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Saturday, December 15, 2018

Hetlioz: The Body Clock Brain Pellet

It's been a while since I last blogged. GSK has, seemingly, been good boys and girls for a while and Twitter seems to be where all the action is these days regarding the defence of brain pellets and some shocking behaviour from the field of psychiatry. More on that if you follow me on Twitter.

Today, I'm going to revisit a 2014 blog post of mine that was recently brought to my attention by a reader. The post, Blind Date With Vanda's Hetlioz, can be viewed here.

Hetlioz (tasimelteon) is an FDA approved medication for the treatment of Non 24 Sleep-Wake Disorder in the totally blind and is marketed and manufactured by Vanda Pharmaceuticals.

What is Non 24 Sleep-Wake Disorder?

According to Vanda Pharmaceuticals Hetlioz webpage, it's a "serious, chronic disorder that disrupts a person's circadian rhythms. Non-24 affects up to 70% of people who are totally blind, whether you were born blind or became so later in life."

All seems to be above board until you peel back some of the layers.

The clinical trials for Hetlioz are surrounded in controversy:

 - The design of Vanda's primary phase III study changed numerous times, including a complete replacement of the primary endpoint just one month before study results were announced

 - The replacement primary endpoint installed to assess tasimelteon's benefit was created by Vanda and has never been used before in sleep-drug clinical trials, nor was it endorsed by the FDA.

 - Vanda was forced to cut in half the patient enrollment into the tasimelteon clinical trials because totally blind patients with non-24 could not be identified. Even then, Vanda was only able to enroll patients by stretching the clinical definition of non-24.

 - Tasimelteon was only able to demonstrate a benefit for non-24 patients by combining data from two phase III studies. Despite Vanda's claims to the contrary, the phase III studies may have actually failed on their own.

The marketing of Hetlioz has also come under close scrutiny too. Back in 2015, Stat News ran an article regarding the airtime that Vanda Pharmaceuticals had bought to advertise its sleep/wake disorder drug, $29 million worth of airtime to be exact.

Stat News posed a pertinent point, they pointed out that the target audience for Vanda Pharmaceuticals were blind members of the public, so why the heavy promotional push on TV?

Here's one of the ads they ran across America.

Stat News also claimed that the adverts helped Vanda Pharmaceuticals net a tidy profit of $73 million in revenue.

Hetlioz Indications

The product labelling for the drug does not specifically state that it is to be used by blind people only. This leaves the door open for Vanda Pharmaceuticals to target other patients (non-blind).

Public Citizen, a nonprofit consumer advocacy organization, has filed a petition asking the FDA to correct the labeling to indicate the drug is only for patients with the disorder and who are totally blind, a population numbering approximately 100,000. Public Citizen is concerned the existing labeling may encourage off-label use in people who are not blind and have some other type of sleep disorder.

A Concerned Citizen

A concerned citizen recently wrote to me and told me he, and others, were digging into recent activities of the promotion of Hetlioz. He told me, "We are extremely confused by what we are finding. First off, it appears they are targeting Medicaid patients for Hetlioz with an estimated 80% of revenue coming from Medicare part D. Second, how can they be seeing 2x-3x demand from sighted patients vs blind if non-24 affects mostly blind people and is rare in sighted patients? Third, Cafepharma and glassdoor posts seem to indicate that there is rampant off-label promotion of Hetlioz going on via the company's psychiatric initiative.  This is just a sampling of what we are finding."

Vanda Drug Reps

The same citizen sent me two videos in which we can see Vanda Pharmaceuticals drug reps target patients and not doctors, as is the norm for drug company reps. The first video sees two reps for Vanda speak with what appears to be a mixed audience of visually impaired and blind subjects at Lighthouse, an organisation that promotes the independence, equality and self-reliance of people who are blind or have low vision. What is striking is the Vanda rep at the beginning of the first video asks the audience to fill out the paperwork if they feel they have any symptoms and give it to her and she will contact their physician. I'm unsure of the legality of this. The second rep throws out the question, "How many of you have difficulty sleeping at night?" When 6 or 7 raise their hands he tells them that it could be because they have 'Non 24 sleep/wake disorder'. He then goes on to tell the audience how everyone has a "master body clock in their brains."

I have to point out that neither of the reps mentioned the drug Hetlioz.

One of the audience members tells the rep she has Non 24 and takes Seroquel for it. Hmm.

If anything, this video gives an insight into how drug company reps play their audience. I found it fascinating, I hope you do too.

PS - He's not very good.

**Raw copies of both videos have been downloaded.

So, just as brain pellets were promoted because people had a 'chemical imbalance', along comes another mystery brain anomaly, this time it involves some sort of ticking clock. If you watched the video above you'll note how many times the rep drums home the 'body clock' claim.

The second video is much shorter than the first and shows pamphlets left behind by the Vanda reps. The leaflets, although visible are also written in braille and direct readers to - where there's more talk about the 'body clock.' Again, there doesn't seem to be any direct-to-consumer advertising of Hetlioz on the webpage but there's plenty of talk about patients going to see their doctor to explain they may have symptoms of Non-24.

I can only speculate that Vanda reps have already visited their doctors and planted the 'Non-24' seed and what new drug can treat it.

As I mentioned above, I'm not sure if drug company reps targeting patients is entirely ethical so I wrote to a former drug company rep turned whistleblower for her opinion. I asked her if this was legal. She replied:

"No, this is not legal in the U.S. but I cannot provide any documentation to this effect. We were just instructed by the companies that I worked for that it was illegal to interact with patients regarding care/drug regimens. Unless something has changed...I left the industry in the year 2000."

In my 2014 blog post I mentioned the link between Vanda Pharmaceuticals and The National Sleep Foundation (NSF). 

New information I've learned is that Charles A. Czeisler, an American physician and sleep researcher, was President of NSF and is/was on Vanda's scientific advisory board. Also, Dr. Stephen Lockley, the Harvard sleep expert overseeing the Hetlioz clinical trials, received grant support from Vanda Pharmaceuticals.

Blogger, 'Frugal Nurse', has also been investigating Non-24 and Hetlioz. She writes:

On January 31, the Food and Drug Administration announced its approval of tasimelteon for treatment of Non-24.
Approval was based on results of 2 trials: . . . a 26-week study that included 84 patients, . . . and a 19-week trial that included 20 patients . . .
Really? Market approval based on 104 patients over 6 months?
And what were they testing for exactly? Patients experiencing a better night’s sleep, or less daytime drowsiness? No, something called “entrainment” or re-setting of circadian rhythm, measured by melatonin byproducts in the urine.
Frugal nurse also has an opinion on the Non-24 website. She writes:

The informational website for Non-24 is classic pharmaceutical advertising.
It’s not about selling a drug—at least not directly. It’s about helping you understand what Non-24 is and why you might suffer from it. The site helpfully (and slyly) provides a sidebar of symptoms to aid self diagnosis:
Not being able to sleep when you want
Excessive sleepiness during the day
Daytime napping or dozing off during the day
Periods of poor sleep quality at night
Sleeping through the night, but not waking up feeling alert and refreshed
Problems with focus and concentration; trouble with memory
Difficulty with daily tasks
Feeling irritable
Oh my God, I’ve got Non-24!!
If you are “experiencing any of these symptoms,” you are invited to fill out your name and address and “give permission” for Vanda to send you “information about Non-24 and about medicines that treat Non-24.”
As an added incentive, when you sign up, Vanda will make a $24 donation to the “blindness community.”
We can see from her research that Vanda's marketing is widening the net. They don't just want blind or partially sighted people to ask for this drug, they want, it appears, people with insomnia too, a condition that Hetlioz is not indicated for.

Jet Lag

In March this year, Vanda Pharmaceuticals announced that Hetlioz demonstrated significant and clinically meaningful benefits in nighttime and daytime symptoms of jet lag disorder. The press announcement stated:
Vanda intends to seek marketing approval for the use of Hetlioz in the treatment of jet lag disorder.  Vanda believes that if Hetlioz is approved by regulatory authorities for the treatment of jet lag disorder it will potentially offer a therapeutic solution to many travellers and will likely represent an important commercial opportunity for the company. 

You're not kidding! According to the cost for Hetlioz oral capsule 20 mg is a staggering $15,186 for a supply of 30 capsules, depending on the pharmacy you visit.

It's no surprise that Vanda are trying to tap into the market of jet lag. It is reported that more than 30 million US residents make trips abroad each year to overseas destinations. Of these, 60% (approximately 20 million) travel to destinations in Europe, Middle East and Asia. That's an awful lot of potential customers for Vanda.

Another market they will no doubt be persuading doctors to prescribe to is the insomnia market. Around 1 in 3 people have at least mild insomnia. Many poor sleepers have developed poor sleep habits.

So, the body clock drug that was initially aimed at blind people now has a much larger potential. Jet lag and insomnia will become the new 'Non 24 Sleep/Wake Disorder'. Sufferers will be spun the story about 'body clocks' and the importance of setting the timing of that clock back to normal.

What next?

Will we see Hetlioz pushed on kids who can't sleep because they have normal teenage worries, or perhaps the man or woman who are facing employment stresses and can't sleep? Remember, the FDA left the door wide open when they agreed that this drug could come to market. Hetlioz has not been studied in children and it is not recommended for use in children but history shows that drug companies always try to widen the net when selling to the public. One only has to look at the group of SSRIs that are currently prescribed off-label to children.

How Does Hetlioz Work?

Hetlioz works to enhance the effects of the receptors for melatonin. In particular, it binds and augments the MT1 and MT2 receptors within the brain. This induces sleep.

So, is Hetlioz merely another brain pellet then, one being sold on the back of a spinning story that involves body clocks in the brain, just as SSRIs were heavily promoted on the spinning story of a chemical imbalance in the brain?

Finally, last month the FDA issued a warning letter to Vanda Pharmaceuticals. The warning letter chastized Vanda for failing to warn Hetlioz users of its most common adverse reactions, namely; headaches, increased alanine aminotransferase, which is the term used for elevated liver enzymes, nightmares or unusual dreams, and upper respiratory or urinary tract infection. These are common adverse reactions, folks!

Nightmares or unusual dreams? Nothing like taking a drug to help you with sleep, huh.

Bob Fiddaman

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