Novartis achieves important regulatory milestone for AMG 334 (erenumab) in migraine prevention with EMA filing acceptance

Jun 21, 2017
  • AMG 334 (erenumab) is the first anti-CGRP monoclonal antibody developed for migraine prevention to receive EMA regulatory filing acceptance
     
  • Filing is supported by a comprehensive clinical program of over 2,600 migraine patients demonstrating sustained efficacy and placebo-like safety profile of AMG 334 (erenumab)
     
  • EMA submission acceptance is a first step towards addressing a significant unmet need for people with migraine, who have had very few new treatment options since the 1990's

Basel, June 21, 2017 - Novartis today announced that the European Medicines Agency (EMA) has accepted its Marketing Authorization Application (MAA) for AMG 334 (erenumab) for the prevention of migraine. Erenumab is an anti-CGRP monoclonal antibody developed to prevent migraine. It is the only one that is fully human and binds selectively to the CGRP receptor, believed to play a critical role in mediating the incapacitating pain of migraine.[1]

"Novartis has a longstanding history of redefining clinical practice in neurology by bringing innovative medicines to those with the greatest need. We look forward to continuing this legacy by working with the European health authorities on our goal to make our fully human monoclonal antibody, erenumab, the first new therapy available to migraine patients in over a decade," said Vas Narasimhan, Global Head Drug Development and Chief Medical Officer for Novartis.

The regulatory submission to the EMA includes data from four Phase II and III clinical studies involving more than 2,600 patients experiencing four or more migraine days per month. These and other data will be presented at the 3rd Congress of the European Academy of Neurology (June 24-27, 2017, Amsterdam, the Netherlands). Across the comprehensive clinical program, erenumab demonstrated clinically meaningful, statistically significant and sustained efficacy versus placebo in reducing the number of migraine days per month. Erenumab also showed significant improvements on the impact migraine had on patients' disability and Quality of Life (emotional well-being and everyday life, such as missed work days or time spent away from friends and family), compared to placebo. In all studies, the safety profile of erenumab was comparable to placebo.[2],[3],[4] In addition, an extension trial is ongoing, evaluating its long-term safety in people with migraine for up to five years.

Migraine is a chronic neurological disease characterized by recurrent attacks of moderate to severe head pain that is typically pulsating, often unilateral and associated with nausea, vomiting and sensitivity to light, sound and odors.[5],[6] Migraine has a profound and limiting impact on patients' abilities to carry out everyday tasks and as such, the World Health Organization has declared migraine to be one of the top ten causes of disability for men and women.[7],[8] It remains an area of significant unmet medical need. Existing preventive therapies have been repurposed from other indications and are often associated with poor tolerability and lack of efficacy, which lead to increasing discontinuation rates and dissatisfaction among patients.[9],[10]

Novartis and Amgen will co-commercialize AMG 334 (erenumab) in the US. Amgen has exclusive commercialization rights in Japan and Novartis has exclusive commercialization rights in rest of world. The companies will continue global co-development.[11]

About the AMG 334 (erenumab) Clinical Trials Program
Erenumab has been extensively studied in several large global, randomized, double-blind, placebo-controlled trials to assess its safety and efficacy in migraine prevention in more than 2,600 people. It has the longest established safety profile of all CGRP therapies and has an ongoing extension trial assessing safety out to five years.

About the AMG 334 (erenumab) Phase II chronic migraine study
This pivotal Phase II study is a global, randomized, 12-week, double-blind, placebo-controlled study evaluating the efficacy and safety of erenumab in the prevention of chronic migraine (characterized as at least 15 headache days per month, of which eight or more are migraines, for more than three months).[12] In the study, 667 patients were randomized to receive once-monthly subcutaneous placebo or erenumab 70mg or 140mg in a 3:2:2 ratio respectively.[12] Patients experienced an average of approximately 18 migraine days per month at baseline. The primary outcome measure was the change in monthly migraine days from baseline to the last four weeks of the 12-week treatment phase in patients with chronic migraine (the number of migraine days between weeks nine and 12).[12]

About AMG 334 (erenumab) Phase III episodic migraine studies
STRIVE (NCT02456740) is a global Phase III, multicenter, randomized 24-week, double-blind, placebo-controlled study evaluating the safety and efficacy of erenumab in episodic migraine (characterized as up to 14 migraine days a month) prevention.[13] In the study, 955 patients were randomized to receive once-monthly subcutaneous placebo, or erenumab (70mg or 140mg) in a 1:1:1 ratio.[13] Patients experienced between four and 14 migraine days each month, with an average of 8.3 migraine days per month at baseline.[13] The primary endpoint was change in mean monthly migraine days from baseline over the last three months of the double-blind treatment phase of the study (months four, five and six).[13]

The ARISE study (NCT02483585) is a global Phase III, multicenter, randomized 12-week, double-blind, placebo-controlled study evaluating the safety and efficacy of erenumab in episodic migraine prevention.[14] In the study, 577 patients were randomized to receive once-monthly subcutaneous placebo or erenumab (70mg) in a 1:1 ratio.[14] Patients enrolled in ARISE were experiencing between four and 14 migraine days each month with an average of approximately 8.3 migraine days per month at baseline.[14] The primary endpoint was change in monthly migraine days from baseline to the last four weeks of the 12-week treatment phase in patients with episodic migraine (the number of migraine days between weeks nine and 12).[14]

About AMG 334 (erenumab)
Erenumab is a fully human monoclonal antibody specifically designed to target and block the Calcitonin Gene-Related Peptide (CGRP) receptor, believed to play a critical role in mediating the incapacitating pain of migraine.[15] Erenumab has been studied in several large global, randomized, double-blind, placebo-controlled trials to assess its safety and efficacy in migraine prevention.

About Migraine
Migraine is a distinct neurological disease. It involves recurrent attacks of moderate to severe head pain that is typically pulsating, often unilateral and associated with nausea, vomiting and sensitivity to light, sound and odors.[5],[6] Migraine is associated with disability and reduced quality of life, and financial cost to society.[8] It has a profound and limiting impact on an individual's abilities to carry out everyday tasks, and was declared by the World Health Organization to be one of the top 10 causes of years lived with disability for men and women.[7] It remains under-recognized and under-treated.[8],[9] Existing preventive therapies have been repurposed from other indications and are often associated with poor tolerability and lack of efficacy, which lead to increasing discontinuation rates and dissatisfaction among patients.[10] The cause and triggers of migraine are not fully understood as no two migraines are the same. However, Calcitonin Gene-Related Peptide (CGRP) has long been thought to play a role in the underlying pathophysiology of migraine.[16] CGRP is a molecule that binds to the CGRP receptor complex, and is thought to be responsible for transmitting the pain signals associated with migraine.[17] Levels of CGRP have been found to increase at the onset of migraine symptoms, and to return to normal when the migraine pain diminishes.[18] CGRP is also involved in vasodilation and sensory transmission which takebelei place during a migraine.[15]

About Amgen and Novartis Neuroscience Collaboration
In August 2015, Amgen entered into a global collaboration with Novartis to jointly develop and commercialize pioneering treatments in the field of migraine and Alzheimer's disease (AD). The collaboration focuses on investigational Amgen drugs in the migraine field, including erenumab (Biologics License Application submitted to U.S. FDA and EU EMA in May 2017) and AMG 301 (currently in Phase 1 development). In April 2017, the collaboration was expanded to include co-commercialization of erenumab in the U.S. For the migraine program, Amgen retains sole commercialization rights in Japan, and Novartis has commercialization rights in Europe, Canada and rest of world. Also, the companies are partnering in the development and commercialization of a beta-secretase 1 (BACE) inhibitor program in AD. The oral therapy CNP520 (currently in Phase II/III for AD) is the lead molecule and further compounds from both companies' pre-clinical BACE inhibitor programs may be considered as follow-on molecules.

Novartis in Neuroscience
Novartis has a strong ongoing commitment to neuroscience (NS) and to bringing innovative treatments to patients suffering from neurological conditions where there is a high unmet need. We are committed to supporting patients and physicians in multiple disease areas, including Multiple Sclerosis (MS), Alzheimer's disease, Parkinson's disease, Epilepsy and Attention Deficit Hyperactivity Disorder, and have a promising pipeline in MS, Alzheimer's disease, migraine and specialty neurology (e.g. neuropathic pain).

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "milestone," "first step," "believed," "look forward," "continuing," "will," "ongoing," "evaluating," "pioneering," "investigational," "submitted," "may," "commitment," "committed," "promising," "pipeline," "goal" or similar terms, or by express or implied discussions regarding potential marketing approvals for AMG 334, CNP520, AMG 301, other BACE inhibitors of Novartis and Amgen, and other investigational compounds of Novartis and Amgen subject to the collaboration, potential new indications or labeling for products in the Novartis Neuroscience portfolio, or regarding potential future revenues from such investigational compounds and products, and potential future revenues from the collaboration with Amgen. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that AMG 334, CNP520, AMG 301, other BACE inhibitors of Novartis and Amgen, or other investigational compounds of Novartis and Amgen subject to the collaboration will be submitted or approved for sale in any market, or at any particular time. Neither can there be any guarantee that the collaboration with Amgen will achieve any or all of its intended goals and objectives, or be commercially successful. Nor can there be any guarantee that any product in the Novartis Neuroscience portfolio will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that AMG 334, CNP520, AMG 301, any of the other investigational compounds subject to the collaboration with Amgen, or any product in the Novartis Neuroscience portfolio will be commercially successful in the future. In particular, management's expectations regarding such investigational compounds and products, and the collaboration with Amgen, could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing and reimbursement pressures; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

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References
[1] Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013 Oct 1;81(14):1191-6. doi: 10.1212/WNL.0b013e3182a6cb72.
[2] Novartis presents new positive data at EHMTIC showing AMG 334 significantly reduces monthly migraine days in chronic migraine. https://www.novartis.com/news/media-releases/novartis-presents-new-positive-data-ehmtic-showing-amg-334-significantly-reduces. Accessed June 2017.
[3] Novartis announces Phase III study shows AMG 334 significantly reduces monthly migraine data in people with episodic migraine. https://www.novartis.com/news/media-releases/novartis-announces-phase-iii-study-shows-amg-334-significantly-reduces-monthly. Accessed June 2017.
[4] Novartis announces AMG 334 significantly reduces monthly migraine days in second pivotal Phase III episodic migraine study. https://www.novartis.com/news/media-releases/novartis-announces-amg-334-significantly-reduces-monthly-migraine-days-second. Accessed June 2017.
[5] Migraine Research Foundation. Migraine Fact Sheet. 2015. http://www.migraineresearchfoundation.org/fact-sheet.html. Accessed June 2017.
[6] National Institute for Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/All-Disorders/Migraine-Information-Page (link is external). Accessed June 2017.
[7] World Health Organization. Estimates for 2000-2012. Disease Burden. 2012.
[8] World Health Organization. Headache disorders. http://www.who.int/mediacentre/factsheets/fs277/en/ (link is external). Accessed June 2017.
[9] Diamond S et al. Patterns of Diagnosis and Acute and Preventive Treatment for Migraine in the United States: Results from the American Migraine Prevalence and Prevention Study. Headache. 2007;47(3):355-63.
[10] Hepp Z, et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015; 35(6):478-88.
[11] Novartis expands global collaboration with Amgen to commercialize first-in-class AMG 334 (erenumab) program in migraine prevention in the US and Canada https://www.novartis.com/news/media-releases/novartis-expands-global-collaboration-amgen-commercialize-first-class-amg-334 Accessed June 2017.
[12] ClinicalTrials.gov A study to evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine Prevention. https://clinicaltrials.gov/ct2/show/NCT02066415?term=20120295&rank=1(Link  Accessed June 2017.
[13] ClinicalTrials.gov. Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (STRIVE). https://clinicaltrials.gov/ct2/show/NCT02456740 (link is external). Accessed June 2017.
[14] ClinicalTrials.gov. Study to Evaluate the Efficacy and Safety of AMG 334 Compared to Placebo in Migraine Prevention (ARISE). https://clinicaltrials.gov/ct2/show/NCT02483585?term=ARISE+amg+334&rank=1 (link is external). Accessed June 2017.
[15] Bigal ME et al. Calcitonin Gene-Related Peptide (CGRP) and Migraine Current Understanding and State of Development. Headache. 2013;53(8):1230-1244
[16] Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552.
[17] Hansen JM et al. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010; 30(10):1179-86.
[18] Lassen et al. CGRP may play a causative role in migraine. Cephalalgia. 2002 Feb;22(1):54-61. Available http://www.ncbi.nlm.nih.gov/pubmed/11993614.

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