APRIL 16-18, 2019

BOSTON, MA USA

 

The Official Blog of the Annual Translational Microbiome Conference

The official blog of the Annual Translational Microbiome Conference provides readers with information, insight and analysis regarding the microbiome.

Gut Bugs May Modulate the Efficacy of Anti-PD1 Immunotherapy

These microbiome insights are brought to you by Dr. Vancheswaran Gopalakrishnan and Dr. Jennifer Wargo of The University of Texas MD Anderson Cancer Center, and Arrowhead Publishers. Dr. Gopalakrishnan will be presenting MD Anderson’s work at Arrowhead’s 4th Annual Translational Microbiome Conference, 18th-20th April, 2018.

Pioneering research performed at the MD Anderson Cancer Center1 suggests that the gut microbiome influences how cancer responds to immunotherapy; potentially creating new opportunities to improve treatment.

Cancer patients who saw no benefit from anti-PD1 checkpoint blockade immunotherapy lacked certain beneficial gut bacteria. On the other hand, cancer patients who responded to anti -PD1 immunotherapy possessed gut bacteria whose abundance in the gut correlated with the presence of cancer-killing T-cells. When the researchers transferred gut bacteria from human cancer patients into germ-free mice using fecal matter transplantation (FMT), the rodents mirrored the patient’s fates.

Anti-PD1 immunotherapy “unleashes the brakes on the immune system” by preventing programmed-death-1 (PD-1) binding to programmed-death ligand-1 (PD-L1) on cancer cells, allowing T-cells to attack. However, anti-PD1 immunotherapy is not effective for all cancer patients and responses are not always durable.

The Answer’s in the Poop!

To assess the impact of the microbiome, the MD Anderson team analysed oral and fecal samples of 112 metastatic melanoma patients undergoing anti-PD1 immunotherapy1. 16rRNA and whole genome sequencing was performed to determine diversity, composition and functional potential of the oral and fecal microbiomes. Baseline tumor and blood samples were also analysed.

While no differences in response or progression were found in connection with the oral samples; the 43 fecal samples told another story. Analysis of the fecal microbiome samples (30 of which were responders and 13 non-responders) found that patients with a greater diversity of bacteria in their gut microbiome at baseline had a longer median progression-free survival (PFS). While the high diversity group had not reached median PFS, intermediate and low diversity groups had median PFS of 232 and 188 days, respectively. 

Additional analysis showed that responding patients with high levels of beneficial Clostridiales/Ruminococcaceae had greater presence of anti-tumor T-cells in their tumors, and higher levels of circulating T cells that kill abnormal cells. On the other hand, patients abundant with Bacteriodales had higher levels of circulating regulatory T cells, myeloid derived suppressor cells and a blunted cytokine response, resulting in diminished anti-tumor immunity.

To investigate causal mechanisms, the team transplanted fecal microbiomes from responding patients and non-responding patients into germ-free mice. Those receiving transplants from responding patients had significantly reduced tumor growth as well as higher densities of beneficial T cells in their gut and tumor sites and lower levels of immune suppressive cells. They also had better outcomes when treated with PD-1 axis blockade

Antibiotics May also Affect Anti-PD1 Immunotherapy  

Interestingly, the MD Anderson’s findings complement those of the Gustave Roussy Cancer Campus, France2. Lung, kidney or bladder cancer patients who received antibiotics to treat infection shortly before or after starting anti-PD1 immunotherapy, did not respond as well to treatment. The presence of Akkermansia muciniphila bacteria in both humans and mice was linked to improved responses to anti- PD1 immunotherapy.

Modulation of the Gut Microbiome Could Improve Cancer Prognosis

Although these findings are early, they suggest the connection between the gut microbiome and immune system could have major implications for cancer treatment and prognosis. Further work is needed to analyse the diversity and composition of the gut microbiome to predict response to anti-PD1 immunotherapy; and to modulate the gut microbiome to enhance treatment.

Research has shown that the human microbiome may be modulated by diet, exercise, probiotic or antibiotic use or FMT – however these need to be carefully studied in clinical trials. 

On that note, the MD Anderson team is now planning a clinical trial using strategies to modulate the gut microbiome in patients with metastatic melanoma going onto anti-PD1 (in collaboration with the Parker Institute for Cancer Immunotherapy and Seres Therapeutics). The primary hypothesis of this trial will be that we can safely modulate the gut microbiome in metastatic melanoma patients going on to anti-PD1 therapy.

Tremendous promise but challenges ahead

These findings have important potential implications, though challenges are also evident.  Several issues have been raised by Dr Jennifer Wargo and Dr Vancehswaran Gopalakrishnan given these results.  “These findings have important implications, but we don’t know all the answers yet. Should we be profiling the gut microbiome of patients going onto immunotherapy? And should we tightly monitor antibiotic use in these patients? Furthermore, what other factors – including diet – may be influencing the microbiome? Should we also be profiling the gut microbiome in pre-clinical models where we are testing therapeutic strategies to fight cancer and other diseases? And finally, can we manipulate the microbiome to improve overall health and to facilitate cancer immunosurveillance?”

In addition to this, strategies such as FMT have their own inherent challenges. Although first documented in 4th century China as ‘yellow soup’; FMT has slowly gained popularity over the past years in the US for the treatment of inflammatory gastrointestinal disorders

FMT as a novel adjuvant cancer therapy could bring many rewards, though poses tough challenges. As a cutting-edge forefront therapy, FMT follows unique regulatory oversight. In May 2013, the FDA announced it would regulate FMT as an Investigational New Drug (IND) and Biologics. This classification restricted physicians to file an IND application to use FMT in a clinical trial. However, both patients and physicians raised concerns this would restrict patient access to FMT.

In June 2013, the FDA responded to these concerns and issued its Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies (http://fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm361379.htm).

Under this ruling, qualified physicians can perform FMT for recurrent C. dfficile not responding to standard treatment outside clinical trials without filing for an IND application.

FMT also has other challenges, given variation between preparations. Ultimately, the MD Anderson team and their collaborators hope to identify a live bacterial product incorporating consortia of bacteria implicated in enhancing immunity and therapeutic responses. Though challenges exist, given the potential far-reaching rewards, these efforts are clearly worth pursuing.

References:

  • Gopalakrishnan V. et al., Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 2017 Nov http://dx.doi.org/10.1126/science.aan4236
  • Routy B. et al., Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2017 Nov http://dx.doi.org/10.1126/science.aan3706
  • Matson V. et al., The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science, 2018 Jan http://doi1126/science.aao3290

#microbiome #Arrowhead #cancer #melanoma   #PD-1 inhibitors #Gopalakrishnan #Wargo #MD Anderson Cancer Center #FMT #FDA #Seres Therapeutics #Parker Institute for Cancer Immunotherapy

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YUN Overcomes European Regulatory Issues Surrounding the Use of Live Probiotic Bacteria for Topical Skin Application

These microbiome insights are brought to you by Dr. Ingmar Claes, Chief Scientific Officer at YUN, and Arrowhead Publishers and Conferences. Dr Claes will be presenting YUN’s work at Arrowhead’s 4th Annual Translational Microbiome Conference, 18th-20th April 2018. (www.microbiomeconference.com).

We all know that the skin is critical for our health by serving as a protective layer against external factors, but we tend to overlook the importance of the skin microbiome. The skin microbiome, acid mantle and epidermal skin barrier functions as our first layer of defense against pathogens. Use of products with live beneficial bacteria, also known as probiotics, pharmabiotics, or live biotherapeutic products (LBPs), have the potential of improving dysbosis for a multitude of skin disorders. Such restoration of the microbiome using ‘live’ probiotic bacteria to treat disorders is known as probiotherapy.

YUN is a Belgian-based biotech company with a totally new vision on health and hygiene. YUN aims to take healthcare to the next level. YUN believes in maintaining and restoring the skin microbiome; and the importance of the microbiome for human health. Working closely with leading probiotherapy experts from the University of Antwerp over the past decade, YUN has developed a world premier range of skin products including treatments for pimples (ACN and ACN+) and athlete’s foot (FNG).

World Premier ACN and ACN+ Products
YUN’s ACN and ACN+ products are the first creams (oil in water cream) in the world that contain ‘live’ probiotic bacteria in a dose that will have an impact on the skin microbiome. This major breakthrough was made possible by the development of an innovative type of microcapsule. This new microcapsule contains the ‘live’ bacteria in a core suspension, surrounded by multiple layers to protect them from the water in the cream. Furthermore, YUN strains are ‘probiotic’ which are specifically selected lactobacilli strains. These have some shared mechanisms of action with other probiotic strains, but also have some very specific properties against a selection of pathogenic or problem-causing micro-organisms such as Propionibacteriuim acnes, Trichiphyton spp, Staphylococcus spp., Malassezia spp., Candida spp.

Tough Regulatory Approval Challenges
LBP products face tough regulatory hurdles. Unlike the US in which the FDA’s Center for Biologics Evaluation and Research (CBER) has issued LBP guidelines for industry, the EU lacks regulatory framework. Regulations are lagging behind the new innovations. As in all regulations, safety is considered the most important factor. Thus, safety should always be the first concern when using LBPs.

As a completely new field of products for topical application, YUN faced tough European regulatory approval challenges. YUN has been looking from the start to market its products outside the EU, and it is clear that there are differences in regulations between the US and Europe. Indeed, regarding the FDA LPB product guidelines, it is unclear whether YUN’s topical products fall under the FDA’s definition of LBPs.

Further complicating matters is there are major differences between the safety assessment of oral medical drugs and LBPs for topical use. Specifically, for topical application, the challenges regarding safety should not be neglected. Even though our epidermal skin barrier, the acid mantle layer and the skin microbiome seem to be protective for systemic problems, carefully selected safe ‘probiotic’ strains should be selected for topical application.

As YUN’s topical skin care LBP products are safe and work by restoring or maintaining the skin’s natural defense layer, namely the skin microbiome, they fall in the EU under the cosmetic regulations. These products must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use (cfr. Regulation (EC) N° 1223/2009) and data proving the safety of the probiotic strains being used must therefore be provided.
YUN specifically substantiated for the safety of all their topical products, both at the probiotic strain level and the final product itself. YUN goes even one step further as it wants to address the issues at hand of many of the current topical products which neglect safety on the skin microbiome.

Probiotic Strain Safety Research
YUN specifically performed research for the safety of the probiotic strains both in vitro and in vivo. Indeed, Dr Claes emphasized the importance of the safety of YUN’s probiotic strains particularly during the pre-clinical in vitro screening phase of development. Consequently, all the YUN’s strains were thoroughly characterized at the strain level. Mobile antibiotic resistance elements and virulence factors were investigated and excluded. Furthermore, interactions with human cells were also investigated.

Final Product Level Safety Research
At the final product level, aseptic filling, absence of contaminant pathogenic bacteria and amount of ‘live’ probiotic bacteria had to be proven by YUN. Additionally, the products with ’live’ probiotic strains were clinically evaluated by YUN to underline their level of safety for topical application on the skin.

Quality Control Issues
YUN guarantees the viability of its probiotic bacteria through patented breakthroughs in new galenic formulation and the development of microcapsules shielding its ‘live’ probiotics from water present in creams. Keeping the bacteria in a water-free core suspension ensures a minimal viable dose for up to six months at room temperature as the bacteria’s metabolical activity is minimal in the water-free suspension.

New Regulatory Framework is Needed
Dr Claes explains that by constructing the safety documentation and quality controls in the production of YUN’s products, they could be notified to EU authorities and placed safely on the market. It is therefore clear that safety is the most important aspect for LBPs and should always be addressed correctly. The added therapeutic benefits of these products for topical skin application might be the future for addressing specific skin disorders by using carefully selected probiotic strains.

Furthermore, YUN is a member of the Pharmabiotic Research Institute (PRI) and hopes to constructively interact with the European Medicine Agency (EMA). YUN believes that for some specific applications and products a completely new regulatory framework should be proposed for these new innovative products, which in the first place should always tackle safety before efficacy.

Clearly, approval regulation is lagging behind innovation. European drug authorities must tackle regulatory challenges to produce concise guidelines for industry in the development of LBPs. YUN deserves much credit for not only developing the world’s first ‘live’ probiotic creams in a dose to maintain and restore the skin microbiome, but overcoming tough European regulatory approval challenges.

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Analysis of the Human Microbiome Pipeline: Promising Opportunities to Develop Innovative Products

The human microbiome is an exciting revolutionary space which is captivating the interest of academia and industry alike. Consequently, the current human microbiome pipeline is emerging as a red- hot space with promising opportunities to develop innovative products.

The human microbiome pipeline can be divided into two major applications; therapeutics and diagnostic products. To date, no human microbiome therapeutic or diagnostic product has gained regulatory approval, leaving investors everything to play for. Pipeline therapeutics which modulate the human microbiome include fecal microbiota transplant (FMT), small molecules and live microbes. The human microbiome therapeutic pipeline encompasses a broad range of diseases including cancer, diabetes, asthma, atherosclerosis, nutrition, arthritis, neurological disorders and clostridium difficile infection (CDI). Currently, the human microbiome therapeutic pipeline involves a heated race-to-market for the treatment of CDI, featuring three late- stage products.

Rebiotix’s RBX2660 delivers live, human-derived microbes via enema into the Gl tract for treatment of recurrent CDI.  Rebiotix recently announced it has begun its Phase III trial. Rebiotix’s Phase II trial, known as PUNCH CD found overall efficacy of RBX2660 at treating recurrent CDI was 87%. The Phase IIb PUNCH-CD 2 trial found efficacy was 88%; while the open-label Phase II trial, PUNCH Open Label, showed efficacy was 79% compared with a historical control of 52% (p<0.000). RBX2660 was found to be safe and well tolerated. RBX2660 has been granted FDA Fast Track, Orphan Drug and Breakthrough Therapy designations.

Seres Therapeutics/Nestlé Health Science’s SER-109 is a single-dose oral capsule consisting of bacterial spores enriched and purified from stool samples of healthy, screened human donors. In June 2017, SER-109 commenced its Phase III trial (ECOSPOR III) for the prevention of recurrent CDI. Phase /II results at eight weeks found 97% of patients achieved a clinical cure. Additionally, 87% of patients achieved no diarrhea associated with a positive test for C. difficile. ECOSPOR results at 24 weeks found relatively little new efficacy data compared to eight weeks.  The Phase II open-label extension study ECOSPOR II found SER-109 led to a 32% recurrence rate.  SER-109 was found to be safe and well tolerated. SER-109 has been granted FDA Orphan Drug and Breakthrough Therapy designations.

Synthetic Biologic’s SYN-004 (ribaxamase) is an oral tablet in Phase II development for the prevention CDI and antibiotic-associated diarrhea (ADD). SYN-004 is designed to degrade certain IV beta-lactam antibiotics within the GI tract and maintain the natural balance of the gut microbiome for the prevention of CDI, pathogenic overgrowth and the emergence of antimicrobial resistance (AMR). Phase IIb results found SYN-004 significantly reduced the risk of CDI by 71% versus placebo (p=0.045). Furthermore, SYN-004 significantly reduced new colonization by vancomycin-resistant enterococci versus placebo (p=0.0002). SYN-004 received Breakthrough Therapy Designation from the FDA for the prevention of CDI.

Other gastrointestinal Phase II pipeline candidates include Synthetic Biologics’ SYN-010 and Osel’s CBM588.

Synthetic Biologics’ SYN-010 is continuing to prepare for the initiation of pivotal Phase II/III clinical trials. SYN-010 is a modified-release formulation of lovastatin lactone designed to treat the underlying cause of irritable bowel syndrome with constipation (IBS-C).

Osel’s CBM588 is an oral Clostridium butyricum strain with a strong safety record undergoing development for antibiotic associated diarrhea and CDI. A Phase II study found CBM588 was safe. CBM588 has also been used safely in all age groups in Japan primarily for diarrheal disorders. Recent nonclinical studies support the use of CBM588 in treating IBS.

Other pipeline candidates to watch include:

  • Osel’s Lactin-V live biotherapeutic product for recurrent UTI and Bacterial Vaginosis in Phase II development
  • Microbiome Therapeutics’ NM504 for prediabetes and Type 2 diabetes; and NM505 for diabetes metformin gastrointestinal intolerance, both microbiome modulators in Phase I development
  • Ritter Pharmaceutical’s RP-G28 an oral galacto-oligosaccharide microbiome modulator for lactose intolerance undergoing Phase IIb/III development
  • Intrexon/Orgenics/Merck’s AG103 novel mouth rinse biotherapeutic for oral mucositis in Phase I development

The latest frontier of human microbiome research involves the development of diagnostic methods and tests that provide accurate assessment of the taxonomic compositions of microbiomes associated with complex samples.

Currently there is a head-to-head market race for two key colorectal cancer diagnostics; Metabiomic’s Colon Polyp and Colorectal Cancer Test and Origin Sciences’ Colorectal Cancer (CCR) Test. Metabiomics’ Colon Polyp and Colon Cancer Test is a non-invasive screening test for the detection of colon polyps and colorectal cancer. The Colon Polyp and Colon Cancer Test detects microbial biomarkers linked to dysbosis and colorectal cancer.

Origin Sciences’ CCR Test is under development for the detection of colorectal cancer in both asymptomatic and symptomatic patients. The CRC Test is designed to detect colorectal cancer using biomarker analysis of patient rectal mucosal samples collected using Origin Sciences’ proprietary OriCol device. A pilot study found that ELISA analysis of protein biomarkers collected with OriCol offers a pre-colonoscopy screening tool in patients referred under a two- week criteria rule. Data from the study suggests that a sensitivity of ≥95% can be achieved.

Although no human microbiome therapeutic or diagnostic product has gained FDA approval, promising new opportunities exist to develop novel therapeutics and diagnostic products across a wide range of diseases/therapeutic areas.

Join us to hear more on the human microbiome pipeline at Arrowhead’s 4th Annual Translational Microbiome Conference taking place in Boston, Massachusetts on April 18-20, 2018. (www.microbiomeconference.com)

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