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Wednesday, August 7, 2019

Rise in opioid use seen for migraine treatment

An increasing number of Americans are using opioids to treat their migraine headaches, despite the fact that opioids are not the recommended first-line therapy for migraine in most cases. That’s according to the ObserVational Survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study, a web-based patient survey of people living with migraine. Migraine care specialist Sait Ashina, MD, a neurologist and Director of the Comprehensive Headache Center at the Arnold-Warfield Pain Center at Beth Israel Deaconess Medical Center (BIDMC), presented the survey findings at the 61st annual meeting of the American Headache Society.

“These data show that, despite the known potential risks of using opioids for migraine, far too many continue to do so,” said Ashina, who is an Assistant Professor in the Department of Neurology and Department of Anesthesia, Critical Care and Pain Medicine BIDMC and Harvard Medical School. “Against the backdrop of the U.S. opioid epidemic, it’s concerning that people may be using these drugs in place of conventional therapies proven to be safer and more effective for migraine.”

A prospective, web-based patient survey designed to follow two U.S. population samples of 20,000 people with migraine for two years, the OVERCOME study began enrollment in 2018, with a second population sample slated to begin enrollment in 2020. Analysis of data from the first group showed that 19 percent of people with migraine were currently using opioids specifically to treat migraine — up from the 16 percent reported in 2009 in the American Migraine Prevalence and Prevention Study. Moreover, nearly a quarter of people who reported having four or more migraine headaches per month were currently using opioids to treat their pain, and more than half of these respondents reported taking opioids at least once to treat a migraine headache.

“OVERCOME showed that, overall, opioids are being used in place of medicines that are approved and indicated to treat migraine – particularly among those who experience migraine headaches more frequently,” said Ashina. “Patients and doctors should work together to develop a personalized treatment plan tailored to address patients’ particular health concerns and needs.”

Migraine is a disabling neurological disease afflicting more than 37 million Americans, a burden disproportionately carried by women. In addition to severe headache pain, migraine symptoms vary from person to person – and from migraine episode to episode – but may include nausea and vomiting, extreme sensitivity to light, sound, smells and sensations, fatigue, and changes in mood. Migraine attacks can be brought on by specific triggers such as foods, stressors, hormones, or nothing at all, and can last for hours or days at a time.

Clinical guidelines from the American Headache Society encourage the use of triptans, a class of drugs introduced in the 1990s that stop about 75 percent of headaches within an hour and half, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen as first-line treatment for migraine headaches in most cases. The use of opioids as treatment for migraine headaches is typically reserved for patients in whom the use of triptans or NSAIDS is contraindicated.

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The OVERCOME study is being conducted by Kantar, a private research firm, on behalf of Eli Lilly and Company, with expert guidance provided by a scientific advisory board. In addition to Ashina, the OVERCOME Scientific Advisory Board includes; study chair Richard B. Lipton, M.D., and Dawn C. Buse, Ph.D., of the Albert Einstein College of Medicine; Michael L. Reed, Ph.D., of Vedanta Research; Robert E. Shapiro, M.D., Ph.D., of Larner College of Medicine at the University of Vermont; and Susan Hutchinson, M.D., of Orange County Migraine and Headache Center.

As a member of the scientific advisory board, Ashina is a paid consultant for this study for Eli Lily and Company.

https://www.eurekalert.org/pub_releases/2019-08/bidm-ndi080719.php

FDA Panel: Split Decision for Descovy in PrEP

An FDA advisory panel overwhelmingly voted 16-2 to recommend Descovy, the fixed-dose combination of emtricitabine and tenofovir alafenamide (F/TAF), as pre-exposure prophylaxis (PrEP) to reduce HIV acquisition in men who have sex with men (MSM) and transgender women.

But murmurs echoed throughout the room as the FDA’s Antimicrobial Drugs Advisory Committee split 8-10 on whether to recommend a PrEP indication for F/TAF in cisgender women.

While committee members recognized the precedent they were setting in recommending an HIV prevention drug in certain populations over others, it came down to the lack of efficacy data, as drugmaker Gilead Sciences presented only pharmacokinetic data to support the indication for cisgender women, looking to extrapolate efficacy data from the DISCOVER trial. That study had demonstrated F/TAF’s effectiveness in MSM and transgender women having sex with men.

The slim majority of committee members who voted no also appeared unmoved by Gilead’s claim of logistical challenges in conducting a non-inferiority trial among women. The company argued that a dedicated non-inferiority trial would need 22,000 women and 8-10 years to conduct.

“I feel like Arrowsmith — we’re in a desperate situation, so let’s do something because we can do something,” chair Lindsey Baden, MD, of Brigham and Women’s Hospital in Boston, said. “For us to presume the good data are the ones we should hang our hats on [is] presumptuous [and] I cannot support an indication that says efficacy.”

Consumer representative Roblena Walker, PhD, of EMAGAHA Inc. in Mableton, Georgia, went one step further with her “strong no” vote, adding, “I’m highly appalled that more dedication and passion wasn’t put into the study.”

Among the members who voted yes, few expressed enthusiastic support for the data — with several saying they “almost voted no” or “wanted to abstain.” But several cited the potential public health message of having an HIV prevention product that was not recommended for women.

“I reached back to the FDA’s mission statement — to promote and protect public health by helping safe and effective products reach the market in a timely manner,” said Peter Weina, MD, PhD, of Defense Health Headquarters in Falls Church, Virginia. “[We should] follow the FDA’s mission statement to get to market for broadest population possible and monitor the product for continued safety.”

Sarah Read, MD, of the National Institute of Allergy and Infectious Diseases (NIAID) in Rockville, Maryland, voted yes because she said she felt that women were a population “clearly in need of more prevention choices,” adding that it was “reasonable to extrapolate the data.”

Indeed, Gilead said that they are “dedicated to generating this data,” and will be supporting a number of studies in over 3,400 women and adolescents, as well as pregnant and breastfeeding women.

As for the indication in MSM and transgender women, the committee was mostly united — with certain members expressing skepticism over the low number of transgender women included in the study. They also emphasized the need for post-marketing surveillance, given certain concerns over lipid profiles. But the general consensus was that the DISCOVER trial provided the needed safety and efficacy data for Descovy as PrEP in MSM and transgender women.

The two members who voted no had different reasons for doing so. Lori Dodd, PhD, of the NIAID, voted no because of the lack of data in transgender women, but Walker voted no because of the lack of African-American representation in the DISCOVER trial, calling it “a lost opportunity to provide substantial data reflective of the community that is [most] impacted by HIV.”

If approved, F/TAF would be the second product to win a PrEP indication, the first being the fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (F/TDF, Truvada), also made by Gilead.

The FDA does not have to follow the advice of these advisory committees, but it often does.

https://www.medpagetoday.com/hivaids/hivaids/81482

Rhythm hits its obesity endpoints after excluding some patients

Setmelanotide looks approvable, but patients were stratified for inclusion in some measures.

Initial pivotal data on Rhythm Pharmaceuticals’ melanocortin 4 agonist setmelanotide in two rare genetic obesity indications look pretty positive, and the company plans approval applications by the end of next year’s first quarter. Rhythm’s shares have popped 20% so far today as investors digest the likelihood of approvals here and of further success in ongoing trials in other similar disorders.

But questions remain about the analytical basis of these trials, and whether the proportion of responding patients is high enough to lead to decent commercial traction.

Setmelanotide activates the melanocortin 4 receptor, part of a pathway that regulates energy expenditure and appetite. Variants in genes in this pathway are associated with unrelenting hunger and severe, early-onset obesity.

Most hungry

Both phase III trials administered a therapeutic dose of setmelanotide open label for 12 weeks. This was followed by an eight-week blinded placebo phase in the same patients, intended to illustrate the effect of the drug – neither trial had a dedicated control arm. After the withdrawal phase subjects received 32 weeks of therapeutic dose, bringing them to the one-year time point.

In the first trial eight of 10 patients with pro-opiomelanocortin (POMC) deficiency obesity hit the primary endpoint, losing at least 10% of their weight over a year, after adjusting for historical controls.

Secondary endpoints were also hit. These included reduction in body weight, reduction from baseline in most hunger rating – this is based on a 0-10 answer to the question, “In the last 24 hours, how hungry did you feel when you were the most hungry?” – and the proportion of patients seeing an improvement in self-reported hunger scores of at least 25%. The data and statistical analyses are shown below.

POMC trial data

Rhythm Pharmaceuticals

In the other study, in subjects with leptin receptor (LEPR) deficiency obesity, five of 11 patients met the primary endpoint, which was the same as in the POMC trial. Rhythm said that the same secondary endpoints were hit too, again with a high degree of statistical significance.

LEPR trial data

Rhythm Pharmaceuticals

All very impressive, and probably good enough for approval – even though less than half the LEPR patients hit the primary. During the placebo washout period patients in both trials gained weight – around 5kg on average in both trials – and became hungrier.

FDA submissions for these rare disorders are to be made at the end of this year or the beginning of next, with a request for priority review. EMA filings will follow shortly afterwards.

The hunger games

Eyebrows have been raised, however, over the small print. As can be seen in the slides above, only the primary endpoint and the final secondary, the proportion of patients who had a 25% drop in hunger, were analysed on the whole trial population.

The other two secondaries, change from baseline in bodyweight and in most hunger rating, had a filter applied. They were analysed based on what Rhythm calls the evaluable population – those participants who achieved a weight loss threshold of 5kg, or 5% if their baseline weight was 100kg, after the first open-label period.

In other words, the final analysis was only conducted in patients in whom setmelanotide had already been shown to work. Nine POMC and seven LEPR patients made the cut.

These statistical gymnastics were only conducted on a couple of secondary measures, not the main endpoint, so maybe the regulators will not object.

In that case, a more pressing issue for Rhythm will be just how big the market might be. The group is attempting to broaden the drug’s reach, and is also conducting a phase III trial of setmelanotide in Alström and Bardet-Biedl syndromes, slated to report in a year or so, and earlier trials are under way in Smith-Magenis syndrome and other genetic defects in the leptin-melanocortin pathway.

But the sellside’s forecasts for the project are hovering at less than $450m in 2024, according to consensus compiled by EvaluatePharma. Perhaps these data will give them a boost, though doctors and payers might well raise the issue of how great the overall weight loss might be when all patients are considered.

https://www.evaluate.com/vantage/articles/news/trial-results/rhythm-hits-its-obesity-endpoints-after-excluding-some-patients