Galcanezumab for Prevention of Chronic Cluster Headache

March Horizon Scanning Research & 2017 Intelligence Centre

Galcanezumab for prevention of chronic cluster headache

NIHR HSRIC ID: 11257

Lay summary

Galcanezumab is a drug for chronic cluster headaches, which are severe headaches on one side of the head that require constant pain relief. Most attacks occur during sleep, with recurring attacks lasting a year or more. Galcanezumab is taken once a month, blocking a protein which is involved in this type of headache.

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

• Cluster headache (CH): chronic – prophylactic therapy.

TECHNOLOGY

DESCRIPTION

Galcanezumab (LY-2951742) is a humanised monoclonal antibody that selectively binds to calcitonin gene related peptide (CGRP), a potent vasodilator released from neurons which acts locally on smooth muscle in blood vessels causing neurogenic inflammation1. Results from several human studies have demonstrated that serum levels of CGRP obtained from the external jugular vein are elevated in patients during cluster headaches2.

In clinical trials, galcanezumab is administered by subcutaneous (SC) injection (3 x 1mL aliquots) at 300mg once every 30 days.

Galcanezumab is also in a phase III clinical trial for the prevention of migraine headache.

INNOVATION and/or ADVANTAGES

Inhibiting the activity of CGRP has the potential to reduce its effects on vasodilation, inflammation and pain thereby offering an additional treatment option for the prevention of chronic cluster headache. Galcanezumab also has a long half-life and therefore requires infrequent dosing, which may be preferred for the management of chronic headache conditions1.

DEVELOPER

Eli Lilly and company Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Cluster headache is the most prominent of the idiopathic primary headaches, also termed the trigeminal autonomic cephalalgias (TACs), which result from vascular changes in cranial circulation driven by trigeminal autonomic reﬂex activation3. Cluster headache present as unilateral, often severe headache attacks in the trigeminal nerve area lasting from 15 minutes to 3 hours, and usually with cranial autonomic symptoms such as rhinorrhoea, lacrimation, miosis, ptosis, and periorbital oedema on the same side3,4. Around 85-90% of patients have episodic cluster headache (eCH), where attack periods may last from 7 days to 1 year, separated by month long pain-free intervals. The remaining 10-15% have chronic cluster headache (cCH) with attack periods lasting for >1 year either without remission or with remission periods of less than a month3. Cluster headache appears to be seasonal with episodes occurring at the same time each year, peaking soon after the longest or shortest Horizon Scanning Research & Intelligence Centre

days of the year; and at the same time each day with about two-thirds of attacks occurring during sleep. The periodicity of the attacks suggests the involvement of hypothalamic function and circadian rhythm5.

Factors shown to induce cluster headache attacks include subcutaneous injection of histamine; stress; allergens; seasonal changes; nitro-glycerine; and alcohol6. Risk factors for cluster headache include gender (cluster headache predominantly occurs in males); age (most common in those <30 years); vasodilators (e.g. alcohol); previous head trauma or surgery; and smoking, with around 80% of cluster headache patients being heavy smokers6.

CLINICAL NEED and BURDEN OF DISEASE

The lifetime prevalence of cluster headache is around 0.1-0.3%7,8, and the 1-year prevalence is estimated at 5 per 10,0008 (approximating 27,400 people with cluster headache, and between 2,700-4,100 people with chronic cluster headache in England). Cluster headache can be life-long with recurrent attacks and occasional transformation of episodic cluster headache to chronic and vice versa6.

Cluster headache imposes substantial burdens on quality of life and health care resource utilisation, with typical health care costs of more than €11,000 per year9. Cluster headache worsens work absenteeism and social functioning, and is typically accompanied by clinically signiﬁcant disability such as psychiatric comorbidities3. Patients with cluster headache are at increased risk for self-injury during attacks, as well as substance abuse, cigarette smoking, peptic ulcer disease, and suicidal tendencies in severe cases6. Late onset of the disorder, male gender, and previous episodic cluster headache all predict a less favourable course6. Both direct costs (e.g. medication, clinic visits) and indirect costs (e.g. reduced work capacity) have been found to be substantially higher for patients with chronic cluster headache than for those with episodic cluster headache9.

In 2015, there were 1,720 admissions for cluster headache (G44.0) in England, resulting in 1,465 bed days and 1,537 finished consultant episodes10.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE clinical guideline. Headaches in over 12s: diagnosis and management (CG150). September 2012. • NICE quality standard. Headaches in over 12s (QS42). August 2013. • NICE interventional procedure guidance. Transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine. (IPG552). March 2016. • NICE interventional procedure guidance. Implantation of a sphenopalatine ganglion stimulation device for chronic cluster headache (IPG527). June 2015. • NICE interventional procedure guidance. Deep brain stimulation for intractable trigeminal autonomic cephalalgias (IPG381). March 2011.

NHS England Policies and Guidance

• NHS England. 2013/14 NHS Standard Contract for Specialised Pain: Specialised Services for Pain Management (Adult). D08/S/a.

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• NHS England. Clinical Commissioning Policy: Occipital Nerve Stimulation for Adults with Intractable Chronic Migraines and Medically Refractory Chronic Cluster Headaches. NHS England D08/P/c. July 2015.

Other Guidance

• The American Headache Society. Treatment of Cluster Headache: The American Headache Society Evidence-Based Guidelines. 201611. • Scottish Intercollegiate Guidelines Network. Management of chronic pain (SIGN 136). 201312. • NHS Clinical Knowledge Summary. Headache – cluster. 201213. • Evers S, Áfra J, Frese A et al. Cluster headache and other trigemino-autonomic cephalgias. 201114. • British Association for the Study of Headache. Guidelines for all healthcare professionals in the diagnosis and management of migraine, tension-type, cluster and medication- overuse headache. 201015. • Scottish Intercollegiate Guidelines Network. Diagnosis and management of headache in adults (SIGN 107). 200816. • European Federation of Neurological Societies. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. 200617

CURRENT TREATMENT OPTIONS

The treatment of cluster headache can be divided into acute, transitional and prophylactic treatment. Prophylactic therapy is perhaps the most important component of management and aims to reduce the frequency, severity and duration of attacks18,19. Current treatment options for chronic and episodic cluster headache include20,21,22,23:

Acute First-line • 5HT1-receptor agonists o Sumatriptan (SC [unlicensed for this indication]). o Zolmitriptan (intranasal [unlicensed for this indication]). • 100% oxygen therapy. Second-line • Ergot Alkaloids o Ergotamine tartrate (SC [unlicensed for this indication]) – for short bouts only. • 5HT1-receptor agonist o Sumatriptan (intranasal [unlicensed for this indication]). Refractory • Transcutaneous stimulation of the cervical branch of the vagus nerve • Deep brain stimulation – chronic • Implantation of a sphenopalatine ganglion stimulation device – chronic • Radiofrequency ablation of the sphenopalatine ganglion – chronic

Prophylaxis • Pizotifen. • Verapamil hydrochloride (unlicensed for this indication). • Corticosteroids o Prednisolone (unlicensed for this indication) alone or in combination with verapamil hydrochloride. • Lithium (unlicensed for this indication).

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• Ergot Alkaloids o Ergotamine tartrate (SC [unlicensed for this indication]). • Topiramate (unlicensed for this indication).

EFFICACY and SAFETY

Trial NCT02397473, 15780, I5Q-MC-CGAL, NCT02438826, 15781, I5Q-MC-CGAM, 2015-000149-22; LY2951742 vs placebo; 2014-005429-11; LY2951742 vs placebo; phase III. phase III. Sponsor Eli Lilly and Company. Eli Lilly and Company. Status Ongoing. Ongoing. Source of Trial registry24, manufacturer. Trial registry25, manufacturer. information Location EU (incl UK), USA, Canada and other EU (incl UK), USA, Canada and other countries. countries. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=162 (planned); aged 18-65 years; n=162 (planned); aged 18-65 years; episodic cluster headache. chronic cluster headache. Schedule Randomised to LY2951742 300mg SC or Randomised to LY2951742 300mg SC or placebo SC, once every 30 days for 8 placebo SC, once every 30 days for 12 wks. wks. Follow-up Active treatment for 8 wks. Active treatment for 12 wks. Primary Change in number of weekly cluster Change in number of weekly cluster outcome/s headache attacks. headache attacks. Secondary ≥50% reduction in number of weekly ≥50% reduction in number of weekly outcome/s cluster headache attacks; ≥30% reduction cluster headache attacks; ≥30% reduction in number of weekly cluster headache in number of weekly cluster headache attacks; Patient Global Impression of attacks; PGI-I; anti-drug antibodies. Improvement (PGI-I); anti-drug antibodies. Expected Study completion date reported as Apr Study completion date reported as May reporting 2018. 2019. date

Trial NCT02797951, 16351, I5Q-MC-CGAR 2015-005234-21; LY2951742; phase IIIb extension. Sponsor Eli Lilly and Company. Status Ongoing. Source of Trial registry26, manufacturer. information Location EU (incl UK), USA, Canada and other countries. Design Non-randomised, uncontrolled. Participants n=300 (planned); aged 18-65 years; episodic or chronic cluster headache; completed study NCT02397473 or NCT02438826. Schedule LY2951742 300mg SC once every 30 days for 12 mths. Follow-up Active treatment for 12 mths, follow-up for 3 yrs. Primary Treatment emergent adverse events (AEs) or Serious AEs; suicidal ideation and outcomes behaviors collected by Columbia - Suicide Severity Rating Scale (C-SSRS). Secondary Anti-drug antibodies. outcome Expected Study completion date reported as Aug 2020. reporting date

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ESTIMATED COST and IMPACT

COST

The cost of galcanezumab is not yet known. Pizotifen is currently the only drug licensed for the prevention of cluster headache. A pack of pizotifen 28 x 1.5mg tablets (for once daily administration) costs £2.3220.

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other: improved quality of life for patients,  No impact identified wider societal benefits (e.g. earlier return to normal activities, including employment).

Impact on Health and Social Care Services

 Increased use of existing services: SC  Decreased use of existing services administration.

 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: additional costs for  Other reduction in costs SC administration in clinic.

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Karsan N and Goadsby PJ. Calcitonin gene-related peptide and migraine. Current Opinion in Neurology 2015;28(3):250-54. 2 Durham PL. Inhibition of calcitonin gene-related peptide function: a promising strategy for treating migraine. Headache 2008;48(8):1269-75. 3 Silberstein SD, Mechtler LL, Kudrow DB et al. Non-Invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 Study. Headache 2016;56(8):1317-32. 4 UpToDate. May A. Cluster headache: Epidemiology, clinical features, and diagnosis. May 2014. http://www.uptodate.com/contents/cluster-headache 5 Pringsheim T. Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. The Canadian Journal of Neurological Sciences 2002;29:33-40. 6 Medscape. Blanda M. Cluster headache. Accessed 18 January 2017. http://emedicine.medscape.com/article/1142459-overview 7 Stovner LJ and Andree C. Prevalence of headache in Europe: a review for the Eurolight project. The Journal of Headache and Pain 2010;11(4):289-99.

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8 Fischera M, Marziniak M, Gralow I et al. The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia. 2008;28(6):614-18. 9 Morris J, Straube A, Diener HC et al. Cost-effectiveness analysis of non-invasive vagus nerve stimulation for the treatment of chronic cluster headache. The Journal of Headache and Pain 2016;17:43. doi: 10.1186/s10194-016-0633-x 10 Health & Social Care Information Centre. Hospital episode statistics for England. Admitted patient care, 2015-16. www.hscic.gov.uk 11 Robbins MS, Starling AJ, Pringsheim TM et al. Treatment of cluster headache: The American headache society evidence-based guidelines. Headache 2016;56(7):1093-106. 12 Scottish Intercollegiate Guidelines Network. Management of chronic pain. National clinical guideline 136. Edinburgh: SIGN; December 2013. 13 National Institute for Health and Clinical Excellence. Clinical knowledge summaries. Headache – cluster. Revised November 2012. http://cks.nice.org.uk/headache-cluster#!backgroundsub:2 Accessed 25 January 2017. 14 Evers S, Áfra J, Frese A et al. European handbook of neurological management: volume 1, 2nd edition. Edited by N. E. Gilhus, M. P. Barnes and M. Brainin. 2011 Blackwell Publishing Ltd. 15 British Association for the Study of Headache. Guidelines for all healthcare professionals in the diagnosis and management of migraine, tension-type, cluster and medication-overuse headache.3rd edition (1st revision). September 2010. 16 Scottish Intercollegiate Guidelines Network. Diagnosis and management of headache in adults. National clinical guideline 107. Edinburgh: SIGN; November 2008. 17 May A, Leone M, Afra J et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. European Journal of Neurology 2006;13(10):1066-77 18 National Institute for Health and Clinical Excellence. Headaches in over 12s: diagnosis and management. Clinical Guideline CG150. London: NICE; September 2012. 19 Becker WJ. Cluster headache: Conventional pharmacological management. Headache 2013; 53(7):1191-96. 20 Joint Formulary Committee. British National Formulary. BNF September 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com 21 Patient. Cluster headaches. http://patient.info/health/cluster-headaches-leaflet Accessed 25 January 2017. 22 National Institute for Health and Care Excellence. NICE Pathways. Management of headaches. Cluster headaches. https://pathways.nice.org.uk/pathways/ Accessed 25 January 2017. 23 National Institute for Health and Care Excellence. Transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine. Interventional procedure consultation document. London: NICE; November 2015. 24 ClinicalTrials.gov. A study of LY2951742 in participants with episodic cluster headache. https://clinicaltrials.gov/ct2/show/NCT02397473 Accessed 17 January 2017. 25 ClinicalTrials.gov. A study of LY2951742 in participants with chronic cluster headache. https://clinicaltrials.gov/ct2/show/NCT02438826 Accessed 17 January 2017. 26 ClinicalTrials.gov. A study of LY2951742 (galcanezumab) in participants with cluster headache. https://clinicaltrials.gov/ct2/show/NCT02797951 Accessed 17 January 2017.