“For such a beastly month as February, 28 days as a rule are plenty,” said the Pirate King. But you would be surprised at the number of interesting snippets of news in the health-care realm that landed in my inbox during this short month. I’ll lead off with one that gave me a particular kick.
FDA advisory panel votes to approve J & J’s esketamine
When I was writing the piece about ketamine (“Ketamine: Menace or Miracle”) which posted on January 21st, I had no notion that Johnson & Johnson was working on this agent, which was developed by Janssen Pharmaceuticals, a division of J & J. Esketamine is an antidepressant delivered by means of a nasal spray, and it is an enantiomer of ketamine. The advisory panel voted 14 to 2 in favor of approving the drug, which makes it highly likely that it will get full FDA approval. Some advisors expressed the view that esketamine might be the most important drug for treating depression in about 40 years.
… breaking news!
In fact, yesterday (March 5th) as I was writing this (as you see, I’m a bit late in getting it over the net), the FDA did approve esketamine for patients who have not responded to current antidepressants. It will be marketed under the name Spravato and available only under a controlled distribution plan. Patients will not be able to take the drug at home. It must be taken while the patient is under observation by a health-care provider for at least two hours. And patients will be cautioned not to drive or operate heavy machinery on the day of treatment.
The plan, at least at the start, is for two treatments per week for four weeks, at a cost of $4,720 to $6,785. Patients who respond to treatment initially will progress to weekly or semi-weekly treatment at a somewhat lower cost. However, it is thought that most health insurers will cover esketamine/Spravato.
What is the difference between ketamine and esketamine? The ketamine molecule can exist in two forms, one of which is the precise mirror image of the other. The name “esketamine” refers to S-ketamine, one of the two forms of ketamine. The two forms are called enantiomers, dubbed S and R enantiomers, meaning left (sinister) and right (rectus). All the atoms in the molecule are identical and identically linked, but the two mirror images (like our left and right hands) can have different physiologic effects based on their shapes. One of the enantiomers can precisely bind to a receptor, while the other enantiomer cannot. For example, esketamine, the S enantiomer, has approximately four times the affinity for the glutamate N-methyl-D-aspartate (NMDA) receptor as its mirror image, R-ketamine. Blocking this receptor is thought to be responsible for the anaesthetic effects of ketamine.
Physicians have been using ketamine as an antidepressant off-label for about 20 years, usually to treat patients who have not responded to treatment with currently-approved antidepressants. Experience with ketamine as an antidepressant in general supported the view that ketamine was not only effective in previously non-responsive patients, but also that it had a much faster onset of action than traditional antidepressants.
J & J ran three pivotal trials with esketamine, two of which missed their primary endpoints. However, the evidence from these trials was enough to convince the advisors that the benefits of esketamine conclusively outweighed the risks. For example, response rates to esketamine were over 60% as early as four and a half hours after a single dose. These benefits were sustained at the 24 hour mark. About 40% of subjects experienced continued benefits from esketamine after 7 days.
It’s obvious that depression is not something that can be observed and measured accurately from exterior signs, so studies of depression perforce need to rely on some form of patient-reported information. In the studies with esketamine, the efficacy endpoints were changes in the score from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS). Even though in two of the trials, the primary endpoint was missed, the advisors gave considerable weight to the need for a fast-ac