Is It the Hype…? Or Is There Something about Esketamine You Really Want…?
Ok, you’ve been wishing for a remedy for your distress with this mood disorder. I get it. Something that will do more than take the edge off, but instead will really help you feel good again. You’ve heard about ketamine treatment, but having to go to an office and undergo IVs 6 times sounds just a bit daunting..? Then you heard about esketamine nasal spray, and that it’s close to receiving FDA approval. And it’s a nasal spray! How easy is that??
What’s more, you’ve looked on the internet and its cost will probably be a great deal less than a series of IV ketamine infusions in a doctor’s office because you should be able to administer it yourself..? What a perfect alternative! …or is it?
So your excitement is building that hope is around the corner…within a few short months…or maybe even weeks…?
Take a breath…ok? Of course, it’s possible…but…
Just a couple weeks ago, Janssen (a company under Johnson & Johnson’s umbrella) announced that things haven’t been going all that well with their testing.
Well, they didn’t exactly say it like that.
You know that it takes a ginormous amount of testing to get FDA approval on a drug. And all that testing costs lots of money.
When a pharma company pours years of resources into R&D (research and development), they hope the compound they’ve made will do what it’s designed to do, what it’s supposed to do. But they’re taking the risk it may not.
And they have lots of investors to please.
It’s a bit early to make judgments about esketamine nasal spray. Janssen has had some good trial results, but some weren’t that convincing at all.
Back in May, they made an announcement that even though they’d had both promising and disappointing results with esketamine nasal spray, they weren’t discouraged about its potential. They were determined to continue the trials.
Of course, investors want to see a return on their investment. Insignificant or conflicting results won’t butter their bread, if you know what I mean.
Then, after announcing September 4, 2018, that they were applying for a New Drug Application (NDA) for esketamine, a few weeks later they announced that esketamine failed yet another study in their Phase III trials.
They said esketamine nasal spray had failed to meet its primary end point in this study…to lower the depression scale for these subjects significantly from the level they were at the beginning by 4 weeks after the esketamine doses began.
Frustrating for Janssen.
So much money, so much work, in laboratories across the globe.
So, let’s take a closer look at Janssen’s quest for FDA approval of esketamine.
It’s easy to understand that even as they made the announcement that esketamine had failed this study, they continued to point out all the tests it has passed. Reminding investors that a disappointment is no reason to throw the baby out with the bath water. (At least, they hope that won’t happen.)
When they filed the NDA on September 4, it was based on 5 Phase III studies of esketamine in treating people with treatment-resistant depression: 3 short term studies, one “withdrawal maintenance of effect” study, and one long-term study.
The long term study was aimed at establishing the safety of esketamine use up to 52 weeks, and it found that esketamine is generally well tolerated. Not that surprising, since ketamine is well-tolerated in controlled, small doses.
HUGE Disappointment for Janssen
But this most recent study, where results were announced September 21, 2018, showed esketamine nasal spray failed to meet a primary end point. It did not have a statistically significant positive effect in reducing depression symptoms in the subjects. Janssen is quick to say however, that even though the response didn’t meet the goal it was intended to meet… the numbers still support the use of esketamine combined with an antidepressant.
Really…?? How is that?
You get the feeling Janssen tries to do damage control in each of its press releases…. Pay attention to the good stuff…and minimize the bad. (There seems to be a lot of that going around.)
Still, look at this: The trial investigated esketamine plus an antidepressant at two different doses, 84mg and 56mg. The plan was to test both doses.
However, the larger dose didn’t shake out better than placebo! So obviously there was no point in testing the lower dose.
What a blow for Janssen.
I’ve not made it a secret that I’m skeptical of esketamine nasal spray. But, I’ll concede for now that the jury is still out as psychiatrists and researchers evaluate all of the results coming in from all of the clinical trials.
We’ve got a medicine with IV ketamine treatment that works — and more and more basic science, translational, and clinical research supports this. But look at all the cards stacked against esketamine.
And…if the goal is to have a nasal spray form that’s more affordable, comfortable, and accessible to more people, that’s understandable. We get it. (Even if that nasal spray form would make it easy to hide, easy to share, and easy to abuse. Those risks are formidable risks that need to be addressed.)
But why use just esketamine when ketamine works so well?
You know why.
Because of money. Ketamine can’t be patented after 50 years of use. Esketamine can be, if they can just get it to work…even half as well.
To take this a step further let’s look at the problem that happened in May.
May 2018 Press Release More of the Same
So in May, Janssen made another announcement. That it had just completed 2 studies in its Phase III trials. In one of the two studies, they announced that in a group of subjects 65 or older, esketamine nasal spray had failed to show statistically significant findings. (Yep, just like it did in this most recent study.)
So…wait…Does that mean 2 out of 5 studies failed to show any significant advantage over a placebo…?
Now let’s be clear.
In all of these studies, Janssen is investigating esketamine nasal spray in conjunction with an antidepressant in comparison to an “active” placebo compound delivered by nasal spray along with an antidepressant.
So, even with esketamine bolstered by an antidepressant like Lexapro, Cymbalta, Zoloft, or Effexor… esketamine showed no statistically significant beneficial response in patients with treatment-resistant depression. Even at the highest dose they tested.
Reasons Why Esketamine May Fall Far Short of IV Ketamine Treatment
1. It’s NOT ketamine! Esketamine is only the left-facing form of ketamine . Ketamine consists of right- and left- facing forms and esketamine is the left-facing. So with esketamine, some of the beneficial aspects of having both available may be missing. We’d love to think esketamine is the important one, and that maybe it does all the work, right? But…maybe not.
2. Traditional SRIs and SNRIs have not helped a full third of people suffering psychiatric disorders…so why would adding these partially effective medications help esketamine do a better job??
3. It’s a nasal spray, for goodness’ sake. Let’s talk about that.
Problems with Esketamine Nasal Spray
We’ve talked before about the differences in various routes of administration with ketamine.
A huge factor is bioavailability. You know, the amount of medicine that actually reaches your brain to treat it. Everything else is digested, or somehow altered, or bound by proteins, or otherwise eliminated by your body … which does you no good at all.
We give ketamine by IV, so it can go straight into the blood stream and straight to your brain where it’s needed to treat the problem. Virtually 100% of the ketamine we infuse into your blood stream goes exactly where it’s needed. And because the brain’s structures and systems are so very delicate, we want to be very precise about how much reaches it and how fast.
With a precise infusion pump and IV access, we can control those factors exactly. There are no obstacles that prevent ketamine from reaching the systems in the brain in the amount we want, at the rate we want. And we can slow it, and we can stop it at any time.
But what is it about a nasal spray?
In the case of a nasal spray, there are all sorts of variables.
It has to be absorbed through mucous membranes to find its way into your bloodstream.
So picture this:
- It has to emit a spray that’s a perfectly suspended and evenly concentrated mist to saturate your mucous membranes—that are hopefully healthy enough and not bogged down by inflammation from allergies or a cold to absorb it properly. (It wouldn’t be a good thing if some days you can’t absorb your medication because you’ve got a cold.)
- When you spray it into your nostril, it has to be aimed just right…high enough that it won’t drip right back out your nose and straight enough that it will be absorbed before it runs down the back of your throat and into your stomach to be digested — where it’s bioavailability will drop even further.
- It has to be sprayed so carefully that none is wasted in the air and gently enough that it isn’t sneezed right back out.
Then add to all this, that once sprayed, there are only a few seconds for absorption to bring change to the critical and delicate brain systems…the ones vital to you getting better.
With IV ketamine, there are at least 40 minutes that ketamine is being continuously infused into the blood stream reaching the brain at a precise dose and rate. 40 minutes vs. a few seconds!
Esketamine nasal spray has been in the news all this year…and last year too.
Anytime Janssen has an announcement to make about esketamine we want to hear it.
Even if it’s disappointing. Not meeting a primary endpoint on its large major Phase III trial for approval? HUGELY disappointing. Shocking, really.
So, while we wait, we’re so thankful we do have ketamine treatment. It doesn’t work perfectly and it doesn’t work for everyone. But when it does, it can save lives by stopping suicidal thinking in 4 hours or less. It can bring relief and remission to those who suffer the most with severe depression, bipolar disorder, social anxiety, PTSD, OCD, substance abuse disorders… It works fast.
And extremely well, better than anything we’ve ever seen.
At Innovative Psychiatry we see so many patients who get better every day. Not just 50% better, but completely better. We see them achieve remission, and they go on to enjoy life as the best they’ve ever been.
They’re creative again, motivated, full of initiative …and hope. With lives that have meaning. And they’re glad to be alive.
So if you’ve invested your hope in esketamine nasal spray, don’t let disappointing news stories push you to give up.
There’s still all kinds of hope available that we’ve never had before. It just isn’t in esketamine nasal spray.
At least not yet.
But ketamine is still going full steam ahead helping many patients who thought they were treatment-resistant turn around… heal… and be restored.
To enjoy their lives fully.
If you suffer from treatment-resistant depression, and the problems that often go along with it, call us.
We’re all about helping you reconnect with the best you you can be.
To the restoring of your best self,
Lori Calabrese, M.D.