MICA: A Developmental Trial of Personalised Medicine for Repurposing Zibotentan, a Selective Endothelin A Receptor Blocker, in Microvascular Angina.

Angina is a symptom triggered by a lack of blood supply to the heart. Usually, angina is considered as being due to blockages in the main heart arteries, but angina may also occur due to problems with the small vessels (typically, as thin as a hair). In the UK, angina affects around 2 million people, at least one third of whom may have small vessel problems in the heart (microvascular angina (MVA)). The current medicines are used largely by trial and error since the available drugs were not specifically tested in patients with MVA.
Microvascular angina is caused by abnormalities of the small vessels in the heart. The walls of the blood vessels become stiff or thicken and prone to spasm. These problems may limit blood supply to the heart causing anginal chest symptoms during exercise and at other times e.g. cold weather, emotional stress. Physical and psychological symptoms curtail daily activities and reduce quality of life for those affected.
Endothelin is a small chemical that circulates in the blood and can accumulate in the blood and blood vessel walls in patients with MVA. Endothelin causes blood vessels to narrow or go into spasm, and thicken in the longer term especially when endothelin levels are increased in the blood. Endothelin works by acting on one of two pathways (A- or B) and it is the 'A' pathway that causes the blood vessel problems in the heart. Zibotentan is an endothelin A blocker. To our knowledge, zibotentan is the most selective blocker of the A pathway with no effects on the B pathway. Zibotentan had been developed as a treatment for cancer but it did not improve survival. Much is known about zibotentan and the safety profile is better than other endothelin blocker drugs.
Zibotentan is given as a once daily dose of a single tablet (10 milligrams). Based on previous studies, the safety and potential benefits of zibotentan are well established for the 10 mg dose. Research in our University indicates that zibotentan relaxes the small blood vessels of patients with MVA which lends support to the idea that zibotentan may bring benefits to patients with MVA.
What does the study involve? Patients with a diagnosis of MVA will be invited to participate. The eligibility criteria are: age >18 years, angina without blocked heart arteries, NHS test results that indicate a diagnosis of MVA, exercise limitation as revealed by a treadmill test. Patients who have exercise limitation due to non-cardiac health problems would not be eligible to take part. The study will take place in 4 hospitals across the UK.
Initially, 356 patients will be invited to take part for a gene test (eligibility criterion), then 144 will then be enrolled into screening (<= 6 weeks), a 3 week 'run-in' phase to become familiar with the study medication, and finally 100 patients will progress into the main study to receive zibotentan or a dummy tablet (placebo). The main study involves two periods of 12 weeks, with zibotentan (10 mg daily) or a matched placebo. Patients and researchers will not know the type of tablet being taken. The hospital will provide a supply of the tablets for the duration of the study. Overall, there will be 5 visits over approximately 34 weeks. A health check will be performed at each visit, including a blood and a urine test, some quality of life questionnaires, and an exercise test. The patient will be guided and supported by trained staff on how to do the exercise test. Feedback from patients indicated an exercise test was preferable to an MRI heart scan, therefore, MRI is entirely optional. The MRI scanner is shaped like a large polo-mint, and by lying inside it, images of the heart and blood flow can be obtained whilst a drug called adenosine is given to relax the blood vessels. The MRI would be performed on 3 occasions.
Favourable results in this study will support a 'next stage' grant application for a definitive study involving a longer treatment period eg. 6 - 12 months, and in a larger group of patient.

We propose a randomised, double-blind, placebo-controlled, sequential crossover clinical trial of zibotentan in patients with microvascular angina (MVA) to gather information on safety, tolerance, efficacy and potential theragnostic biomarkers (treatment response, discontinuation). The primary outcome, treadmill exercise duration (s) on the Full Bruce protocol, is a measure of aerobic capacity that reflects disease severity. An improvement in exercise time is meaningful to patients and regulators e.g. FDA for licensing medicines for angina. Secondary - quantitative stress cardiac MRI (prioritised), blood/urine biomarkers, QoL & angina questionnaires (patient-orientated outcome measure (PROM)) and zibotentan levels/Pk/Pd.

POWER - To achieve 80% power to detect a mean difference of 30s between treatments in a 2(x)2 crossover design 65 subjects will be needed with complete data. Taking account of test-retest reliability (10%), the final analysis population is n=72. Screen n=356, enrol n=144, randomise n=100.
SETTING - A multicentre study (Cambridge, Glasgow, KCL, Oxford, Royal Free & Blackpool). Reserve sites will cover logistical problems.

INCLUSION
1. Age >18 years
2. MVA confirmed with stress perfusion MRI and/or invasive tests of coronary function.
3. Effort intolerance (impaired exercise time vs. predicted)
EXCLUSION
1. Vasospastic angina without MVA
2. Non-cardiac exercise-limiting problem
3. Women of child-bearing potential
4. Lack of consent
5. Inability to comply with the protocol
6. Genotype criteria not met
INTERVENTION - Adjunctive treatment with zibotentan 10 mg based on efficacy in prior trials (AZ Investigator Brochure (IB)) or matched placebo, once daily for 3 months. Justification (dose): Zibotentan has been extensively studied in preclinical-, healthy volunteer- and phase 2/3 oncology studies. The IB supports safety (no liver toxicity), side-effects (mild-BP lowering, peripheral oedema) & efficacy (Pk-Pd models on vascular function.

Small vessel disease (SVD) in patients is extremely difficult for NHS clinicians to diagnose and treat and is a common cause of unexplained, persistent, chest pain. Genetic and environmental factors are implicated in SVD. Hypertension, obesity, ageing, and diabetes are major public health problems and SVD is causally implicated in the morbidity and mortality from these conditions. Our proposal is directly relevant to public health. Current research indicates that cardiac SVD is a major driver of repeated attendances in Primary and Secondary Care increasing NHS expenditure. In the absence of a specific, evidence-based treatment, microvascular angina (MVA) represents a condition of unmet need worldwide. Our proposal for personalised medicine addresses this gap through advancing scientific knowledge and developing new tests (novel SNP/genomic test and imaging). Zibotentan is an oral endothelin A receptor specific antagonist (ERA) that was discontinued after lack of benefit in oncology trials. We propose a developmental clinical study to reposition zibotentan as a novel treatment for MVA, reducing the health burden of patients with MVA through improvements in symptoms and quality of life, therefore reducing dependency on the NHS. The medicine is 'off-patent' so should be available at low cost to the NHS, potentially driving down the very high costs of ERAs currently.
We have partnered with AstraZeneca (AZ) through the Open Innovation scheme. Impact will be ensured through our Commercial Development Plan that incorporates IP and realistic options for engagement with pharmaceutical industry, notably AZ. We have responded to feedback from the DPFS Panel Members on IP. Opinion from a Patent Attorney supports the case for new IP. Our commercial plan received favourable feedback from other experts (e.g. LifeArc, MRC Workshop, 11 June 2018).
In addressing the challenge, our programme brings together the exceptional expertise of internationally renowned clinicians, scientists and industry partners. Impact will be delivered through a novel approach with genetic testing to stratify patients and enrich the statistical power of the study; pursue and discover new insights into disease mechanisms; advance novel MRI measurements of blood flow in the heart that potentially represent 'diagnostic signatures' of SVD; and repurpose an existing drug as a novel therapy for patients with health problems related to SVD. We will test the concept that a genetic approach for repurposing zibotentan will bring patient benefits, measured by patient reported outcome measures (PROMS) and mechanistic biomarkers (myocardial blood flow quantitative MRI). If our hypotheses are confirmed, we will design a multicentre, Phase 2B trial that will have sufficient scale to impact on guidelines e.g. NICE-95. We have already discussed this possibility with downstream funders (BHF & NIHR-EME; Jan/March 2018).
Carers, including partners, family members and friends, will benefit since improvements in health, well-being and independence should reduce the burden of care generally. Our specific PPI plans will promote knowledge exchange and communicate relevance to society. The NHS will benefit through cost savings in resources through reductions in clinic attendances, hospitalisations and unnecessary medicines.
Impact will be enhanced through 4 leading BHF Centres of Research Excellence (Cambridge, Glasgow, KCL, Oxford), NPL (http://www.npl.co.uk/) and infrastructures enabled by the MRC and EPSRC (Glasgow Molecular Pathology Node). We will partner with collaborators in the US NIH (Arai & Hsu, Cardiovascular MRI) to exploit imaging science. The study involves enthusiastic and meaningful commitments from industry.
The impact from this study will be measured by academic outputs including publications in high impact biomedical journals, citations in clinical guidelines (NICE-95, ESC), and new IP. Impact will be reflected by the outcomes from the Communication Plan from Year 1.