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12 Articles in Volume 18, Issue #4
A New Frontier in Migraine Management: Inside CGRP Inhibitors & Migraine Prevention
Assessment of Patients with Rheumatoid Arthritis or Osteoarthritis
Biosimilars in Rheumatology: How Popular Will They Be?
Case Studies in Regenerative Cellular Therapy: Tendinopathy and Osteoarthritis
Commentary: Make the Easy Choice for Care
Editorial: The Emergence of Trackable Pill Technology: Hype or Hope?
Editorial: The Practicality of Pain Acceptance
How to Avert Government Scrutiny When Prescribing Opioids
Letters to the Editor: DEA and Prescribing, the War on Statistics, Failing Treatments, Patients' Options
Meet the Migraine Game-Changers
Platelet-Rich Plasma and Stem Cell-Rich Prolotherapy for Musculoskeletal Pain
With concerns over opioids, could novel receptors be useful?

Meet the Migraine Game-Changers

Amgen/Novartis, Allergan, Lilly, and Teva recap the data that is moving their CGRP migraine preventives to the finish line.

In  this exclusive roundtable, Amgen/Novartis, Allergan, Lilly, and Teva recap the data that is moving their CGRP migraine preventives to the finish line.

Introduction to CGRPs by Lawrence Robbins, MD

Update: Key CGRP prescribing considerations and possible long-term side effects.

 

Amgen/Novartis

HQ: Thousand Oaks, CA and Basel, Switzerland
Product: erenumab-aaoe (Aimovig, preventive)
Status: FDA approved Aimovig in May 2018 for the prevention of migraine in adults.

Perspective by Cen Xu, PhD
Scientific Director, Amgen

Patients endure and manage around migraine disease. As such, people with migraine may feel as though time has been taken from them, or constantly live in anticipation of the next migraine attack. Compounding this effect, many migraine patients may not find the relief they need with existing treatment options, or cannot tolerant them.1

Aimovig is a newly approved agent specifically designed to prevent migraine by blocking the receptor of the calcitonin gene-related peptide (CGRP), which plays a key role in migraine pathophysiology. It is the result of a decade-long neuroscience research and development effort using Amgen’s 35-plus years of experience—particularly in antibodies technology. We are applying this expertise in entering into the neuroscience space to treat some of the most debilitating diseases, as part of our mission to serve patients.

Aimovig was approved by the FDA in May 2018 for the preventive treatment of migraine in adults. Aimovig is administered once monthly using Amgen’s SureClick autoinjector, a single-use autoinjector. Monthly self-injection offers patients the ability to administer their medication from home, while still under the regular supervision of their care provider.

Aimovig brings a long-awaited novel, treatment option to patients living with a disease that has been largely misunderstood and plagued with significant gaps in the way it is both perceived by the public and treated in the clinic. Amgen, and our collaborator Novartis, hope this will offer excitement and a new chance of relief for patients living with this disease.

Perspective by Marcia Kayath, MD, PhD, MBA
Senior Vice President, US Clinical Development & Medical Affairs Head, Novartis

Over the course of clinical research and development, Aimovig was studied in several large global, randomized, double-
blind, placebo-controlled studies to assess its safety and efficacy in migraine prevention. More than 3,000 patients participated in the Aimovig clinical program across four placebo-controlled Phase 2 and Phase 3 clinical studies and their open-label extensions.

In the pivotal Phase 3 STRIVE study in patients with episodic migraine, patients taking Aimovig experienced a significant reduction in monthly migraine days versus placebo and were significantly more likely to achieve a 50% or greater reduction in monthly migraine days than those taking placebo. The results of this study reinforced existing evidence for the consistent benefits of Aimovig demonstrated across the spectrum of chronic and episodic migraine, including patients who failed on previous preventive treatments.2

In the STRIVE study, adverse events occurring in greater than 5% of all treatment arms were nasopharyngitis and upper respiratory tract infection. More than 90% of patients in the Aimovig-treated arms completed the six-month study. Adverse events leading to discontinuation of treatment occurred in 2.2% of patients in either Aimovig treatment arm and in 2.5% of patients receiving placebo.

People living with migraine are missing out on many daily activities due to this debilitating neurological disease, and are in need of additional preventive treatment options. Together with Amgen, Novartis is committed to bringing this much-needed treatment option to patients as soon as possible. As a leader in neuroscience for more than 70 years, we are dedicated to partnering with patients and doctors in an effort to change the lives of people impacted by neurological conditions, and it is our hope that Aimovig will help patients get back more days from migraine.

Allergan

HQ: Dublin, Ireland
In the Pipeline: ubrogepant (acute); atogepant (preventive)
Status: In March 2019, Allergan announced the FDA Acceptance of their NDA for Ubrogepant. A PDUFA date has been set by the FDA for Q4 2019. Click here to learn more; atogepant Phase IIb topline results expected in 2018.

Perspective by David Nicholson,
Chief Research and Development Officer

While acute and preventive treatment options currently exist, of the 30 million migraine patients in the United States, less than one third – or an estimated 8 million people – are treated with a prescription medication.3-5 Clearly, there are patients who are underserved, underdiagnosed, and undertreated. Allergan, which has been studying migraine for more than 20 years, continues to work toward advancing the science behind migraine.

The new category of CGRP receptor antagonists may offer an opportunity in the treatment of migraine. Allergan has four investigational oral CGRP trials for ubrogepant (acute treatment of migraine attack) and one for atogepant (preventive treatment of migraine) running in the US, where safety and efficacy have yet to be established. CGRP receptor antagonists may provide additional acute and preventive treatment options through a new mechanism of action for treating migraine. CGRP receptors have been localized to many areas of the central nervous system (CNS) that are involved in the pathophysiology of migraine, with studies suggesting that serum CGRP levels elevate during migraine attacks.6,7

Two pivotal Phase 3 trials for ubrogepant, ACHIEVE I and ACHIEVE II, demonstrated positive topline results in efficacy, safety, and tolerability; results were released earlier this year. ACHIEVE I included 1,327 US adult patients randomized to placebo, ubrogepant 50mg, or ubrogepant 100mg, who were treated for a single migraine attack of moderate-to-severe headache intensity. The study met co-primary endpoints. Both doses showed a statistically significant greater percentage of ubrogepant patients achieving pain freedom at 2 hours after initial dose compared to placebo patients (50 mg vs placebo, p = 0.0023; 100 mg vs placebo, p = 0.0003) and a statistically significant greater percentage of ubrogepant patients achieving absence of the most bothersome migraine-associated symptoms at 2 hours after the initial dose compared to placebo patients (50 mg vs placebo, p = 0.0023; 100 mg vs placebo, p = 0.0023).

ACHIEVE II evaluated the efficacy, safety, and tolerability of orally administered ubrogepant 25 mg and ubrogepant 50 mg compared to placebo in a single migraine attack in adults. The study included 1,355 US adult patients (modified ITT population) randomized (1:1:1) to placebo, ubrogepant 25 mg and 50 mg respectively, who were treated for a single migraine attack of moderate-to-severe headache intensity.

In ACHIEVE I and ACHIEVE II, ubrogepant was well tolerated with an adverse event profile similar to placebo. The most common adverse events were nausea, somnolence, and dry mouth (reported with a frequency ≤5%).

We are very excited about the potential of CGRP-blocking drugs that may provide new treatment options for many patients living with this debilitating disease.

Eli Lilly and Company

HQ: Indianapolis, IN
In the Pipeline: galcanezumab (preventive migraine and cluster headache) ; lasmiditan (acute)
Status: Galcanezumab - Update: approved by FDA Sept. 27, 2018 as Emgality for preventive migraine, June 2019 for episodic cluster headache; lasmiditan NDA to be filed in Q4 2018. 

Perspective by Eric Pearlman, MD, PhD
Medical Fellow

Lilly has spent more than two decades working to develop innovative migraine therapies, including galcanezumab, a preventive treatment option that may help people experience fewer migraine days. A monoclonal antibody specifically designed to bind to and inhibit the activity of CGRP, which is believed to play a role in migraine and cluster headache, without binding to the receptor, galcanezumab is under evaluation as a once-monthly, self-administered subcutaneous injection.

Pivotal Phase 3 studies (EVOLVE-1, EVOLVE-2, and REGAIN) evaluating galcanezumab have demonstrated patients treated with two doses of galcanezumab (120 mg and 240 mg) experienced a statistically significantly greater decrease in the average number of monthly migraine headache days compared to placebo. In all three studies, the primary endpoint was the mean change from baseline in monthly migraine headache days over the six-month (EVOLVE-1 and EVOLVE-2) and three-month (REGAIN) double-blind treatment periods, respectively.

FDA is reviewing galcanezumab for the prevention of migraine in adults, and a decision is expected in the third quarter of 2018. Lilly also recently completed a Phase 3 trial evaluating the antibody for the treatment of episodic cluster headache. The study met both its primary and secondary endpoints, demonstrating statistically significant differences in reduction of weekly cluster headache attacks compared to placebo and statistically significant improvements in response rate compared to placebo. (Of note, a separate Phase 3 study for patients with chronic cluster headache, which represents 10 to 15% of cluster headache cases, did not meet its primary endpoint.) These studies, which evaluated a combined 343 patients, are the largest controlled preventive trials conducted in cluster headache to date.

If galcanezumab is approved, we hope that the once-monthly, self-administered solution will enable the safe and accurate delivery of this new preventive therapy. As demonstrated in two Phase 3 studies of patients with episodic migraine, a statistically significantly greater percentage of patients treated with both doses of galcanezumab achieved at least a 50%, 75%, and 100% reduction in the number of migraine headache days compared to placebo over the six-month treatment period, in both studies after multiplicity adjustment. Looking ahead, galcanezumab may provide a much-needed treatment option for the millions of Americans struggling to effectively manage migraine who may be losing up to 50 days of productivity a year.

There are a number of acute treatments used for migraine that are available over-the-counter or as a prescription, including triptans and non-steroidal anti-inflammatory drugs (NSAIDs). The preventive treatments that are currently approved for episodic and chronic migraine were all developed for other indications initially. There are also a number of acute, preventive, and transitional treatments used for cluster headache that are available over-the-counter or as a prescription, including triptans and corticosteroids. Despite these approved options, there are still many people with migraine and cluster headache who are poorly served by currently available therapies, demonstrating a strong unmet need for new, innovative treatment options.

In the US, in particular, approximately 39% of people diagnosed with migraine are eligible for preventive treatment, but less than half actually receive a preventive treatment. Approximately 50% of patients with migraine discontinue a newly prescribed preventive treatment within 60 to 90 days. The CGRP antibodies – including galcanezumab – represent a significant innovation in the preventive treatment of migraine and cluster headache, aimed at reducing the number of migraine attacks, lessening the intensity of pain, and preventing the onset of future attacks.

Migraine can occur at any age but is most prevalent among people between ages 25 and 55, often a person’s most productive years. Knowing this, it is our hope that products like galcanezumab may provide a treatment regimen that supports these individuals’ active lifestyles through a once-monthly, self-administered injection via auto-injector pen or prefilled syringe.

Overall, Lilly is excited to be a part of ushering in a new era of potential choices for people with primary headache disorders, and we hope to soon be able to equip physicians with options that may help address the unique and varied needs of those with migraine and cluster headache.

Additional perspective by Kraig Kinchen, MD
Sr. Medical Director, Migraine & Related Therapeutics

Lilly’s pain portfolio includes lasmiditan, an oral, first-in-class molecule under evaluation for the acute treatment of migraine. Lasmiditan represents one of the first significant innovations for the acute treatment of migraine in more than 20 years. Lasmiditan is the only oral drug in development of its kind that selectively targets 5-HT1F receptors, including those expressed in the trigeminal pathway, and has been designed for the acute treatment of migraine without the vasoconstrictor activity associated with some migraine therapies.

In SPARTAN, a second Phase 3 study, a greater percentage of patients treated with lasmiditan were migraine pain-free compared to placebo at two hours following the first dose. Lasmiditan also demonstrated statistically significantly greater percentage of patients free of their most bothersome symptom (MBS) compared with placebo at two hours following the first dose. In SPARTAN, patients chose their MBS from nausea, sensitivity to sound or sensitivity to light.

It is important to note that even with effective preventive treatment, many people living with the disease may still experience migraine attacks. Lilly does not have evidence to support lasmiditan’s effectiveness in preventing migraine from becoming chronic.

Teva Pharmaceuticals

HQ: North Wales, PA
In the Pipeline: fremanezumab (preventive); Update: FDA Approved September 2018
Status: BLA submitted; FDA action expected Q3/Q4 of 2018.

Perspective by Joshua M. Cohen, MD, MPH, FAHS
Global Therapeutic Area Lead Migraine & Headache, Global Medical Affairs

Teva Pharmaceutical’s fremanezumab is an investigational, fully humanized monoclonal antibody (IgG2∆a) that selectively targets CGRP. Clinical trials to investigate the efficacy and safety of fremanezumab included two Phase II trials – one in episodic migraine and one in chronic migraine – and two Phase III trials known as HALO.

Patients in HALO were jointly screened and then randomized into either the chronic migraine or episodic migraine trial based upon their baseline frequency of headache days per month. The Phase III clinical trials included a subset of patients – approximately 20% in each trial – who continued use of a pre-existing preventive medication to more closely mimic real world clinical practice. Fremanezumab was evaluated in two distinct subcutaneous dosing regimens – monthly and quarterly (once every three months).

In the Phase III chronic migraine study (n = 1,036), patients receiving fremanezumab monthly experienced 4.6 fewer headache days per month, on average, compared to 2.5 days with placebo. Patients receiving fremanezumab quarterly experienced 4.3 fewer headache days per month, on average, compared to 2.5 days with placebo. In the Phase III episodic migraine trial (n = 875), the baseline mean number of monthly migraine days was 8.9, 9.2, and 9.1 days in monthly dosing, quarterly dosing, and placebo groups, respectively. During the 12-week period after the first dose, fremanezumab treatment significantly reduced monthly migraine days to 4.9 days for monthly (P < 0.001) and 5.3 days for quarterly (P < 0.001) dosing compared with 6.5 days for placebo.

Responder rates may provide a clinically relevant assessment for clinicians as patients may wish to understand their likelihood of achieving a certain level of response. In the episodic migraine trial, 47.7% of patients receiving fremanezumab monthly and 44.4% of patients receiving fremanezumab quarterly experienced a reduction of at least 50% in the monthly average number of migraine days (27.9% with placebo). In the chronic migraine trial, 40.8% of patients receiving fremanezumab monthly and 37.6% of patients receiving fremanezumab quarterly experienced a reduction of at least 50% in the monthly average number of migraine days (18.1% with placebo).

In the fremanezumab Phase II and III trials, the most common adverse events occurring in greater than or equal to 2% of patients and with greater frequency in treatment arms than placebo were the injection site reactions induration, erythema, and pruritus. Less than 2% of patients in fremanezumab and placebo groups discontinued treatment due to adverse events. Anti-drug antibodies (ADAs) were detected in 6 out of 1701 (0.4%) fremanezumab-treated patients over the course of the 12-week trials.

Recognizing the burden of migraine, currently ranked second among all diseases in years lost to disability, fremanezumab trials included validated migraine disability assessments – HIT-6 and MIDAS – as key secondary outcome measures in the Phase III program. In the chronic migraine trial, 63% of patients achieved a clinically meaningful reduction in HIT-6 score versus 53% with placebo, while in the episodic migraine trial, patients experienced an average 55% reduction in disability as measured by the MIDAS versus 47% for placebo.

Data for other Phase III endpoints have been presented at the following congresses: American Headache Society (June 2017), International Headache Congress (September 2017), European Headache Federation (December 2017), and the American Academy of Neurology (April 2018). Primary and secondary outcome measures for the Phase III chronic migraine trial were published in the New England Journal of Medicine in November 2017, while Phase III outcomes for episodic migraine were released in JAMA in May 2018. Fremanezumab is also being evaluated in two active Phase III clinical trials for the prevention of episodic and chronic cluster headache (which was granted FDA fast-track designation) and a Phase II clinical trial for the prevention of post-traumatic headache.*

Read about Teva's research into fremanezumab for cluster headache.

 

Device Options Continue to Emerge

In addition to the new CGRP class, there are a number of medical devices continuing to make headway in the treatment and prevention of migraine. Neuromodulators deliver targeted pharmaceutical agents, electrical signals, or other forms of energy to the neural pathways affected by the disease. Among those entering the market are single pulse transcranial magnetic stimulation (sTMS) devices, such as the eNeura from Spring TMS, which offers a portable, self-administered option, and elecroCore’s gammaCore, a non-invasive vagus nerve stimulator, indicated for the acute treatment of pain associated with migraine and episodic cluster headache in adult patients. (electroCore is close to completing migraine prevention trials as well).

Also available is Cefaly Technology’s external trigeminal nerve stimulation (e-TNS) device, which features acute and preventive settings for use during a migraine attack with or without aura. The device has proved successful in clinical trials examining effect on migraine abortion and pain relief compared to triptans and the investigative oral anti-CGRP therapies. More alternative devices are in the works, including Theranica’s electrical arm patch.

Just how do these devices compare to traditional medication? A Cephalalgia study published by Starling et al. in March 2018 analyzed the effects of sTMS devices using headache diary submissions from approximately 220 eligible patients with migraine; data incorporated a 1-month baseline followed by 3 months of treatment. The protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients were asked to describe their daily headache status and medication use, and data was compared to a statistically-derived placebo estimate (performance goal).

Researchers reported a −2.75 ± 0.40 mean reduction in headache days from baseline (9.06 days) compared to the performance goal (−0.63 days) (p < 0.0001). Secondary results were also significant, with migraine frequency reduced.

It is possible these standalone devices may also help patients reduce or avoid Medication Overuse Headache, which is common among chronic migraine sufferers who use a variety of medications to relieve their pain, noted the research team.

*Editor’s Note: Alder Pharmaceuticals, whose CGRP inhibitor eptinezumab is scheduled for regulatory review in 2019, and BioHaven Pharmaceuticals, developer of the oral CGRP rimegepant, were unable to contribute to this roundtable.

Last updated on: June 7, 2019
Continue Reading:
At Stake: The Possible Long-Term Side Effects of CGRP Antagonists
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