abrilumab (AMG 181) / Amgen, AstraZeneca - LARVOL DELTA

Gut-directed therapeutics in inflammatory bowel disease. (PubMed, Curr Opin Gastroenterol) - "Gut-targeted therapies range from novel variations on traditional drugs (i.e., mAbs and small molecules) to microbiome-based therapeutics and engineered delivery systems. They can be used alone or in combination with currently available therapies. Future directions should focus on the development of tried-and-true modalities (mAbs, small molecules) as well as the microbiome and more innovative delivery systems."

Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Gene Therapies • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins (PubMed, Korean J Gastroenterol) - "Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG)."

Journal • Review • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Ulcerative Colitis • TNFA

Increased stable integration efficiency in CHO cells through enhanced nuclear localization of Bxb1 serine integrase. (PubMed, BMC Biotechnol) - "This study demonstrates that optimizing the NLS sequence fusion for Bxb1 integrase significantly enhances the stable genomic integration efficiency. These findings provide a practical approach for constructing larger libraries in mammalian cells through the stable integration of genes into a genomic landing pad."

Journal

Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis. (PubMed, Drug Saf) - "A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents."

Retrospective data • Review • CNS Disorders • Hematological Disorders • Human Immunodeficiency Virus • Immunology • Infectious Disease • Multiple Sclerosis • Oncology • Primary Immunodeficiency • Rare Diseases • Solid Tumor

Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives. (PubMed, Clin Exp Gastroenterol) - "Natalizumab (anti-α4) is approved for moderate to severe Crohn's disease (CD), but its use is limited due to potential risk of progressive multifocal leukoencephalopathy. Vedolizumab (anti-α4β7) is approved for the treatment of ulcerative colitis (UC) and CD...Large phase 3 clinical trials evaluating efficacy of etrolizumab in the induction and maintenance of patients with IBD are underway. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG)."

Journal • Review • CNS Disorders • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Rare Diseases • Ulcerative Colitis • ITGA4

Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): Insights into promising agents. (PubMed, Expert Opin Investig Drugs) - "This review summarizes efficacy and safety data from phase 1, 2 and 3 clinical trials on investigational drugs, including monoclonal antibodies (etrolizumab, abrilumab, ontamalimab) and oral small molecules (AJM300, PTG-100). Among the most exciting features of this class are the gut selectivity, the convenient subcutaneous and oral administrations and the reassuring safety profiles. Most of the new anti-integrins seem to improve outcomes in UC but not in CD, however these data are far from definitive and several pivotal trials are still under way."

Clinical • Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

Emerging Treatment Options in Inflammatory Bowel Disease: Janus Kinases, Stem Cells, and More. (PubMed, Digestion) - "Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn's disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4β7 or endothelial MadCAM-1. The α4β7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules..."

Journal • Review • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Transplantation • Ulcerative Colitis

AMG 181 phase 2 study in subjects with moderate to severe ulcerative colitis (clinicaltrials.gov) - P2, N=360; Sponsor: Amgen; Suspended; Primary completion date: Apr 2014 -> May 2017.

Trial primary completion date • Immunology • Inflammatory Bowel Disease

Pharmacokinetics/pharmacodynamics (PK/PD), efficacy, and safety of AMG 181 in subjects with active, mild to moderate ulcerative colitis - an initial assessment (DDW 2013) - Presentation time: Saturday, 8:00AM - 5:00PM; Abstract #Sa1207; P1, N=36; NCT01164904; NCT01290042; Sponsor: Amgen; "Initial assessment of available data suggests that AMG 181 has PK/PD, immunogenicity, safety, and efficacy profiles suitable for further testing in subjects with UC or CD."

P1 data • Immunology • Inflammatory Bowel Disease

Clinical pharmacology of AMG 181, a gut-specific human anti-α4 β7 monoclonal antibody, for treating inflammatory bowel diseases (Br J Clin Pharmacol) - P1, N=72; Sponsor: Amgen; NCT01164904; "Following SC dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg SC and 70-420 mg IV ranges....AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12, and/or 28. The placebo-treated UC subject experienced colitis flare at week 6."

P1 data • Immunology • Inflammatory Bowel Disease

AstraZeneca: Q3 2014 Results (AstraZeneca) - Anticipated completion of P2 trial in Japan for moderate to severe ulcerative colitis in Q2 2015; Anticipated external presentation of P2 data in Japan for moderate to severe ulcerative colitis in 2016; Anticipated completion of enrollment in P2 trial in Japan for moderate to severe ulcerative colitis in Q1 2015

Anticipated enrollment status • Anticipated P2 data • Anticipated trial completion date • Immunology • Inflammatory Bowel Disease

Pharmacokinetics/pharmacodynamics and safety of AMG 181, a fully human anti-α 4 β 7 antibody for treating inflammatory bowel diseases (IBD) (ECCO 2012) - P1, N=68; NCT01290042; AMG 181 had a linear elimination range half-life of 36 days, with terminal target-mediated disposition occurring below 1 µg/mL; The extent and duration of α 4 β 7 RO increased with AMG 181 dose; Blinded safety data showed a 44% adverse event rate, with no treatment-related ≥ Grade 3 events, serious adverse events, deaths, or dose limiting toxicities

Safety & efficacy data • Immunology • Inflammatory Bowel Disease

Multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of AMG 181, a human anti-α4β7 antibody for treating inflammatory bowel diseases (IBD) (DDW 2013) - Presentation time: Saturday, 8:00AM - 5:00PM; Abstract #Sa1206; P1, N=36; NCT01290042; Sponsor: Amgen; "The safety profile and PK/PD properties of AMG 181 under once-a-month multiple fixed SC dose regimens of 7 to 210 mg warrants continued clinical development."

P1 data • Immunology • Inflammatory Bowel Disease

AZ: Investor Day (AstraZeneca) - Anticipated data from P2 trial for Crohn's disease in 2014; Anticipated data from P2 trial for ulcerative colitis in 2014

Anticipated P2 data • Inflammatory Bowel Disease

AMG 181 in Subjects With Moderate to Severe Crohn's Disease (clinicaltrials.gov) - P2; N=254; Active, not recruiting; Sponsor: Amgen; Trial primary completion date: May 2015 ->Dec 2014

Trial primary completion date • Biosimilar • Crohn's Disease • Immunology • Inflammation • Inflammatory Bowel Disease

EFFICACY AND SAFETY OF ABRILUMAB (AMG 181/MEDI 7183) THERAPY FOR MODERATE TO SEVERE CROHN'S DISEASE (DDW 2017) - "Although the primary endpoint was not met, beneficial effects of abrilumab were observed for remission and response rates. There was no safety imbalance compared with placebo."

Clinical • Biosimilar • Crohn's disease • Immunology • Inflammatory Bowel Disease

AstraZeneca: Q2 2014 Results (AstraZeneca) - Anticipated completion of enrollment in P2 trial for moderate to severe ulcerative colitis in Q4 2014; Anticipated completion of P2 trial for moderate to severe ulcerative colitis in Q1 2015; Anticipated external presentation of data from P2 trial for moderate to severe ulcerative colitis in 2016; Anticipated completion of enrollment in P2 trial for moderate to severe Crohn’s disease in Q4 2014; Anticipated completion of P2 trial for moderate to severe Crohn’s disease in Q2 2015; Anticipated external presentation of data from P2 trial for moderate to severe Crohn’s disease in 2016; Anticipated completion of P2 trial in Japan for moderate to severe ulcerative colitis in Q1 2015

Anticipated enrollment status • Anticipated P2 data • Anticipated trial completion date • Immunology • Inflammatory Bowel Disease

MEDI7183 Phase 2 Study in Japanese Ulcerative Colitis Patients (clinicaltrials.gov) - P2; N=53; Recruiting; Sponsor: AstraZeneca; Trial primary completion date: Oct 2014 ->Feb 2015

Trial primary completion date • Biosimilar • Immunology • Inflammatory Bowel Disease

Interfering with leukocyte trafficking in Crohn's disease. (PubMed, Best Pract Res Clin Gastroenterol) - "Targets for modulators of leukocyte trafficking include (examples in brackets) ICAM-1 (alicaforsen, efalizumab); MAdCAM-1 (PF-00547 659); α4 and related receptors (abrilumab, etrolizumab, natalizumab, vedolizumab); chemokine receptor CCR9 (vercirnon); and sphingosine 1-phosphate receptors (etrasimod, fingolimod, ozanimod). Oral and subcutaneous therapies are in development. The safety, efficacy and practice points of licensed drugs are discussed, in addition to initial results from therapeutic trials."

Journal • Review

Emerging Therapies for Inflammatory Bowel Disease. (PubMed, Adv Ther) - "Treatments such as vedolizumab and ustekinumab, as well as second-generation corticosteroids have been approved by the US Food and Drug Administration (FDA) for the treatment of IBD. Other agents are currently being developed at various stages of clinical trials including anti-adhesion agents such as etrolizumab and abrilumab, JAK inhibitors such as tofacitinib, and anti-trafficking molecules...It is projected that many therapies will become available in the coming years if supported by the results of current clinical trials. This will provide IBD patients with a wide array of options and allow physicians to choose the best therapies for each individual patient."

Journal • Review

"Modest efficacy of a new SC anti-integrin (abrilumab) for UC. A 90% decrease in free α4β7 levels on naïve CD4+ T cells did not translate to a major efficacy gain. The unmet need for #personalized therapy & in #IBD remains. https://t.co/qlQrfZYz9d" (@moss_md)

Clinical

Efficacy and safety of abrilumab, an α4β7 integrin inhibitor, in Japanese patients with moderate-to-severe ulcerative colitis: a phase II study. (PubMed, Intest Res) - "Abrilumab 70 mg and 210 mg yielded numerically better results in terms of clinical remission rate at Week 8 than placebo, with the 210 mg dose showing more consistent treatment effects. Abrilumab was well tolerated in Japanese patients with UC."

Clinical • Journal • P2 data

αβ Integrin Inhibitors: A patent review. (PubMed, Expert Opin Ther Pat) - "...Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically...Among these mAbs, etrolizumab selectively against the β-subunit and AMG-181 specifically against the αβ integrin are the most promising anti-αβ integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM 300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective αβ integrin inhibitors."

Journal • Review