Coeliakie > Coeliakie in de publiciteit en onderzoeken

Resultaten coeliakiemedicijn AMG 714 vallen tegen

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tine:
Kan het medicijn AMG 714, van oorsprong bedoeld voor de behandeling van reuma, ook iets betekenen voor mensen met coeliakie? Tot nu toe vallen de resultaten tegen. Dat blijkt uit twee verschillende experimenten die uitgevoerd zijn in 2016 en 2017. De resultaten werden toegelicht tijdens het coeliakiecongres in Parijs. Vrijwel gelijktijdig verschenen twee publicaties in een internationaal medisch tijdschrift voor maagdarmleverartsen. 

Refractaire coeliakiepatiŽnten

In het ene experiment kregen patiŽnten met refractaire coeliakie het medicijn toegediend via een injectie, 7 maal in 10 weken. Deze patiŽnten hebben gevaarlijke immuuncellen in hun darmen, die kunnen uitgroeien tot kankercellen. Het medicijn kon het aantal gevaarlijke immuuncellen niet genoeg omlaag brengen. Wel hadden de proefpersonen minder last van diarree. Verder kreeg een deel van de proefpersonen (42%) een luchtweginfectie als bijwerking van het medicijn.

Gluten eten en injectie met medicijn

Een andere groep coeliakiepatiŽnten kreeg in een periode van 10 weken om de week een injectie met AMG 714. Ook aten ze elke dag 2 tot 4 gram gluten (een hoeveelheid van 1 tot 2 boterhammen). De bedoeling was dat AMG 714 hun darmen zou beschermen, maar dat gebeurde niet. De dunne darm van de proefpersonen raakte toch beschadigd. Wel hadden ze minder last van diarree in vergelijking met patiŽnten die een nepmedicijn (placebo) kregen. Misschien kan het medicijn iets betekenen voor coeliakiepatiŽnten die geen baat hebben bij een glutenvrij dieet (non-responders), opperen de onderzoekers. Daar zal het vervolgonderzoek zich op richten.     

Zie ook het vorige bericht over AMG 714: http://www.coeliakieforum.nl/index.php?topic=26131.msg660544#msg660544


Lancet Gastroenterol Hepatol. 2019 Sep 4. pii: S2468-1253(19)30265-1. doi: 10.1016/S2468-1253(19)30265-1. [Epub ahead of print]
Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study.
Cellier C1, Bouma G2, van Gils T2, Khater S3, Malamut G3, Crespo L4, Collin P5, Green PHR6, Crowe SE7, Tsuji W8, Butz E8, Cerf-Bensussan N9, Macintyre E10, Parnes JR11, Leon F12, Hermine O10, Mulder CJ2; RCD-II Study Group Investigators.

BACKGROUND:
Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2.

METHODS:
This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36).

FINDINGS:
From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was -4∑85% (90% CI -30∑26 to 20∑56; p=0∑75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was -38∑22% (90% CI -95∑73 to 19∑29; nominal p=0∑18); the difference in change in Marsh score from baseline was 0∑09% (95% CI -1∑60-1∑90; nominal p=0∑92); the difference in VHCD ratio was 10∑67% (95% CI -38∑97 to 60∑31; nominal p=0∑66); and the difference in change in total intraepithelial lymphocyte count was -12∑73% (95% CI -77∑57-52∑12); nominal p=0∑69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0∑0008); and the difference between the groups in change in GSRS score was -0∑14 (SE 0∑19; nominal p=0∑48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group).

INTERPRETATION:
In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2.

PMID: 31494097 DOI: 10.1016/S2468-1253(19)30265-1


Lancet Gastroenterol Hepatol. 2019 Sep 4. pii: S2468-1253(19)30264-X. doi: 10.1016/S2468-1253(19)30264-X. [Epub ahead of print]
Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study.
Lšhdeaho ML1, Scheinin M2, Vuotikka P3, Taavela J4, Popp A5, Laukkarinen J1, Koffert J6, Koivurova OP3, Pesu M7, Kivelš L8, Lovrů Z9, Keisala J3, Isola J10, Parnes JR11, Leon F12, Mški M7.

BACKGROUND:
Interleukin 15 (IL-15) is implicated in the pathophysiology of coeliac disease. AMG 714 is the first anti-IL-15 monoclonal antibody to be investigated for the treatment of coeliac disease. We aimed to investigate the effects of AMG 714 in patients with coeliac disease who underwent gluten challenge.

METHODS:
This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial was done at three clinical sites in Finland. Inclusion criteria included age 18-80 years, a confirmed diagnosis of coeliac disease, and adherence to a gluten-free diet for at least 12 months before screening. Patients were randomly assigned (1:1:1) to 150 mg AMG 714, 300 mg AMG 714, or placebo using permuted blocks and stratified by study site and sex. Patients and study staff were masked to treatment assignment. Treatments were administered by two subcutaneous injections every 2 weeks for 10 weeks (total six doses). Patients without severe villous atrophy at baseline received a gluten challenge (2-4 g daily) during weeks 2-12. Small bowel biopsy samples were obtained for histological assessments at baseline and week 12. The primary efficacy endpoint was the percentage change from baseline to week 12 in villous height-to-crypt depth (VHCD) ratio. Secondary endpoints were CD3-positive intraepithelial lymphocyte density; clinical symptoms measured by gastrointestinal symptom rating scale (GSRS), coeliac disease GSRS, and Bristol stool form scale (BSFS); and changes in anti-tTG and anti-DGP antibodies from baseline. The primary analysis was done in the per-protocol 1 population of patients who received at least one dose of study drug and who underwent the gluten challenge. Safety analyses were done in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, NCT02637141 and EudraCT, 2015-003647-19.

FINDINGS:
Between April 13, 2016, and Nov 22, 2016, 64 patients were enrolled and randomly assigned to either the 150 mg AMG 714 group (n=22), the 300 mg AMG 714 group (n=22), or the placebo group (n=20). Two patients did not start treatment and two did not provide post-treatment biopsy samples. 49 patients underwent the gluten challenge (per-protocol 1 population) and 11 patients did not because of baseline villous atrophy. AMG 714 did not prevent mucosal injury due to gluten challenge. The least square mean difference in the relative change from baseline in VHCD ratio was -2∑49% (95% CI -16∑82 to 11∑83; p=0∑73) between 150 mg AMG 714 and placebo and 6∑39% (-7∑07 to 19∑85; p=0∑34) between 300 mg AMG 714 and placebo. Neither comparison was statistically significant. The density of CD3-positive intraepithelial lymphocytes increased in all groups, with smaller increases in the 300 mg group (-41∑24% [95% CI -79∑28 to -3∑20] vs placebo, nominal p=0∑03) but not the 150 mg group (-14∑32% [-54∑39 to 25∑74], nominal p=0∑47). Clinical symptoms were ameliorated with AMG 714 treatment between baseline and week 12, particularly diarrhoea as measured by the BSFS (nominal p=0∑01 for 150 mg vs placebo, and nominal p=0∑0002 for 300 mg vs placebo). Serum antibody titres for anti-tTG and anti-DGP antibodies increased in all three treatment groups, with no significant difference between AMG 714 and placebo. Treatment-emergent adverse events occurred in 21 (95%) patients in the 150 mg AMG 714 group, 0 (95%) in the 300 mg AMG 714 group, and 19 (100%) in the placebo group. The most common treatment-emergent adverse events were gastrointestinal disorders (17 [77%] participants in the 150 mg AMG 714 group, 16 [76%] in the 300 mg AMG 714 group, and 13 [68%] in the placebo group). Injection site reactions were the most common individual adverse event, reported in eight (36%) patients in the 150 mg AMG 714 group, 11 (52%) in the 300 mg group, and five (26%) in the placebo group. No serious adverse events occurred.

INTERPRETATION:
The primary endpoint, change in VHCD ratio from baseline after 12 weeks of treatment in patients with coeliac disease undergoing gluten challenge, was not significantly different between placebo and AMG 714 at either 150 mg or 300 mg. Effects on intraepithelial lymphocyte density and symptoms suggest that further research of AMG 714 may be warranted in patients with non-responsive coeliac disease.

PMID: 31494096 DOI: 10.1016/S2468-1253(19)30264-X

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