"In this work, we present the results from a Phase 1/2 randomized, double-blind, placebo-controlled trial of a novel immunotherapy approach to optimize innate immune function in CD. QBECO, an investigational immunotherapy derived from an inactivated GI pathogen, aims to elicit an acute innate immune response targeting the GI tract to re-establish competent barrier function and immune competency (
14)."
QBECO SSI, published two days ago:
Original Research ARTICLE
Front. Med., 19 July 2019 |
https://doi.org/10.3389/fmed.2019.00170
Novel Microbial-Based Immunotherapy Approach for Crohn's Disease
Simon Sutcliffe1, Shirin Kalyan1,2, Jim Pankovich1, Jenny M. H. Chen1, Rashieda Gluck1, Darby Thompson3,4, Momir Bosiljcic1, Mark Bazett1, Richard N. Fedorak5†, Remo Panaccione6, Jeffrey Axler7, John K. Marshall8, David W. Mullins9, Boyko Kabakchiev10, Dermot P. B. McGovern11, Julie Jang1, Andrew Coldman12, Gillian Vandermeirsch1, Brian Bressler13 and Hal Gunn1*
- 1Qu Biologics Inc., Vancouver, BC, Canada
- 2Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- 3Emmes Canada, Burnaby, BC, Canada
- 4Department of Statistics and Actuarial Sciences, Simon Fraser University, Burnaby, BC, Canada
- 5Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
- 6Inflammatory Bowel Disease Unit, University of Calgary, Calgary, AB, Canada
- 7Toronto Digestive Disease Associates Inc., Vaughan, ON, Canada
- 8Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
- 9Department of Microbiology, Immunology and Medical Education, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
- 10Zane Cohen Centre for Digestive Diseases, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- 11Cedars-Sinai Medical Center, Los Angeles, CA, United States
- 12Cancer Control Research, British Columbia Cancer Agency, Vancouver, BC, Canada
- 13Gastrointestinal Research Institute, Vancouver, BC, Canada
Background: Current Crohn's disease (CD) therapies focus on suppressing immune function and come with consequent risk, such as infection and cancer. Notwithstanding, most CD patients still experience disease progression. There is a need for new CD treatment strategies that offer better health outcomes for patients.
Aims: To assess safety, efficacy, and tolerability of a novel microbial-derived immunotherapy, QBECO, that aims to restore rather than suppress immune function in CD.
Methods: A randomized, double-blind, placebo-controlled trial was conducted in 68 patients with moderate-to-severe CD. Primary endpoints: safety and Week 8 clinical improvement. Secondary endpoints: Week 8 clinical response and remission. Week 8 responders continued blinded treatment through Week 16; non-responders received open-label QBECO from Weeks 9–16. Exploratory analyses included immune biomarker and genotype assessments.
Results: QBECO was well-tolerated. Mean reduction in Crohn's Disease Activity Index (CDAI) score was −68 for QBECO vs. −31 for placebo at Week 8. Improvement with QBECO continued through Week 16 (-130 CDAI reduction). Week 8 QBECO clinical response, improvement and remission rates were 41.2%, 32.4%, 29.4% vs. 26.5%, 23.5%, 23.5% for placebo. TNFα inhibitor-naïve subjects achieved higher response rates at Week 8 with QBECO (64%) vs. placebo (26%). Specific immune biomarkers were identified that linked to QBECO response.
Conclusion: This proof-of-concept study supports further investigation for the use of QBECO as a novel immunotherapy approach for CD. Biomarker analyses suggests it may be feasible to personalize CD treatment with QBECO. Larger trials are now needed to confirm clinical improvement and the unique biological findings.
Clinical Trial Number: NCT01809275 (
https://clinicaltrials.gov/ct2/show/NCT01809275)
...
Introduction
Accumulating clinical and genetic evidence suggests that a defective innate immune response may be fundamental to the pathogenesis of CD (
5–
8) and precedes the consequent over-reactive adaptive immune response that is characteristic of the disease and the target of current treatments (
9,
10). Segal and Lowei first demonstrated that patients with CD exhibited an impaired systemic acute inflammatory response (
11). Subsequent genetic studies provided further support for the hypothesis that defective or inefficient innate immune function, particularly that of macrophages, is linked to CD (
12,
13). In this work, we present the results from a Phase 1/2 randomized, double-blind, placebo-controlled trial of a novel immunotherapy approach to optimize innate immune function in CD. QBECO, an investigational immunotherapy derived from an inactivated GI pathogen, aims to elicit an acute innate immune response targeting the GI tract to re-establish competent barrier function and immune competency (
14). Treatment is self-administered by subcutaneous injection. Promising early clinical experience with QBECO for the treatment of CD in a compassionate use program (
15) and a translational study in ulcerative colitis showing improved GI barrier function with QBECO treatment (
14) motivated this proof-of-concept clinical trial to explore safety, efficacy, and tolerability of this novel immunotherapy in subjects with moderate-to-severe CD.
...
Table 2. Clinical response, improvement, and remission rates at Week 8 by treatment.
Figure 3. Mean change in Crohn's Disease Activity Index (CDAI) score in study groups Week 8 and Week 16. Mean change in CDAI score for subjects randomized to QBECO (solid red line) and placebo (solid blue line) from baseline to Week 8 and Weeks 16 of study treatment. Those responding to allocated blinded treatment at week 8 continued blinded treatment for another 8 weeks [light blue solid line for responders originally blinded to placebo treatment (n = 9); light red solid line for QBECO responders (n = 13)]. All placebo (n = 22) and QBECO (n = 14) non-responders at week 8 received open-label QBECO (dashed red lines) for weeks 9–16. Dark solid red line represents the average of all subjects on QBECO for weeks 9–16.
Patients naïve to anti-TNFα agents achieved a 64% response rate at Week 8 with QBECO vs. 26% placebo (
p = 0.041; ITT analysis), and more than double the improvement and remission rates (
Table 2). Anti-TNFα naïve Week 8 placebo non-responders (
n = 17) treated with 8 weeks open-label QBECO from weeks 9 to 16 achieved response, improvement and remission rates of 71, 47, and 47%, respectively. This was similar to the response, improvement and remission rates observed after 8 weeks of treatment in the anti-TNFα naïve group initially randomized to QBECO. A longitudinal analysis including previous TNFα inhibitor exposure interaction with treatment following week 8 shows that subjects previously treated with anti-TNFα agents may respond to QBECO treatment with longer course of treatment (
Supplement Figure 1).
In subjects with baseline CDAI ≥ 250 (
n = 24 [70.6%] QBECO,
n = 19 [55.9%] placebo), the response, improvement and remission rates in subjects treated with QBECO vs. placebo were: 42%, 29%, 25% vs. 16%, 11%, 11%, respectively. To account for differences in baseline characteristics that may be important in the change in CDAI score by treatment, a regression analysis was performed taking into account baseline CDAI, disease severity at baseline (>250), use of concomitant immunosuppressive medication, disease duration and prior exposure to anti-TNFα agents (
Supplement Figure 2). Following adjustment for imbalanced prognostic variables, the reduction in CDAI at Week 8 was 48 points greater in the QBECO than placebo treated cohort (
p = 0.024; ITT analysis).
...
Immune Biomarker Analysis
Forty-two serum immune factors were assessed at baseline, Week 8, 16, and 24. Interleukin-18 (IL-18) increased from baseline to Week 8 and 16 with QBECO treatment (median change 24 pg/mL, adjusted
p = 0.066 at Week 8 and 56 pg/mL, adjusted
p = 0.067 at Week 16), but not with placebo treatment. None of the serum cytokine biomarkers remained elevated at Week 24 (i.e., 8 weeks after stopping study treatment).
Among QBECO treated subjects, IFNγ, IL-12p70, IL-17A, and TGFα were significantly elevated in QBECO responders vs. QBECO non-responders (adjusted
p = 0.037 for all) (
Figure 4).
Figure 4. Serum cytokines that differed in QBECO responders and non-responders. A 42-plex cytokine/chemokine analysis was performed on serum. Four cytokines- IFNγ, IL-12p70, IL-17A, and TGFα- differentiated QBECO responders from non-responders over the study period after adjusting for multiple comparisons.
Week 8 clinical remission with QBECO treatment occurred more frequently in patients with lower baseline serum Eotaxin-1 levels (adjusted
p = 0.0062) and IL-10 and IL-12p40 (
p > 0.05 after correcting for multiple comparisons). This relationship between lower Eotaxin-1 levels and increased Week 8 remission was not found in placebo treated patients. These 3 cytokines tended to be higher in patients previously treated with TNFα inhibitors (
Supplement Table 2), and in a longitudinal analysis, as performed with previous anti-TNFα agent use, patients with high baseline Eotaxin-1 levels responded equally well to QBECO treatment with a longer course of treatment (
Supplement Figure 3).
CRP, an acute phase response protein upregulated in response to bacterial infections, and FCP, a cation-binding protein released by granulocytes in response to infection, were not anticipated to be reduced during active QBECO treatment given its mechanism of action. We assessed levels of these immune biomarkers leading up to Week 24 (when subjects were off study treatments). At Week 24, 44% of those who had been on QBECO from the beginning of the study, 42% of those who had switched to QBECO from placebo at Week 8, and 0% of those who were on placebo since the beginning had CRP levels < 5 mg/L (
Supplement Table 3). Similarly, 35% of those who had been on QBECO from the beginning of the study, 18% of those who had switched to QBECO from placebo at Week 8, and 0% of those who were on placebo since the beginning had FCP levels of <250 ug/g (
Supplement Table 4).
Genetic Associations With Response to QBECO
One hundred and thirteen SNPs reported to be linked to IBD were analyzed for response to QBECO treatment. A gene risk score, which is a weighted value based on variation in multiple genetic loci, was computed to assess the ability to stratify subjects' response to QBECO.
Figure 5 shows that the gene risk score could differentiate QBECO responders from non-responders in this cohort,
p = 0.0000243.
Supplement Table 5 lists the IBD-linked SNPs and their weighted contribution to the construction of the gene risk score.
Figure 5. Gene risk score separates QBECO responders from non-responders. One hundred and thirteen inflammatory bowel disease (IBD)-related SNPs were included in computing the gene risk score for response to QBECO to assess the potential contribution of subjects' genetics to treatment outcome. The derived gene risk score could successfully distinguish QBECO responders from non-responders, p = 0.0000243.
Some of the Supplementary Material:
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Discussion
In this proof-of-concept study assessing QBECO, a first-in-class microbial-based immunotherapy, for the treatment of CD, a greater reduction in disease was observed by Week 8 in subjects randomized to QBECO compared to placebo. For the pre-specified Week 8 primary analysis in this 68-patient study, the difference did not reach statistical significance, but secondary analyses suggest that the biological effect induced by QBECO may be of benefit to patients with moderate-to-severe CD and warrants further study.
Notably, patients with prior exposure to anti-TNFα agents, who are known to generally be more difficult to treat (
22,
23), were less likely to respond to QBECO by Week 8. Due to unequal randomization, these patients were significantly more prevalent in the QBECO arm than in the placebo arm. However, subjects previously treated with TNFα inhibitors did experience symptom improvement with QBECO as treatment continued to Week 16, suggesting that a longer course of treatment may be required to achieve optimal results in these subjects. QBECO Week 8 clinical response, improvement and remission rates in anti-TNFα naïve patients compare favorably to those reported at similar time-points in recent Phase 3 trials with biologics such as vedolizumab and ustekinumab (
22,
23).
The current treatment approach for CD largely targets the overzealous adaptive immune response to invading bacteria in the GI tract, but accumulating evidence suggests patients with CD have impaired or deficient innate immunity that predisposes to defective barrier function (
3,
5,
7,
8). Identification of genetic variants linked to CD that associate with innate immune function lends support to the idea that innate immune insufficiency plays a role in disease pathophysiology, at least for a significant segment of those suffering from CD (
5,
7). Serum cytokine analysis in this study demonstrated a QBECO-induced increase in IL-18, a cytokine known to promote phagocytosis and bacterial clearance (
24). This corroborates our findings in experimental models of colitis in which colonic expression of IL-18 increased in response to QBECO treatment—resulting in marked improvements in gastrointestinal histopathology and barrier function (
14). Other studies of colitis have shown a lack of IL-18 results in more severe disease (
25), and the administration of IL-18 can reverse the phenotype (
26). IL-18 with IL-12 acts on natural killer (NK) cells, γδ T cells and other “Th1” cells to stimulate the production of IFNγ (
27,
28), which in turn acts on macrophages to further enhance phagocytosis, bacterial clearance and antigen presentation (
24). CD patients who improved with QBECO treatment produced IL-18 and had increases in serum IFNγ, IL-12p70, and IL-17A levels, whereas, subjects deemed as QBECO non-responders did not show the same increases in these three cytokines. This may reflect an inability to launch a productive immune response to bacterial stimulation. The observed higher incidence of transient flu-like symptoms in QBECO treated subjects likely reflects this immune mobilization, and we believe it is part of QBECO's mechanism of action. Of note, CD patients who improved with QBECO treatment also had increases in their levels of TGFα, which has been reported to be reduced in diseased regions of the colon of patients with inflammatory bowel disease and increased in healthy regions (
29).
Patients with lower baseline levels of Eotaxin-1, IL-10, and IL-12p40 were more likely to achieve response and remission with 8 weeks of QBECO treatment. Of note, these cytokines tended to be higher in those who had previously been treated with anti-TNFα therapy and may reflect greater immune dysregulation in patients (
30–
33). For such individuals, a longer course of QBECO treatment may be required to overcome the presence of greater immune dysfunction, as is suggested by the study's 16-week data showing that patients with higher baseline levels of these cytokines achieved more optimal responses with a longer duration of treatment.
A personalized approach to CD treatment has been elusive to date, possibly because current treatments focus on symptom management (
3,
34,
35), rather than upstream biological processes predisposing CD symptoms. Subject genotype was found to differentiate QBECO responders from non-responders. Collectively, the genetic and cytokine findings of this study provide promise for personalized medicine in CD with QBECO, and they now need replication in larger cohorts.
This proof-of-concept study is limited by its small size, short treatment duration, lack of stratification for previous TNFα inhibitor use, and lack of endoscopic and histological assessment. The therapeutic paradigm has now moved from symptom-based assessment to objective measures of disease activity (
36). QBECO treatment has shown endoscopic and histological improvement in moderate-to-severe ulcerative colitis (
14) and now needs to be demonstrated in patients with CD.
In conclusion, QBECO warrants further study as a novel immunotherapy approach for the management of CD. This approach not only provides a new way of thinking about the treatment of the disease, but also sheds more light on the heterogeneity of CD pathogenesis. QBECO may be the optimal choice for those patients with disease characterized by innate immune dysfunction rather than other underlying etiologies. The data from this trial will inform the design of larger definitive Phase II trials, which will include evaluation of endoscopic and histological endpoints, assessment of the impact of prior TNFα inhibitor exposure on QBECO response, evaluation of patients over a longer treatment period, microbiome assessment, and confirmation of the genetic and immune biomarker findings.
Funding
This study was funded by Qu Biologics and Genome BC (SoFI Program).
Conflict of Interest Statement
SS, DT, RF, RP, DMu, BK, DMc, AC, and BB have served as consultants and/or advisors to Qu Biologics. SK, JP, JC, RG, MBo, MBa, JJ, and GV are (or were) employees of Qu Biologics. HG is the CEO and major shareholder of Qu Biologics. Qu Biologics owns patents across all the major markets (including U.S. Patent No. 8,980,279) relating to the use of Site Specific Immunomodulators derived from components of
E. coli (QBECO) to treat inflammatory bowel disease. Qu Biologics has also filed patents for the use of immune and genetic biomarkers for the use of QBECO in patients with inflammatory bowel disease. In addition to the above, the following author affiliations are non-academic incorporated for-profit entities: Emmes Canada (DT) and Toronto Digestive Disease Associates, Inc. (JA).
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
https://www.frontiersin.org/articles/10.3389/fmed.2019.00170/full
