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Novel Migraine Drugs on the Way

September 29, 2015
Chronic migraine is a common health problem in the US, and currently there is a lack of treatment options to utilize, especially for preventative measures. That may soon change, though, as 4 new drugs could soon be entering phase 3 trials.

Around 36 million Americans live with chronic migraine attacks,1 and yet there are few treatment options for doctors to use. There may be a major update on the way, though.

A new class of drugs, called Calcitonin Gene-Related Peptide (CGRP) monoclonal antibodies, have shown promising results in recent phase 2 trials, which were presented at this year’s meeting of the American Headache Society in Washington, DC.

The drugs focus on blocking CGRP, a peptide and vasodilator in the body. In past studies, elevated levels of CGRP had been found in migraine sufferers,2,3 which suggested that controlling CGRP levels could be a novel mechanism to prevent future migraine attacks.

"This development is a transformative moment in migraine treatment," said Peter J. Goadsby, MD, PhD, Chief of UCSF Headache Center, who was also chair of the scientific program of the AHS’s meeting. "There’s no question that we need something better. In fact, for prevention we really need something designed specifically for migraine.”

It’s been well over 20 years since the development of a migraine drug. Triptans, which companies had started marketing back in 1991, weren’t designed to be preventive agents, though. They worked by treating acute attacks once they occurred.

Prospective anti-CGRP drugs could possibly limit the frequency of such acute attacks, improving the quality life of millions of migraine sufferers. At the moment, 4 different pharmaceutical companies are in the process of testing their own formulations with the intention of moving into phase 3 testing.

The drugs are administered as a once monthly subcutaneous injection, and so far, they have shown strong evidence of preventing migraine attacks, by as much as 50% on average. At the AHS meeting, the companies formally presented the results of their trials.4 To follow is a summary of their findings.

LY2951742 (Eli Lilly and Company)

LY2951742 is an anti-CGRP agent under development by Eli Lilly and Company, which recently collected phase 2b trial data of a randomized, double-blind, placebo-controlled, dose-ranging study. Aaron Schacht, the company’s pain portfolio global brand development leader, presented the study results at this year’s AHS meeting.

The LY2951742 trial:

  • Used study participants that had been suffering from 4 to 14 migraine days with at least 2 attacks per month.
  • Administered LY2951742 doses of 5 mg (n=68), 50 mg (n=68), 120 mg (n=70), 300 mg (n=67), and placebo (n=137) through subcutaneous injections given once every 28 days for a total of 12 weeks.
  • The 120 mg dose showed the only statistically significant change in baseline compared to placebo during the last 28-day period of the 12-week treatment phase (P = 0.004). The other four dosage levels did show numeric superiority over placebo, though. Patient reports were also very positive, where participants reported responses of at least 50% (P = 0.038), 75% (P = 0.003), and 100% (P = 0.038).

TEV-48125 (Teva Pharmaceutical Industries)

TEV-48125 is a monoclonal antibody that works against CGRP, as well. It has promising results as an effective preventative migraine, with positive effects occurring in as early as the first week of therapy, while having a clean safety profile, currently.

The drug originally was developed by Labrys Biologics. Marcelo E. Bigal, MD, PhD, the former chief medical officer for the California-based company and now Teva’s vice president of clinical development, presented the resulting data of a randomized, double-blind, double-dummy, placebo-controlled, multi-dose, parallel-group study into TEV-48125.

The study:

  • Assessed 261 patients, who had been suffering from 8 to 14 days of migraine per month.
  • Randomly administered 675/225 mg, 900 mg, or placebo in a once monthly subcutaneous injection for 3 total months.
  • Used 2 endpoints, primarily looking at the change in baseline in the number of hours with headache at month 3, and secondarily the change in baseline in the number of days with headache of moderate to severe intensity at month 3.

After the first week of therapy, both a low dose (P<0.05) and high dose (P<0.01) achieved a significant reduction in number of hours with headache, compared to placebo. This reduction continued into the third and fourth weeks.

After 1, 2, and 3 months, both low and high dosage levels reduced the number of hours with headache compared to placebo. Weekly headache days also decreased with low and high doses relative to placebo, at P<0.05 and P<0.01 (week 2), respectively.

AMG 334 (Amgen)

Where the other companies’ drugs work by targeting the ligand, AMG 334 works as an antibody to the CGRP receptor, instead. Amgen had conducted a randomized, double-blind (DB), placebo-controlled trial over the course of 12 weeks, evaluating the efficacy and safety its product.

The 12-week trial:

  • Assessed 483 patients (80.5% female, mean age 41 years), who suffered from 4 to 14 migraines a month at baseline.
  • Administered AMG 334 doses of 7 milligrams (n = 108), 21 mg (n = 108), and 70 mg (n = 107). A third of the study group received placebo (n=160).
  • Measured whether there was a significant reduction in days per month where a migraine attack occurred.

After 12 weeks, the 70 mg dose showed the best results, achieving an average reduction of 3.4 days compared to the 2.28 average with placebo. Lower doses did not show statistically significant results, though. 

At the AHS meeting, Robert Lenz, MD, of Amgen’s Department of Global Development, presented the interim findings of the open-label extension (OLE) phase of the original 12-week trial, which found further promising data of the drug’s benefits and long term safety/tolerance profile at 70 mg.

In the OLE trial:

  • 383 patients continued testing, uniformly receiving a 70 mg dose of AMG 334. The patients were stratified into two groups: those who transitioned to a 70 mg regimen after receiving placebo, 7 mg, or 21 mg during the 12-week trial and those who were simply continuing the 70-mg regimen that started in the 12-week trial.
  • Regardless of what treatment the patients had received originally, from week 12 to 64, a further reduction in baseline monthly migraine days occurred, averaging a 4.9-day reduction, compared to the 8.7 days at baseline.
  • After 1 year, 62% of patients cut their monthly migraine days by more than half, with 38% achieving a 75% reduction and 19% even achieving a 100% reduction.

ALD403 (Alder Biopharmaceuticals)

Alder Biopharmaceuticals’ ALD403 is a humanized, IgG1, anti-CGRP. The study, conducted at 26 clinical research centers in the US, aimed at seeing if intravenous (i.v.) infusion of ALD403 could help safely prevent future migraine attacks.5

The study:

  • Employed 174 patients (aged 18 to 55 years), who were sufferers of 5 to 14 migraine days per month. 
  • Randomly administered a single, one-hour infusion of either 1000mg of ALD403 (n=81) or placebo (n=82).
  • Assessed the patients a total of 7 times (screening, dosing, and weeks 2, 4, 8, 12, and 24 post-dose), with a primary endpoint of a change in frequency of migraine days per month.

ALD403 outperformed placebo, where many patients achieved a 50%, 75%, or 100% reduction in migraine days per month during weeks 1 through 4, 5 through 8, and 9 through 12. In fact, between 26.0% and 41.1% of patients experienced no migraines during any 4-week period while taking the drug.

The full chart summary of the study can be found here.

Adverse Events

Out of the 4 products, Teva Pharmaceutical Industries’ TEV-48125, was the only drug that did not report any adverse events. The other products did, however, and more information can be found below:

  • Under 5% of the patients injected with LY2951742 experienced such adverse events: injection site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea (in females), and nausea.
  • When treated with AMG 334, 248 of 383 (63%) experienced an adverse event – usually CTCAE grade 1 or 2 – including nasopharyngitis, upper respiratory tract infection, arthralgia, influenza, back pain, and sinusitis. Thirteen patients (3%) did experience a serious adverse event, though only 1 was determined to be treatment-related.
  • Of the placebo and treatment groups for ALD403, 52.4% and 56.8% did experienced adverse events, respectively. The most frequent adverse events were upper respiratory tract infection, urinary tract infection, fatigue, back pain, and arthralgia and were transient to moderate in severity. There 4 serious adverse events reported, though investigators determined 3 were unrelated to the drug.

Moving Forward: Considering Long Term Safety

Eli Lilly and Company is already enrolling patients for phase 3 testing into its product LY2951742, with the US Food and Drug Administration also giving fast-track authorization as a treatment for cluster headaches.

Yet while the medical community is excited about the potential seen in these novel products, experts are cautious to see what phase 3 data will reveal about the drugs’ long term safety profiles. Granted, the drugs do show promising safety profiles—none of them showed significant vital signs or laboratory safety data compared to their respective placebo groups—but some experts note the complexity of CGRP’s relationship to the body.

CGRP is found in numerous areas of the body, like the liver, kidney, lungs, eyes, gastrointestinal tract, and brain. It’s also been associated with various bodily processes, including cardiovascular processes.6 This could be problematic for certain patients, especially in the long term, according to Thomas N. Ward, MD, a professor of neurology at the Geisel School of Medicine, Dartmouth College, in Lebanon, New Hampshire.

"Could [the drugs] have a long-term effect on intraocular pressure, or renal function, or pulmonary function? CGRP is in your body for a reason and if you perturb it long enough, perhaps some people could accommodate well, but perhaps some people with underlying mild disease might not," Dr. Ward said.

It also remains to be seen whether a major clinical difference exists between AMG 334 and the other prospective medicines, given that the drug has a different mechanism of action. Nevertheless, an effective preventive medicine for chronic migraines is a tool practitioners definitely need, and such products look to be hopeful future options.

"If this class of medications pans out, it's almost essentially the holy grail of prevention for migraine because we wouldn't have a lot of side effects that we have with our current medications, such as weight gain, hair loss, or cognitive abnormalities. It might allow people to live a relatively normal life," he concluded.

All 4 clinical trials were conducted by their respective pharmaceutical companies and were presented at the AHS annual meeting by representatives affiliated with the company in some manner as previously described. Dr. Goadsby was the lead author of the ALD403 clinical trial conducted by Alder Biopharmaceuticals. Dr. Ward has disclosed no relevant financial relationships.

Last updated on: June 23, 2017
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