May 26, 2016

Pharmacoepidemiology in Multiple Sclerosis (PiMS) Research Group – Rapid Funding for DSEN Cont’d II

NPI: Sasha Bernatsky

Co-PI: Helen Tremlett and Louise Pilote

Duration: 1 year

We have been funded to enhance the clinical cohort in multiple sclerosis (MS) and  new oral disease-modifying drugs (DMDs) agents.  With the enhanced cohort project, we will focus on the linkage of prospectively collected, patient-level population-based data to create a unique and powerful dataset of administrative health, prescription, and laboratory monitoring information to describe the use of new oral DMD and MS as well as the incidence and potential predictors of adverse events. Additionally, we will enable the study to be expanded and we plan to include a pharmacogenomic component to enable saliva collection.

The following activities were completed:

  • We have recruited 149 patients for the pharmacogenomic sub-study from Vancouver and Winnipeg, and are expecting an estimated 15 additional samples in the coming weeks from these two sites. Our collaborators in Bern, Switzerland are currently summarizing their clinical data and coordinating sample collection from the MS clinic at the Universität Bern
  • We are currently working through expanding the collection of samples and acquiring research ethics board approvals to include the largest MS clinic in Canada, located at St. Michael’s Hospital in Toronto, Ontario with Dr. Dalia Rotstein and Dr. Jiwon Oh. We are also currently working through expanding the collection of samples and acquiring REB approval from the University of Saskatchewan (Saskatoon MS clinic), including Dr. Michael Levin and Dr. Charity Evans.
  • 18 patients were recruited for a micro-biome sub-study: This pilot study was exploratory in nature; we were primarily test piloting our study design. No sample size estimation was performed. However, we anticipate findings to enable us to both design and perhaps power future studies. With the samples now collected, we are discussing the options: to either sequence now or contribute/combine with a larger study. We are currently proceeding with the possibility of collaborating with other research groups to use these samples alongside larger studies of the gut microbiome.

The PiMS research team was awarded a pilot grant from the National Multiple Sclerosis Society in the United States for $50,000 USD in October 2018. The pilot’s aim is to investigate the genomic variants associated with dimethyl fumarated-induced lymphopenia in MS. This would provide funding for genotyping.

Our broad objective for this DSEN study was to investigate the relationship between the disease modifying therapies for multiple sclerosis (MS) and drug safety by utilising genomic information.

The intersection between microbiomics and drug safety is a highly novel field of inquiry, but holds potential to improve drug safety and patient outcomes. While pharmacogenomics has become established as a useful (although often underused) tool for minimizing the risk of adverse drug reactions, there is newly emerging and significant interest in the role of the gut microbiota in drug safety.1,2 There is a major knowledge gap and a real need to understand and explore this intersection between microbiomics and drug safety.

Specifically, for the microbiome sub-study, we aimed to test pilot the feasibility of sampling stool longitudinally from people with MS (pre- and post-drug) and from those with progressive forms of MS. We dedicated one research assistant to identify, recruit, and follow up with potential study participants for 6 months. After 6 months, we evaluated the study progress. Our evaluation showed that recruitment was challenging and resource intensive. Major reasons included: a) setting: we primarily approached patients via the MS clinic. However, there are many competing factors in this environment e.g., anxiety related to car-parking, missing an appointment, nature of the appointment etc and b) return rates on mailed in (stool) samples was low; increasing this return rate was very time intensive, requiring multiple follow-up calls and/or emails from the research assistant. We concluded that the resources required to recruit a sufficient sample size for a study of the microbiome in MS needs to be funded separately from this DSEN funding. We would also make significant changes to the methods of recruitment, including budgeting for a full-time staff member and allowing a much longer recruitment period.

We have created a unique and powerful dataset of administrative health, prescription and laboratory monitoring information by linking prospective data from British Columbia, as it relates to the use of MS disease modifying therapies. We have leveraged the value from DSEN funding to acquire separate funding from the MS Society of Canada to fund this work.

We have enabled saliva collection for a case-control sub-study to develop genetic predictors of adverse drug reactions for two separate adverse drug reactions related to MS drugs: interferon-beta induced liver injury and dimethyl fumarate induced lymphopenia. Recruitment, analysis, and publication are complete for interferon-beta induced liver injury (During the course of this DSEN funding, we finalised the analyses and submitted the manuscript for publication). For dimethyl fumarate induced lymphopenia, we now have saliva from 149 patients from Vancouver and Winnipeg, and are currently working with collaborators in Toronto (St. Michael’s Hospital) and Switzerland (Universität Bern) to increase our sample size, and are aiming to complete recruitment and analysis within the next 12 months.

Following the publication of our pharmacogenomics study on interferon-beta induced liver injury, we anticipate that individuals with MS who are positive for the specific genetic risk variant could be tested prior to commencing this drug. We are currently determining the feasibility of replicating these findings in a separate cohort, and determine whether testing for this genetic variant in clinic would be feasible in the future.

Additionally, as part of the course of this DSEN funded work, if a genetic variant is identified to be associated with dimethyl fumarate lymphopenia, this would represent an additional area for a potential policy implication.

For the pharmacogenomics sub-study, we have communicated the results by the following means:

  1. Scientific publication in Nature Genetics, published 16 July 2018
  • The publication has received an Altmetric Score of 70, since publication on 16/7/2018
    1. Top 5% of all research outputs scored by Altmetric
    2. It is in the 96th percentile compared to outputs of the same age
  1. Twitter, which reached 239,940 followers from 60 tweets, as captured by Altmetric
  2. Presentation at three large international conferences (listed below, under Abstracts)
  3. Published a news release: We collaborated with the public affairs office at the University of British Columbia to create a news release, which has since been covered by the following media outlets:

Abstracts

(underline indicates presenting author)

  1. Kowalec K, Kingwell E, Carruthers R, Traboulsee A, Wright GEB, Drögemöller BI, Aminkeng F, Bernatsky S, Ross CJD, Carleton BC, Tremlett H. The pharmacogenomics of serious adverse drug reactions associated with disease modifying therapies for multiple sclerosis: work in progress. Poster presentation to the American Society of Human Genetics 2016 Annual Meeting, Vancouver B.C., October 18-22, 2016.
  2. Kowalec K, Wright GEB, Drögemöller BD, Aminkeng F, Bhavsar AP, Kingwell E, Yoshida EM, Traboulsee A, Marrie RA, Kremenchutzky M, Campbell T, Duquette P, Chalasani N, Wadelius M, Hallberg P, Xia Z, De Jager P, Ross CJD, Tremlett H, Carleton B. Genome-wide scan identifies association between an interferon regulatory factor variant and interferon-beta induced liver injury in multiple sclerosis patients. Oral presentation at the Canadian Society for Pharmacology and Therapeutics/Safety Pharmacology Society Annual Meeting, Vancouver B.C., September 2016. Winner of Top Trainee Oral Presentation Award.
  3. Kowalec K, Wright GEB, Drögemöller BD, Aminkeng F, Bhavsar AP, Kingwell E, Yoshida EM, Traboulsee A, Marrie RA, Kremenchutzky M, Campbell T, Duquette P, Chalasani N, Wadelius M, Hallberg P, Xia Z, De Jager P, Ross CJD, Tremlett H, Carleton B. Genome-wide scan identifies association between an interferon regulatory factor variant and interferon-beta induced liver injury in multiple sclerosis patients. Poster presentation at the European Committee for Treatment and Research in Multiple Sclerosis Annual Congress, London, U.K., September 2016. Short-listed for poster prize (Top 5% of 1,985 abstracts).
  4. Kowalec K, Wright GEB, Drögemöller BD, Aminkeng F, Bhavsar AP, Kingwell E, Yoshida EM, Traboulsee A, Marrie RA, Kremenchutzky M, Campbell T, Duquette P, Chalasani N, Wadelius M, Hallberg P, Xia Z, De Jager P, Ross CJD, Tremlett H, Carleton B. Genome-wide scan identifies association between an interferon regulatory factor variant and interferon-beta induced liver injury in multiple sclerosis patients. Poster presentation at the EndMS National Conference, Toronto, ON, December 2016.

Publications

  1. Kowalec K, Wright GEB, Drögemöller BI, Aminkeng F, Bhavsar AP, Kingwell E, Yoshida EM, Traboulsee A, Marrie RA, Kremenchutzky M, Campbell TL, Duquette P, Chalasani N, Wadelius M, Hallberg P, Xia Z, De Jager P, Ross CJD, Tremlett H, Carleton BC. (2018) Common variation near IRF6 is associated with IFN-̟ß-induced liver injury in multiple sclerosis. Nat Genet, 50(8) :1081-85.
  2. Kowalec K, Kingwell E, Carruthers R, Marrie RA, Traboulsee A, Bernatsky S, Ross CJD, Carleton B, Tremlett H. (2017) Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case-control study protocol for dimethyl fumarate induced lymphopenia. BMJ Open, 7(5): e016276.

For more information contact: Jessica (Lifang) Wang. Research Coordinator. [email protected]   514.934.1934 ext.44718