutical drug candidate being developed for the treatment of ulcerative colitis and Crohn’s disease. It is a humanized monoclonal antibody against the β7 subunit of integrins α4β7 and αEβ7. Developed by Genentech (Roche) by engineering the FIB504 antibody to include human IgGl-heavy chain and κ-light chain frameworks; it is manufactured in CHO cells.
In one study, Roche is conducting a two-part, open-label extension and safety monitoring study to examine the safety and efficacy of continued Etrolizumab treatment in patients with moderate to active Crohn’s disease who were previously enrolled in the Etrolizumab phase III Study GA29144. In another multicenter study, Roche is recruiting 1150 patients and plans to conclude in 2021.
In 2017, Roche reported that Etrolizumab can provide meaningful improvements in the treatment of Crohn’s disease.
BI 695501(Humira Biosimilar by Boehringer Ingelheim)
German pharmaceutical company Boehringer Ingelheim is conducting a biosimilar trial to Humira in 130 research sites worldwide. They are recruiting up to 140 patients and plan a conclusion 2019.
A number of global biopharmaceutical ventures are in a race to address Crohn’s disease with advanced, incremental to more advanced improved drug treatments currently in phase 3 global clinical trials. What follows is a summary of key pipeline drug candidate by sponsor vendor. For those that are facing Crohn’s disease, consult your physician to review these pipeline candidates for advisory as to prospective implications.
|Commercial Sponsor||Drug in Phase 3|
|Johnson & Johnson||Guselkumab
|Gilead & Galapagos||Filgotinib|
|Valeant (acquired Salix)||Rifaximin|
|Boehringer Ingelheim||BI 695501|