Merck & Co might have been hoping that reporting two sets of positive pivotal data for its new sleep drug suvorexant and dangling the promise of a US filing later on this year would wake up the markets. Instead the news was greeted with barely suppressed yawns. The drug maker’s shares hardly moved and observers pointed nervously to the novel orexin antagonist mechanism the drug uses.
But getting investors to get the bunting out about any developmental insomnia drug is always going to be a hard task. Not only does a drug have to get past the high bar set by the regulators there is the herculean task of achieving decent sales once a drug is approved, thanks to the number of generic products in the market. This has meant that there are very few new truly novel sleep treatments currently in development (see tables below).
Lack of innovation
Merck’s suvorexant is only one of two new drugs in phase III trials for insomnia and is also the only one of two orexin antagonists in the lab. But the class has not exactly had an illustrious history. In January last year GlaxoSmithKline and Actelion halted their phase III trial of almorexant because of undisclosed safety issues (Actelion and GSK say rest in peace to almorexant, January 28, 2011).
|Status||Product||Generic Name||Company||Pharmacological Class||Proprietary Level 2|
|Phase III||MK-4305||suvorexant||Merck & Co||Orexin receptor antagonist||NME|
|Tasimelteon||tasimelteon||Bristol-Myers Squibb/Vanda Pharmaceuticals||Melatonin MT1/MT2 agonist||NME|
|Phase II||GSK649868||-||GlaxoSmithKline/Human Genome Sciences||Orexin receptor antagonist||NME|
|MK-6096||-||Merck & Co||CNS agent||NME|
|MK-3697||-||Merck & Co||CNS agent||NME|
|EVT 201||-||Roche||GABA A agonist||NME|
|Pruvanserin (EMD 281014)||pruvanserin||Newron Pharmaceuticals/Merck KGaA||5-HT2A (serotonin) antagonist||NME|
|Neu-P11||-||Neurim Pharmaceuticals||5-HT1A & 5-HT1D (serotonin) receptor antagonist||NME|
|MKC-242||osemozotan||Mitsubishi Tanabe Pharma/MedicNova||5-HT1A (serotonin) agonist||NME|
|Temazepam ODT||temazepam||Aptalis Pharma||Benzodiazepine||NDA|
|Zaleplon - GR||zaleplon||Intec Pharma||Nonbenzodiazepine||NDA + Proprietary Drug Delivery|
|SKP-1041||zaleplon||Somnus Therapeutics/SkyePharma||Non-benzodiazepine hypnotic||NDA|
But if Merck can make it work, and that is a big if, it could revolutionise the sleep sector. Originally discovered through studies of dogs with narcolepsy, the neuropeptide orexin is responsible for wakefulness. As such, blocking orexin should help insomniacs to sleep.
This novel approach compares with the older and more prevalent approach to insomnia including benziodiazepines and GABA antagonists like the best selling Ambien, which depress the whole of the central nervous system. These drugs have also shown undesirable side effects including dependency issues and negative withdrawal effects including next day drowsiness.
However, as Merck only released scant details of the trials, waiting for medical conferences later in the year to fully outline the data, it is hard to know how the drug stacks up against older treatments, both in terms of safety and side effect profile.
New and different or old and different
As for the rest of the novel drugs in the insomnia pipeline, companies appear to have differentiated themselves into those working in niche areas such as Vanda Pharmaceuticals, or those trying to use novel delivery mechanisms for old drugs, such as Intec Pharma and Zeleplon.
Out of the two approaches it is hard to know which will be more successful, but Vanda is almost certain to have its market to itself for a while. The company is currently conducting phase III trials in non-24 hour sleep wake disorder for its drug tasimelteon.
The drug, a circadian regulator, aims to reset the body clock, aligning it to a constant 24 hour day; it has been developed especially for totally blind individuals who cannot use the difference between night and day to regulate their body clock.
In January, Vanda reported positive results from a small patient study and aims to unveil the results of two larger phase III trials by the end of the year.
Overcoming the old guard
If any of these new drugs outside of niche uses are to be successful they will have to overcome the patient and doctor loyalty attached to the current branded drugs left in the market. Despite losing patent protection in April 2007, Ambien is still clocking up significant sales and is forecast to pull in more than half a billion dollars in 2016. Similarly, Lunesta still managed to report sales of $561m in 2011.
With these kinds of stats it is not surprising that new entrants to the market have found that it hard to get patients to switch not only from the branded drugs they know and that work for them, but also from the multitude of cheap generic sleep aids available.
Since its approval in March 2010 Silenor has struggled in the market, in the third quarter of 2011 the drug reported sales of just $4m, down from the $6m seen in the second quarter (Somaxon wins approval for Silenor and hunt for partner begins, March 19,2010).
|Biggest branded insomnia drugs|
|Annual Sales WW - Sales ($m)|
|Status||Product||Generic Name||Company||Pharmacological Class||Proprietary Level 2||2011||2016|
|Myslee||zolpidem tartrate||Astellas Pharma||Imidazopyridine||NME (ex. USA Only)||443||387|
|Silenor||doxepin hydrochloride||Somaxon Pharmaceuticals||Histamine H1 receptor antagonist||NDA||18||179|
|Lunesta||eszopiclone||Dainippon Sumitomo Pharma||GABA agonist||NME||561||66|
|Meilax||ethyl loflazepate||Meiji Holdings||Anxiolytic||NDA (ex. USA Only)||46||41|
|Rhythmy||rilmazafone||Shionogi||Sedative||NME (ex. USA Only)||25||26|
|Circadin||melatonin||Lundbeck||Hormone||NME (ex. USA Only)||8||13|
|Approved||Intermezzo||zolpidem tartrate||Purdue Pharma/Trancept Pharmaceuticals||Imidazopyridine||NDA + Proprietary Drug Delivery||-||23*|
|Total available brandedmarket sales**||2,228||1,421|
|*Forecasts for in-market sales booked by Purdue not available, figure represents royalty forecasts Trancept Pharmaceuticals|
|**The insomnia market includes many small branded products for which sales figures are not available|
Tellingly, Somaxon in December called in advisors to review its ‘strategic options’. As such the omens are not looking good for other newly approved sleep drug, Transcept Pharmaceuticals' Intermezzo.
The product, which has differentiated itself by going for a middle of the night indication, does have the advantage of having a partner, but there were doubts whether Purdue Pharma was going to exercise its rights to market the drug in the US (Intermezzo approval not the end of Transcept thriller, November 24, 2011).
The group has now committed and pledged to launch Intermezzo in the second quarter of 2012 and to invest approximately $100 million to support sales and marketing during the first year of commercialization. Transcept will be hoping that this sum will be enough to help Intermezzo, which took three attempts to get approval, crack the market.
But hope may not be lost for the new products both on the market and those in development - analysts at Bernstein believe that some sleep patients are willing to try new and potentially more expensive new medicines as they search for a perfect cure to their symptoms.
This implies that there may after all be a market out there for surovexant, if it gets approval, as well as Trancept’s Intermezzo. Creating that market will be hard work.