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Atogepant, an orally administered “gepant”, reduced the monthly migraine days by more than 50 percent in a phase 3 study. The data from this study and a phase 2/3 study have been submitted to the US Food and Drug Administration for approval.
Atogepant, an oral molecule designed to block the calcitonin gene-related peptide receptor (CGRP), reduced the number of monthly migraine days compared to placebo by more than 50 percent over a three-month test period, according to the results of a phase 3 – Study published August 19 in the New England Journal of Medicine.
Data from this Phase 3 study and another Phase 2/3 study have been submitted to the US Food and Drug Administration (FDA), and the drug is expected to be approved for migraine prevention by the end of the year.
Atogepant belongs to the “gepants” class of drugs that work by blocking cell receptors for CGRP, a protein released from the trigeminal nerve during migraines. Gepants has been shown to reduce future attacks by about 50 percent.
In May, the FDA approved another Gepant, Rimegepant, for the acute treatment of migraines, taken orally under the tongue every other day. Atogepant is taken once a day.
Companies have also developed monoclonal antibodies to block CGRP and they are approved for migraine prevention but are given as an infusion or subcutaneous injection once a month or every three months.
“In this study, we found that some patients improved on the first day,” said study lead author Jessica Ailani, MD, professor of clinical neurology and director of the MedStar Georgetown Headache Center. “It makes a lot of sense for patients to immediately say that they are better.”
The drug is still being studied in patients with chronic migraines. Initially, Allergan developed the drug and AbbVie bought the company and continued filing new drugs with the FDA.
Study design, results
The scientists enrolled over 900 people with episodic migraines from approximately 128 locations across the country and the UK. Study researchers included headache specialists from Georgetown, the Albert Einstein College of Medicine and the Montefiore Headache Center, the National Institute for Health Research-Wellcome Trust King’s clinical research facility, King’s College London, UCLA and AbbVie.
Study participants were not allowed to take preventive migraine medication for 30 days before the first visit and only after the three-month study was completed. The patients were examined weekly during the three-month study. During the pandemic, patients were allowed to make remote visits for up to two months and then come for a face-to-face visit when labs were drawn and other assessments were made.
The researchers analyzed the results of 873 study participants who were randomized into three dose groups: 10 mg, 30 mg, and 60 mg; or a placebo. The patients had a mean baseline of 7.5 to 7.9 migraines per month. The primary endpoint was a reduction in the number of migraine days over 12 weeks.
“In this study, we found that some patients improved on the first day. Letting patients say they feel better immediately is very meaningful. ”- DR. JESSICA AILANI
Investigators reported that people who took the 60-mg dose had 4.2 fewer migraine days; those who received 30 mg had 3.9 fewer migraine days and the 10 mg group had 3.7 fewer migraine days per month. People who received placebo had 2.5 days fewer migraines, which isn’t surprising, said Dr. Ailaini as they are in a blinded clinical trial and placebo effects are common.
But even after taking the placebo response into account, the improvement in the medication groups from 1.2 fewer monthly days to 1.7 fewer monthly days was statistically significant. These improvements could mean up to 20 migraine-free days per year for those on the highest dose, said Dr. Ailani.
The secondary endpoints included the number of monthly headaches, a reduction in monthly migraine days of at least 50 percent compared to baseline, the quality of life and the results of an 11-point daily diary that collects questions about activity and physical impairment: Activity impairment in migraine Diary or AIM-D and AIM-P for physical impairments. Most of the secondary endpoints showed an advantage for the drug over placebo, with the exception of study participants on the 10 mg dose who showed no advantage in the AIM-D and AIM-P measurements.
About 60 percent of those who received the highest dose of the drug had at least a 50 percent decrease in monthly migraine days over the course of the study.
Side effects were constipation in 6.9 to 7.7 percent of the participants and nausea in 4.4 to 6.1 percent. In the 10 mg group, one person had asthma and the other had optic neuritis.
The FDA approved the first anti-CGRP drug in 2018, and more drugs are in development.
“We still don’t understand why some patients do better on certain migraine treatments and others don’t,” said Dr. Ailani from Georgetown. “But people need options to find out which drugs work for them.”
Peter Goadsby, MD, PhD, FAAN, President of the American Headache Society and Professor of Neurology at the David Geffen School of Medicine at UCLA, is one of the few scientists who discovered that CGRP is key to many migraine attacks. Dr. Goadsby worked with Lars Edvinsson, MD, PhD, from Lund University in Sweden to show that the trigeminal nerve releases CGRP during a migraine attack.
“We understand the disease well enough that we are targeting a certain path, and it works,” said Dr. Goadsby, who is also working on the new study. “The response rates of 50 percent are quite good compared to other drugs used to prevent migraines. The other thing about this class of drugs is that it is well tolerated. Not only does it reduce migraine days, but it makes them more functional. A migraine prevention pill to be taken once a day will make it easier for everyone to come to the table. “
“Most people like the idea of taking an oral medication,” said Elizabeth Loder, MD, MPH, director of the headache division in the Department of Neurology at Brigham and Women’s Hospital, who was not involved in the study.
“It would be nice to find a drug that works in more people, but we’re not there yet,” said Dr. Loder. “Choice is very important and these shorter half-life oral CGRP antagonists could be better than the antibodies for women of childbearing potential who may have to stop taking drugs if they become pregnant.”
“This class of drugs (Gepants) offers modest benefits and it would be good to see direct studies of the various CGRP antagonists,” added Dr. Loder added. “It is hoped that each new drug will contribute to our understanding of migraines. Progress is made incrementally and slowly. “
“The response rates of 50 percent are quite good compared to other drugs used to prevent migraines. The other thing about this class of drugs is that it is well tolerated. Not only does it reduce migraine days, but it makes them more functional. A once-a-day pill to prevent migraines will make it easier for everyone to come to the table. ”- DR. PETER GOADSBY
Matthew S. Robbins, MD, FAAN, Associate Professor of Neurology at Weill Cornell Medicine and New York-Presbyterian Hospital agreed. “We know that very subtle differences in medication can have different effects on migraine sufferers. It is good that our patients have more options. “
Dr. Robbins said it would be useful to have a more personalized approach to treatment because the benefits of each of these drugs vary so widely from person to person. That would mean identifying biomarkers that could be used to understand an individual patient’s responsiveness and using those biomarkers to choose the best treatment for the patient.
Dr. Ailani served on the advisory boards of AbbVie, Allergan, Amgen, Axsome, Biohaven, Eli Lilly and Company, Impel, Lundbeck LLC and Teva Pharmaceuticals USA, Inc. She was in the speaker office for AbbVie, Allergan, Amgen. active, Biohaven, Eli Lilly and Company, Teva Pharmaceuticals USA. She was the clinical trial director for Abbie and Allergan; and has advised AbbVie, Allergan, Amgen, Axsome, Biohaven, Ely Lilly and Company, Impel, Revance, Satsuma, Teva Pharmaceuticals USA, Inc. and Vorso. Dr. Loder had no revelations. Dr. Robbins is a member of the Headache editorial team and the AHS board of directors (unpaid positions). He has received an editorial grant from Springer (Current Pain and Headache Reports) and book licenses from Wiley.