February Horizon Scanning Research & 2017 Intelligence Centre

Mirogabalin for pain due to fibromyalgia

NIHR HSRIC ID: 10050

Lay summary

Mirogabalin is a new drug to treat pain associated with fibromyalgia. Fibromyalgia is a long-term condition that causes pain all over the body. Mirogabalin is taken by mouth once a day at bedtime. If licensed, mirogabalin may offer patients with fibromyalgia an additional treatment option.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Pain due to fibromyalgia – first line.

TECHNOLOGY

DESCRIPTION

Mirogabalin (DS5565; mirogabalin besylate) is a voltage-dependent calcium channel subunit alpha-2/delta-1 ligand intended for the treatment of pain associated with fibromyalgia. It is structurally related to gabapentin and pregabalin. In a phase III clinical trial1, it is administered orally at 15mg once a day at bedtime. The intended treatment duration has not been reported.

Mirogabalin does not currently have Marketing Authorisation in the EU for any indication.

Mirogabalin is not currently in clinical development in the EU for any other indication.

INNOVATION and/or ADVANTAGES

If licensed, mirogabalin will offer an additional treatment option for patients with fibromyalgia.

DEVELOPER

Daiichi Sankyo Co.

AVAILABILITY, LAUNCH OR MARKETING

Currently in phase III clinical trials.

PATIENT GROUP

BACKGROUND

Fibromyalgia syndrome (FMS) is a common rheumatologic condition characterised by chronic widespread pain and reduced pain threshold, with hyperalgesia and allodynia. Associated features include fatigue, depression, anxiety, sleep disturbance, headache, migraine, variable bowel habits, diffuse abdominal pain, and urinary frequency2,3. The effects of these symptoms vary from person to person and from day to day. Many people have flare- ups from time to time when their symptoms become suddenly worse2. The pain associated with fibromyalgia is generally continuous, but can fluctuate in severity3. It tends to be felt as diffuse aching or burning, often described as head to toe4. Although the pathogenesis of fibromyalgia is remains unclear, current research indicates increasing evidence for peripheral and central hyperexcitability at the spinal or brainstem level, altered pain perception, and somatisation5,6. The onset of fibromyalgia can be sudden or gradual, traumatic or non-traumatic6.

Until recently, the diagnosis of fibromyalgia was made based on specific tender points in certain areas of the body. However, new guidelines were released in 2010 by the American College of Rheumatology to address concerns about the diagnostic criteria. The previous Horizon Scanning Research & Intelligence Centre

criteria did not take into account other important symptoms, such as fatigue, sleep disturbance and cognitive dysfunction, and did not account for fluctuations in disease, symptom severity or effectiveness of new treatments. The current guidelines recommend that healthcare professionals should consider the following features when making a diagnosis: widespread pain lasting three months or more, fatigue and/or waking up feeling unrefreshed, and problems with thought processes such as memory and understanding (cognitive symptoms)7,8.

CLINICAL NEED and BURDEN OF DISEASE

Fibromyalgia is a common rheumatological illness; it is more common than rheumatoid arthritis and may be even more painful. Fibromyalgia is much more common in women, with females outnumbering males in a ratio of 9:1. The most common age group affected is between 45–60 years, though it can occur at any age, including children. There is no reported difference in frequency between ethnic or social groups6.

The prevalence of fibromyalgia in the general population is estimated to be approximately 5.4% (95% CI 4.7% to 6.1%)9,a. This equates to approximately 2,958,460 people in England.

In 2014-15, there were 3,968 admissions for fibromyalgia (M79.7) in England, resulting in 2,489 bed days and 4,124 finished consultant episodes10.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

No relevant guidance.

NHS England Policies and Guidance

No relevant guidance.

Other Guidance

• The European League Against Rheumatism (EULAR). EULAR revised recommendations for the management of fibromyalgia. 201611. • Scottish Intercollegiate Guidelines Network. Management of chronic pain (SIGN 136). 201312. • The European League Against Rheumatism (EULAR). EULAR evidence-based recommendations for the management of fibromyalgia syndrome. 200713.

CURRENT TREATMENT OPTIONS

There is currently no cure for fibromyalgia, however there are treatments and therapies available to help patients with specific aspects of the condition. These may include pharmaceuticals, but physical and other therapies are also important. Medications to help

a The study used to generate this figure used a modification of the ACR (2010) preliminary diagnostic criteria for fibromyalgia, which relies on self-reported pain and somatic symptoms and was developed specifically for epidemiological studies.

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with pain, sleep disturbance or depression associated with fibromyalgia may be offered. Typically these do not eradicate pain, but they may help to reduce symptoms to a level that will enable gentle physical activity and other rehabilitation therapies.

Drugs routinely offered and recommended by guidelines include11: • Amitriptyline – first lineb. • Serotonin-noradrenaline re-uptake inhibitors (e.g. duloxetine and milnacipran). • Anticonvulsants (e.g. pregabalin and gabapentin). • Opioids (e.g. Tramadol) – usually offered only after amitriptyline, serotonin- noradrenaline re-uptake inhibitor and anticonvulsant therapy, or in combination with these therapiesc.

Non-pharmacological interventions recommended for reducing pain include11: exercise, biofeedback, cognitive behavioural therapies, acupuncture, hydrotherapy, meditative movement, and mindfulness.

EFFICACY and SAFETY

Trial NCT02187471, NCT02187159, NCT02146430, mirogabalin vs pregabalin mirogabalin vs pregabalin mirogabalin vs pregabalin or placebo; phase III. or placebo; phase III. or placebo; phase III. Sponsor Daiichi Sankyo Co. Daiichi Sankyo Co. Daiichi Sankyo Co. Status Ongoing. Ongoing. Ongoing. Source of Trial registry14. Trial registry15. Trial registry1. information Location EU (not incl UK), USA, and EU (incl UK), USA, and EU (not incl UK), USA, and other countries. other countries. Canada. Design Randomised, placebo and Randomised, placebo and Randomised, placebo and active-controlled. active-controlled. active-controlled. Participants n=1,301 (planned); aged n=1,270 (planned); aged n=1,294 (planned); aged ≥18 yrs; fibromyalgia as ≥18 yrs; fibromyalgia as ≥18 yrs; fibromyalgia as defined by the 1990 defined by the 1990 ACR defined by the 1990 ACR American College of criteria for fibromyalgia: criteria for fibromyalgia: Rheumatology (ACR) widespread pain present widespread pain present criteria for fibromyalgia: for ≥3 months and pain in for ≥3 months and pain in widespread pain present ≥11 of 18 specific tender ≥11 of 18 specific tender for ≥3 months and pain in point sites; must also meet point sites; must also meet ≥11 of 18 specific tender the 2010 ACR criteria: WPI the 2010 ACR criteria: WPI point sites; must also meet ≥7 and SS scale score ≥5, ≥7 and SS scale score ≥5, the 2010 ACR criteria: or WPI 3 to 6 and SS or WPI 3 to 6 and SS scale widespread pain index scale score ≥9; symptoms score ≥9; symptoms have (WPI) ≥7 and symptom have been present at a been present at a similar severity (SS) scale score similar level for ≥3 months; level for ≥3 months; ≥5, or WPI 3 to 6 and SS no disorder that would no disorder that would scale score ≥9; symptoms otherwise explain the pain; otherwise explain the pain; have been present at a ADPS ≥4 on the 11-point ADPS ≥4 on the 11-point similar level for ≥3 months; NRS over the past 7 days NRS over the past 7 days no disorder that would (based on completion of (based on completion of otherwise explain the pain; ≥4 daily pain diaries); ≥4 daily pain diaries); average daily pain score documented evidence of a documented evidence of a (ADPS) of ≥4 on the 11- fundoscopic examination fundoscopic examination point numeric rating scale (with pupil dilation) within (with pupil dilation) within (NRS) over the past 7 12 mths prior to screening 12 mths prior to screening days (based on completion or at screening. or at screening.

b Expert personal communication.

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of ≥4 daily pain diaries); documented evidence of a fundoscopic examination (with pupil dilation) within 12 mths prior to screening or at screening. Schedule Randomised to Randomised to Randomised to mirogabalin 15mg oral mirogabalin 15mg oral mirogabalin 15mg oral once daily at bedtime; or once daily at bedtime; or once daily at bedtime; or mirogabalin 15mg oral mirogabalin 15mg oral mirogabalin 15mg oral twice daily (titrated from twice daily (titrated from twice daily (titrated from 15mg once daily after 1 15mg once daily after 1 15mg once daily after 1 week, during the first week week, during the first week week, during the first week subject will take placebo in subject will take placebo in subject will take placebo in the morning); or the morning); or the morning); or pregabalin pregabalin 150mg oral pregabalin 150mg oral 150mg oral twice daily, twice daily, one in the twice daily, one in the one in the morning and at morning and at bedtime morning and at bedtime bedtime (during the first (during the first week of (during the first week of week of blinded-treatment, blinded-treatment, blinded-treatment, subjects will take one subjects will take one subjects will take one pregabalin 75mg capsule pregabalin 75mg capsule pregabalin 75mg capsule in the morning and one in the morning and one in the morning and one pregabalin 75mg capsule pregabalin 75mg capsule pregabalin 75mg capsule at bedtime); or placebo, at bedtime); or placebo, at bedtime); or placebo, taken orally in the morning taken orally in the morning taken orally in the morning and one at bedtime and one at bedtime and one at bedtime Follow-up Active treatment for 13 Active treatment for 13 Active treatment for 13 wks. wks. wks. Primary ADPS. ADPS. ADPS. outcome/s Secondary Patient global impression Patient global impression Patient global impression outcome/s measure; Fibromyalgia measure; FIQ; MFI-20; measure; FIQ; MFI-20; Impact Questionnaire HADS; SF-36 HADS; SF-36 (FIQ); Multidimensional questionnaire; quality of questionnaire; quality of Fatigue Inventory (MFI- life as assessed by EQ- life as assessed by EQ- 20); Hospital Anxiety and 5D; pain associated sleep 5D; pain associated sleep Depression Scale (HADS); interference as assessed interference as assessed Short Form 36 (SF-36) by ADSIS and MOS Sleep by ADSIS and MOS Sleep questionnaire; quality of Scale; BPI-SF; proportion Scale; BPI-SF; proportion life as assessed by of days a rescue of days a rescue EuroQoL Instrument 5 medication was used; medication was used; AEs. Domains (EQ-5D); pain AEs. associated sleep interference as assessed by the average daily sleep interference score (ADSIS) and the Medical Outcomes Study (MOS) Sleep Scale; Brief Pain Inventory Short Form (BPI-SF); proportion of days a rescue medication was used; adverse events (AEs). Expected Estimated study Estimated study Estimated study reporting completion date reported completion date reported completion date reported date as Jan 2017. as Mar 2017. as Mar 2017.

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Trial NCT02234583, mirogabalin 15mg NCT02496884, mirogabalin vs once daily vs twice daily; phase III placebo; phase III. extension. Sponsor Daiichi Sankyo Inc. Daiichi Sankyo Inc. Status Ongoing. Ongoing. Source of Trial registry16. Trial registry17. information Location EU (incl UK), USA, and other countries. USA only. Design Non-randomised. Randomised, placebo-controlled. Participants n=2,091 (planned); completed n=60 (planned); aged ≥18 yrs; estimated participation (i.e. completed the End-of- creatinine clearance between 15- Tapering visit) in a preceding study of DS 59ml/min; meeting the 2010 ACR criteria: 5565 in fibromyalgia (NCT02187471; WPI ≥7 and SS scale score ≥5, or WPI 3 NCT02187159; NCT02146430); not to 6 and SS scale score ≥9; symptoms experienced any significant safety issues have been present at a similar level for during the preceding study that, in the ≥3 mths; no disorder that would investigator's judgment, would adversely otherwise explain the pain; ADPS score impact the subject's well-being in the ≥4 on the 11 point NRS for ≥7 days; no long-term extension. other severe pain that might impair the assessment of neuropathic pain. Newly diagnosed patients: aged ≥18 yrs; fibromyalgia as defined by the 1990 ACR criteria for fibromyalgia: widespread pain present for ≥3 months and pain in ≥11 of 18 specific tender point sites; must also meet the 2010 ACR criteria: WPI ≥7 and SS scale score ≥5, or WPI 3 to 6 and SS scale score ≥9; symptoms have been present at a similar level for ≥3 months; no disorder that would otherwise explain the pain; ADPS ≥4 on the 11-point NRS over the past 7 days (based on completion of at least 4 daily pain diaries): documented evidence of a fundoscopic examination (with pupil dilation) within 12 mths prior to screening or at screening. Schedule Patients receive mirogabalin15mg oral Patients with moderate chronic kidney once daily at bedtime; or mirogabalin disease are randomised to mirogabalin 15mg oral twice daily, once in the 7.5mg oral twice daily, or placebo oral morning and once at bedtime. twice daily. Patients with severe chronic kidney disease are randomised to mirogabalin 7.5mg oral once daily, or placebo oral once daily. Follow-up Active treatment for 52 wks. Active treatment for 13 wks, follow up for 4 wks. Primary AEs; number of subjects experiencing an AEs up to week 13. outcome/s abnormal value of a clinical laboratory test, both up to wk 52. Secondary ADPS; ADSIS; Patient Global Impression ADPS; PGIC. outcome/s of Change (PGIC); HADS; EQ-5D; SF- 36; physical examination; ECG; the Columbia-Suicide Severity Rating Scale (C-SSRS); the Physician Withdrawal Checklist (PWC). Expected Estimated study completion date Estimated study completion date reporting reported as Aug 2017. reported as Jun 2017. date

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ESTIMATED COST and IMPACT

COST

The cost of mirogabalin is not yet known.

A 56 capsule pack of pregabalin 150mg costs £38.6418. Therefore 13 weeks of active treatment with pregabalin 150mg oral twice daily would cost £154.56.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments.

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion suggests that if the intention is for potential patients to continue using mirogabalin beyond 13 weeks, then data is needed to at least 12 months before clinicians will take notice. Furthermore, all guidelines, and particularly recent EULAR guidelines, stress the need for non-medical therapies such as CBT and graduated exercise as well as medication in managing patients with fibromyalgia. Therefore these trials which look at drugs alone don’t reflect what should be done in practice and may underestimate benefit when all measures are used togetherc.

The requirement for potential patients to comply with both 1990 and 2010 ACR criteria (as detailed in the trial inclusion criteria) sets a high threshold as it is well known that many will fit one but not both sets as they are quite different. This may make it difficult to then

c Expert personal communication.

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place the drug for those seen in practice who fulfil one criteria but not the otherd.

An expert also states, ‘I am not sure what the proposed place will be as there is no data yet. If equivalent to pregabalin, then the cheapest will find its way onto the formulary. If only mirogabalin is licensed but more expensive then I think pregabalin will win as it's already so familiar to hospital pain teams. Some may go for gabapentin first (as they do now) if cheaper than pregabalin or mirogabalin in the absence of any comparative trials…In practice, the question will be what to do after amitriptyline and duloxetine/milnaciprin’d.

REFERENCES

1 ClinicalTrials.gov. Treatment of pain associated with fibromyalgia. https://clinicaltrials.gov/ct2/show/NCT02146430 Accessed 09 January 2017. 2 Arthritis Research UK. What are the symptoms of fibromyalgia? http://www.arthritisresearchuk.org/arthritis-information/conditions/fibromyalgia/symptoms.aspx Accessed 09 January 2017. 3 NHS Choices. Fibromyalgia – Symptoms. http://www.nhs.uk/Conditions/Fibromyalgia/Pages/Symptoms.aspx Accessed 09 January 2017. 4 Fibromyalgia Action UK. Patient booklet. http://www.fmauk.org/information-packs-mainmenu- 58/booklet-mainmenu-135/490-patient-booklet Accessed 10 January 2017. 5 BMJ Best Practice. Fibromyalgia. Pathophysiology. http://bestpractice.bmj.com/best- practice/monograph/187/basics/pathophysiology.html Accessed 10 January 2017. 6 Fibromyalgia Action UK. Information: medical pack. http://www.fmauk.org/information-packs- mainmenu-58/medical-pack-mainmenu-59?showall=&start=3 Accessed 10 January 2017 7 Arthritis Research UK. How is fibromyalgia diagnosed? http://www.arthritisresearchuk.org/arthritis-information/conditions/fibromyalgia/diagnosis.aspx Accessed 09 January 2017. 8 UK Fibromyalgia. What is FM? http://ukfibromyalgia.com/what-is-fm.php Accessed 09 January 2017. 9 Jones GT, Atzeni F, Beasley M et al. The Prevalence of Fibromyalgia in the General Population: A Comparison of the American College of Rheumatology 1990, 2010, and Modified 2010 Classification Criteria. Arthritis and Rheumatology 2015;67(2):568-575. 10 Health & Social Care Information Centre. Hospital Episode Statistics for England. Admitted Patient Care, 2014-15. www.hscic.gov.uk 11 Macfarlane GJ, Kronisch C, Dean LE et al. EULAR revised recommendations for the management of fibromyalgia. Annals of the Rheumatic Diseases 2017;76:318-328. 12 Scottish Intercollegiate Guidelines Network (SIGN). Management of chronic pain. National clinical guideline 136. Edinburgh: SIGN; December 2013. 13 Carville SF, Arendt-Nielsen L, Bliddal H et al. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Annals of Rheumatic Diseases 2008;67:536-41. 14 ClinicalTrials.gov. Treatment of pain associated with fibromyalgia. https://clinicaltrials.gov/ct2/show/NCT02187471 Accessed 16 January 2017. 15 ClinicalTrials.gov. Treatment of pain associated with fibromyalgia. https://clinicaltrials.gov/ct2/show/NCT02187159 Accessed 16 January 2017. 16 ClinicalTrials.gov. An open-label extension study of DS-5565 for 52 weeks in pain associated with fibromyalgia. https://clinicaltrials.gov/ct2/show/NCT02234583 Accessed 16 January 2017. 17 ClinicalTrials.gov. Safety study of DS-5565 for treatment of fibromyalgia pain in subjects with chronic kidney disease. https://clinicaltrials.gov/ct2/show/NCT02496884 Accessed 16 January 2017. 18 Joint Formulary Committee. British National Formulary. BNF January 2017. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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