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 http://www.non-24.com/ - 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 drugs.com 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

Back Story

Blind Date With Vanda's Hetlioz

Blind Date With Vanda's Hetlioz

An American friend of mine sent me an email the other day. She told me how she had seen an ad aired on TV for a drug called Hetlioz (tasimelteon). Apparently, it's a pill to help those who suffer with Non-24-hour Disorder.

I admit I had to look this disorder up. My first thought was, Christ! They want to treat people who refuse to watch Kiefer Sutherland's character Jack Baur in FOX TV's 24?

Alas, I was wrong.

Non-24-hour Disorder, according to Hetiloz manufacturers, Vanda Pharmaceuticals, is...

... a chronic circadian rhythm disorder that occurs when individuals are unable to synchronize their endogenous circadian rhythm to the 24-hour day. Non-24 is most commonly found in blind individuals lacking the ability to perceive light, the primary environmental cue for synchronizing the circadian system daily. In general, individuals with Non-24 suffer from a variety of clinical symptoms as they cycle in-to and out-of phase resulting in disrupted nighttime sleep patterns and/or excessive daytime sleepiness.

Vanda had to convince the American drug regulator, the FDA, that their drug worked and was safe through a series of clinical trials. These trials have been slammed.

For instance...

• 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.

[Source]


Despite all of the above, Hetiloz was approved by the FDA earlier this year.

Astroturfing

Now there's a word.

Astroturfing is the practice of masking the sponsors of a message or organization (e.g. political, advertising, religious or public relations) to make it appear as though it originates from and is supported by grassroots participant(s). It is a practice intended to give the statements or organizations more credibility by withholding information about the source's financial connection.

Step forward The National Sleep Foundation.

Trawling through their website I learned that their Non-24-Hour Sleep Wake Disorder section is sponsored by Vanda Pharmaceuticals. I flicked the following email to Vanda...

Dear Sirs,

Many pharmaceutical companies are now suggesting that they are going to be more transparent in regard to clinical trials and sponsorship's etc.

I noticed that the sleep foundation have a section on their website that is sponsored by Vanda Pharmaceuticals.

As a matter of public interest could you tell me if this was a financial arrangement, if so, how much?

In typical Pharmafia fashion Vanda did not reply, opting instead to check me out [fig 1] - Click image to enlarge.

Fig 1

I posed pretty much the same question to the National Sleep Foundation via their Twitter page. [Fig 2]

They had the decency to answer me but didn't really answer the question I put to them.

Fig 2

Not related in any way to Vanda?

Here's the sponsored section on the Sleep Foundation's website [Fig 3] - Click on image to enlarge and read the bottom left of the image.

Fig 3

Alternatively, click here.

I pressed the Sleep Foundation for an answer - to date, they have failed to respond.

I dug a little deeper regarding Vanda's drug Hetiloz.

In July 2013 it was reported that Vanda Pharmaceuticals Inc. were facing at least one shareholder lawsuit surrounding late-stage trials for the company's sleep disorder drug Hetiloz.

In one class-action complaint, Small v. Vanda Pharmaceuticals Inc. et al., it's alleged that Vanda and its officers issued materially false or misleading statements about Tasimelteon’s efficacy and the results of its Phase III clinical trials. Specifically, it is alleged that Vanda changed the design of the  primary Phase III study several times, including a complete replacement of the primary endpoint  one month before results were announced, because the company was in possession of data suggesting that the original primary endpoint was not going to be met; used a replacement primary endpoint that had never been used before in sleep-drug clinical trials and was not endorsed by the FDA; enrolled patients in the Phase III trials by “stretching” the clinical definition of Non-24; and combined data from two Phase III studies in order to demonstrate a benefit for Non-24 patients, where the two Phase III studies failed individually.

The full complaint can be read here.

Amazing that the FDA went ahead and gave a licence to Hetlioz... then again, the FDA are basically an extension of the pharmaceutical industry.

Non-24-hour Disorder is a new one on me. As for the treatment of it, Hetiloz, experiments with rodents revealed fertility impairments, an increase in certain cancers, and serious adverse events during pregnancy at dosages in excess of what is considered the "human dose". [1] [2]

I can only presume that these warnings will be printed in braille for expectant blind mothers?

Then again since when have pharmaceutical companies protected their patients?

Bob Fiddaman 

Blind people need all the facts too

References

[1] "Side Effects Drug Center: Hetlioz Clinical Pharmacology". RxList. February 10, 2014.

[2] Side Effects Drug Center: Hetlioz Warnings and Precautions". RxList. February 10, 2014. "In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically."

You can follow the National Sleep Foundation on Twitter here.

  

GSK's Swine Flu Shot Linked to Sleep Disorder

Ring-a-ring o' roses,

A pocket full of posies,

Pandemrix! Pandemrix!

We all fall down

Narcolepsy:

Narcolepsy is a neurological disorder caused by the brain's inability to regulate sleep-wake cycles normally. The main features of narcolepsy are excessive daytime sleepiness and cataplexy. The disease is also often associated with sudden sleep attacks, insomnia, dream-like hallucinations, and a condition called sleep paralysis - National Sleep Foundation

Glaxo are in the news again... this time it's their vaccine Pandemrix that's making all the wrong sort of headlines for the British based drug giant.

Latest figures have shown that almost 800 children in Sweden who received the Pandemrix H1N1 swine flu vaccine have been left with the incurable sleep disorder, narcolepsy.

According to Fox News similar findings have been found in Finland, Norway, Ireland and France.

Faced with these alarming figures GSK's chief medical officer, Norman Begg, states, GSK views the issue extremely seriously and is "absolutely committed to getting to the bottom of this", adding, "there is not yet enough data or evidence to suggest a causal link."

Of course not, Norm.

I remember when Swine Flu made the news. There was a huge push, in the UK at least, for people to rush out and get vaccinated. I never really bought into it.

Back in 2009 Switzerland restricted the use of Glaxo's swine flu vaccine, they did so by excluding pregnant women, minors and people over the age of 60. Swissmedic, the Swiss medicines regulator, did not allow it to be used in children because they had "received very little information on it."

Also, in 2009, the German Professional Association of Environmental Medicine (Deutscher Berufsverband der Umweltmediziner – DBU) issued a press release regarding Glaxo's Pandemrix, part of which read:

"Pandemrix poses substantial health risk with respect to mass immunization programs due to the lack of proof of safety."

Back in 2010 I wrote about how Glaxo were under investigation for bribery in Finland. In short, the Chancellor of Justice was investigating if bribery was used in narcolepsy-suspect Pandemrix vaccine trade. The investigation was carried out because two individuals had reported their suspicions to the Chancellor. Investigation targeted the Ministry of Health and THL, National Instute for Health and Welfare. THL has received more than six million euros in 2009 from GlaxoSmithKline. THL has also had a key role in the decision to order Pandemrix to every Finnish inhabitant.

Meantime, the narcolepsy link continues to rear its ugly head in Sweden. Goran Stiernstedt, director for health and social care at the Swedish Association of Local Authorities and Regions, has added much fuel to the fire. Speaking with Fox he told them, "This is a medical tragedy, hundreds of young people have had their lives almost destroyed."

GlaxoSmithKline – one of the world's leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.

Fox News article HERE

FDA Approve Another Addictive Drug

I thought I was seeing things when I read this. The FDA, in their infinite wisdom, has just approved Intermezzo, the pill that... well, it basically knocks you out for the count.

Designed by Transcept Pharmaceuticals Intermezzo is for people who wake in the middle of the night. Slip it under your tongue and you'll be out like a light. It's basically the equivalent of stepping in to the ring with Iron Mike Tyson.

Intermezzo - nice brand name. I have a thing about brand-names, I briefly touch on it in my book.

Intermezzo is is interesting. Inter - (tr) to place (a body) in the earth; bury, esp with funeral rites. Mezzo - (a person having) a singing voice between soprano and alto. In music, an intermezzo (Italian, plural: intermezzi), in the most general sense, is a composition which fits between other musical or dramatic entities. Oh, and it's also a coffee so there may be some objections to the name at some point down the line.

The FDA had on two occasions previously refused to approve Intermezzo, their main worry being that people might get up and try to drive before the drug fully wears off. Studies clearly show that the drug badly impairs driving, and that this effect lasts longer in some people than in others. To get around this the manufacturers changed the labelling to state that the drug should only be taken when people have at least four hours of sleep time remaining. They also added, "Moreover, people should not take Intermezzo if they've been drinking alcohol or if they've taken other sleep aids."


A simple tweak of a label and the FDA give it a clean bill of health. Amazing aren't they?

The final three paragraphs from the WebMD website say it all really:

Intermezzo, like other sleeping pills, can cause serious side effects. These include getting out of bed not fully awake and being unaware of doing things or remembering you did them.

Activities reported to the FDA while under the influence of sleep medicines include driving a car, making and eating food, having sex, talking on the phone, and sleep walking. Alcohol or other sleep medicines increase the risk of doing such things.

And like other forms of zolpidem, Intermezzo is a controlled substance that can be abused or that can lead to drug dependence.

"...getting out of bed not fully awake and being unaware of doing things or remembering you did them."

Any defence lawyers out there, I feel a bank robbery coming on.

Ironically, after taking Seroxat for 6 years I now have a sleep disorder, I wake in the middle of the night and can never get back to sleep. In fact, I can fall asleep at inopportune moments too and in the past I have fallen asleep waiting to be served at a bar, on a bus and even a telephone box! Thank you GlaxoSmithKline.

Will I be sampling Intermezzo?  HAHA! Once bitten...

WHAT DO WE WANT?

A CURE FOR INSOMNIA

WHEN DO WE WANT IT?

Zzzzzzzzzzzzzzzzzzzzzzzzzzz

I'm left scratching my head at the logic of this approval. It's not a cure, it's merely papering over the cracks and I can guarantee that more cracks will appear, they always do with these drugs that act on the brain.

Nice job FDA.