SSI Efficacy and Safety

“SSIs are not designed for incremental improvements to the ‘standard of treatment’ – they are designed to re-invent, complement and replace the standard.”

~ Dr. Simon Sutcliffe, Chief Medical Officer, Qu Biologics

Qu scientists crop wide

Since Qu’s inception in 2007, we have initiated a wide range of preclinical and clinical research programs to demonstrate and assess the efficacy and safety of SSI treatment. We have initiated three Health Canada-approved clinical trials in Crohn’s disease, ulcerative colitis and non-small cell lung cancer.  Initial results from our Crohn’s disease study are now available (see below).

From 2008 – 2013, prior to the initiation of our Health Canada-approved clinical trials, 272 patients received Qu Biologics’ SSIs through compassionate use programs, including 254 patients with advanced cancer and 18 patients with other immune-related diseases, including Crohn’s disease, ulcerative colitis and autoimmune arthritis. Our preclinical scientists continue to conduct studies in cancer and inflammatory bowel disease models and collaborate with leading academic researchers to further assess the potential role of SSIs in treating these diseases.

Initial results from Crohn’s disease clinical trial

Based on the Week 8 and preliminary Week 16 results, QBECO SSI appears safe and well-tolerated and demonstrates consistently positive trends throughout the treatment period of the trial, successfully establishing proof-of-concept in Crohn’s disease and supporting continued development of QBECO SSI in inflammatory bowel disease.

Clinical data from compassionate use programs provide precedent for current studies

From 2008 to 2013, 272 patients were treated with Qu Biologics’ SSIs in five compassionate use programs (advanced cancer, Crohn’s disease, ulcerative colitis, autoimmune arthritis and other immune-related diseases), as summarized in the table below:

Compassionate Use Program

Compassionate use program in patients with late-stage cancer

254 patients with advanced cancer (including cancer of the breast, prostate, lung, colon, liver, skin, bone, and ovary) were treated with one or more of Qu Biologics’ SSIs for up to 3.5 years. SSI treatment was reported to have an excellent safety profile and was well-tolerated; there were no treatment related serious adverse events reported and no allergic reactions were observed.

An independent research group initiated a retrospective analysis of patients treated with SSI in the late-stage cancer compassionate use program, comparing survival of patients with metastatic breast cancer (the largest patient group in the clinic) treated with SSI to metastatic breast cancer patients at the same clinic not treated with SSI. The analysis found that patients treated with SSIs had a 20 month longer median survival than those not treated with SSIs. Encouraged by this promising initial clinical data, these researchers initiated a case-matched study in all late-stage cancer patients at the clinic, comparing survival of 43 patients with advanced cancer treated with SSIs to 43 matched patients treated at the same clinic with the same type/stage of advanced cancer who did not receive SSI. This case matched analysis found that patients treated with SSI had a median survival 12 months longer than those patients not treated with SSI.

This experience comprises uncontrolled, unblinded observations in clinical practice. Accordingly it represents preliminary data from which proof of benefit of SSIs cannot be established, but it does provide a precedent for formal clinical trials, including Qu Biologics’ Health Canada-approved Phase 2a clinical trial in recurrent lung cancer, which has completed enrollment.

Compassionate use program in patients with other immune-related diseases

Ten patients with moderate to severe Crohn’s disease, two patients with moderate to severe ulcerative colitis, and five patients with autoimmune arthritis were treated with Qu Biologics’ SSIs. All patients had active disease that was uncontrolled by standard treatment at time of enrollment. SSI treatment was reported to have an excellent safety profile and was well-tolerated; there were no treatment related serious adverse events reported and no allergic reactions were observed. Response associated with SSI treatment was, as follows:

Crohn’s disease
  • Ten of ten patients reported improvement in clinical symptoms.
  • The majority of patients reported clinical improvement within one to three weeks of starting treatment.
  • Eight patients were able to discontinue all other medications at some point while on QBECO SSI treatment.
  • Seven patients (70%) had full resolution of clinical symptoms with a course of QBECO SSI treatment of 2.5 months duration or more.
  • Three patients (30%) are in ongoing sustained clinical remission after discontinuing all medications including SSI treatment.
  • The longest remission is ongoing, since July 2010 (discontinued all medications, including SSI treatment since July 2011).
  • All three patients in ongoing sustained remission have had follow-up colonoscopies or imaging confirming remission.
Ulcerative colitis
  • Both patients went into sustained clinical remission during SSI treatment
  • Both patients were able to discontinue all medications, including SSI treatment
  • Both patients are in ongoing sustained remission, off all medications (more than 4 years after starting SSI treatment)
Arthritis
  • All five patients had a therapeutic response to SSI.
  • Four of five patients reported substantial improvement.
  • All five patients reduced their concomitant medications.
  • The majority of patients noticed reduction in morning stiffness within two to three weeks of starting treatment, with a subsequent reduction in joint pain and swelling.

 

This experience comprises uncontrolled, unblinded observations in clinical practice. Accordingly it represents preliminary data from which proof of benefit of SSIs cannot be established, but it does provide a precedent for Health Canada-approved clinical trials.

SSI Clinical Safety Profile

To date, more than 300 patients have been treated with SSIs in our compassionate use programs and randomized, controlled clinical trials.

In Qu Biologics 68-patient Crohn’s disease clinical trial, QBECO SSI appears safe and well-tolerated.

In Qu Biologics’ compassionate use program, 272 patients with advanced cancer, Crohn’s disease, ulcerative colitis, autoimmune arthritis and other immune-related diseases were treated with SSIs. SSI treatment was well-tolerated with no treatment-related serious adverse events reported and no systemic allergic reactions observed. A small number of patients reported larger than anticipated transient injection site reactions (including one or more of the following symptoms: increased redness, tenderness, induration), or transient mild flu-like symptoms (including one or more of the following symptoms: muscle aches, fatigue) or transient fever. All of these symptoms were reported to resolve within a few days without requirement for treatment. The compassionate use program was uncontrolled and unblinded and in a limited number of patients (n=272), therefore these results cannot be interpreted as establishing the definitive safety of Qu Biologics’ SSIs.

Preclinical Research: SSI Treatment of Inflammatory Bowel Disease

QBECO SSI treatment significantly decreases disease severity in a highly relevant IBD model

Qu Biologics is studying the therapeutic effects of QBECO SSI treatment in a mouse model that mimics the underlying immune system defect and chronic bacterial infection associated with Crohn’s disease and ulcerative colitis.  In this research model, the mice have a defective gastrointestinal mucosal barrier and after time spontaneously develop colitis, resembling ulcerative colitis in humans.

In the 30-day preclinical study comparing QBECO SSI with placebo, QBECO treatment substantially  improved all components of the histopathology score, including infiltration, integrity, hyperplasia, and edema. The infiltration of T lymphocytes in the colonic tissue, a hallmark of IBD in patients and mouse models, was markedly decreased with QBECO treatment. These data demonstrated that QBECO significantly decreases disease severity in a highly relevant IBD model, including substantially dampening adaptive immune system over-response.

More importantly, QBECO was also shown to have a positive impact on the gastrointestinal microbiome. Alterations in bacterial species in the intestinal microbiome can either be detrimental (‘unhealthy’ bacteria) or therapeutic (‘healthy’ bacteria) in IBD patients and mouse models. Some bacteria promote a healthy immune environment and can improve symptoms (for example, Lactobacillus species), whereas others (for example, γ-proteobacteria) can have detrimental effects in IBD. We analyzed the intestinal microbiome before and after QBECO treatment. Lactobacillus species, a major group of “healthy” bacteria, was increased with 30 days of SSI treatment, whereas γ-proteobacteria, a group of generally “unhealthy” bacteria, was decreased by SSI treatment. These results suggest that QBECO treatment has a therapeutic effect on the gastrointestinal microbiome.

Preclinical Research: SSI Treatment of Cancer

SSI treatment of cancers in the lungs

Using mouse models, Qu Biologics’ scientists have studied the use of QBKPN SSI for the treatment of lung cancer (illustration below). In an aggressive mouse model of lung cancer (Lewis lung carcinoma), lung targeted QBKPN SSI treatment significantly reduced the number of tumour nodules (median = 20 per lung) and prolonged survival compared to placebo (median number = 73.5 per lung).

LLC growing in lungs2

Unlike most cancer treatments which are cancer type specific, SSIs are site specific. In other words, SSIs are designed to restore the anti-cancer immune response in the targeted organ, regardless of the type of cancer growing in that organ. Lung targeted QBKPN SSI treatment is designed to restore anti-cancer immune response in the lungs and to treat, not just primary lung cancer, but also metastases to the lungs from a variety of other cancers. In a mouse model of melanoma metastases to the lungs, illustrated below, QBKPN SSI treatment significantly reduced the number of metastatic lesions in the lungs (median = 9.75) compared to placebo (median = 73.75), demonstrating the broad applicability of the SSI approach.

Primary melanoma (skin cancer)

In an established mouse model of primary melanoma (skin cancer), QBSAU SSI (skin-targeted) treatment significantly inhibited skin/subcutaneous tumour growth, reducing tumour volume by 86% compared to placebo-treated mice (as illustrated below). On day 19, a time-point when all the mice in the placebo-treated group had substantial measurable tumours, 63% of mice in the QBSAU SSI-treated group did not have measurable tumours.

QBSAU SSI Preclinical Data

Colon Cancer

In a mouse model of colon cancer, colon-targeted QBECO SSI treatment inhibited colon cancer growth and increased survival time. In the placebo treated group, all mice had either died or had extensive tumour burden and morbidity by Day 29. In contrast, 62.5% of the mice treated with QBECO SSI remained healthy after prolonged observation (74 days) with no evidence of tumours, as illustrated below, even after SSI treatment was discontinued.

QBECO SSI Colon Cancer

Synergistic effects of SSI treatment

Synergy occurs when two treatments help each other work better, producing results that are greater than the sum of their individual effects (i.e., 1 + 1 = >2). In preclinical models, Qu Biologics’ scientific team have demonstrated that lung targeted QBKPN SSI works synergistically with the standard lung cancer chemotherapy Cisplatin (Figure below) to enhance its effectiveness, suggesting that, in addition to their potential as individual cancer treatments, SSIs may be important adjuncts to standard cancer treatments. Read more about how SSIs may help chemotherapy and other cancer treatments to work more effectively. Qu is currently assessing the capacity of SSIs to augment the activity of other standard therapies and novel immunotherapeutics.

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