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Another Shot at Major Depression Fails

This is a big day for clinical trial data, and unfortunately it didn’t get off to a very good start. Everyone is waiting for more data on Biogen’s Alzheimers program later today, but another anticipated trial has already read out.

Sage Therapeutics made quite a few headlines in 2017 and 2018 when their trials of brexanalone (allopregnanolone) showed efficacy against post-partum depression (PPD), an indication that the drug was approved for this year under the name of Zulresso. This neurosteroid is an allosteric ligand of the GABA-A receptor, and this was believed to be its mode of action. But keep in mind, that’s a bit of a hand-wave: no one actually understands what exactly an allosteric GABA modulator is doing to improve depression symptoms, not in any detail. The fact that we don’t understand the molecular workings of depression in general is the place to start. You can go ask people and hear things about serotonin, about GABA, about dopamine and so on, but to be honest, there are surely connections with all of those but when you try to connect the dots you end up with stuff that’s about a half step away from folklore. We don’t know. Any people who speak confidently about the biochemistry of depression are either fooling themselves or trying to fool you, possibly both simultaneously.

Zulresso has to be given i.v., in a long slow infusion under medical supervision, so Sage has been working on an orally available compound with what should be a similar mechanism, SAGE-217 (zuranolone). That one has been in trials against major depressive disorder (MDD), and that readout has been awaited with a mixture of hope and fear by investors, because getting something to work in that field is very, very hard – but getting a new drug with a new mechanism of action would for the same reasons be very good news indeed. The Phase 2 data looked promising, albeit in a small trial. Sage-217 has naturally also been in trials for PPD, and these have shown positive results so far, and it’s also being looked at in bipolar disorder. It perhaps needs to be pointed out that we don’t understand the detailed biochemical differences between post-partum depression, bipolar depression, and major depressive disorder, either. There’s no basis for a theory-based decision here; clinical data rule, as they always do.

Well, it looks like the “very, very hard” side won out this time, sadly. The drug missed its primary endpoint in the MOUNTAIN trial, showing no benefit versus placebo in a depression rating scale at day 15. The company is trying to put a good face on the numbers, pointing out that statistical significance was reached at the earlier time points, but I honestly don’t think that’s worth much: those effects, if they are real, most certainly seem to wear off. Looking quickly at the data, the placebo group did pretty much the same thing in both Phase 2 and Phase 3, while the drug’s efficacy took a powerful drop in the latter, which is exactly what you don’t want to see. Update: an an interesting side issue is that it appears that nearly 10% of the patients in the trial appear not to have been actually complying with the drug dosing, according to the blood work. Trials in depression are not always easy to interpret, because there often is a noticeable placebo effect, but this looks like just another case of “smaller trial good, larger trial bad”. That positive Sage-217 Phase 2 trail had 45 patients in the treatment group, for example. This nasty transitions happen in CNS, in oncology, in cardiovascular, it happens all over the place and it usually means that a drug just doesn’t work. Remember, the eventual market is going to be a larger and more heterogeneous population than even the largest Phase III trial, so if a therapy can’t make the move to a somewhat larger group in the clinic, well. . .

This is not good news for anyone hoping for something new in this therapeutic area, of course, and it’s not good news for the company’s investors, either. Sage stock had been up to pretty high levels on the hopes for further efficacy in MDD, but as I write this it’s down about $94/share (63%) in the premarket, which means that several billion dollars of market cap have evaporated. The arguments will surely be starting up about whether this selloff is overdone or not, but that comes down (from what I can see) to arguments that rest on our ignorance of the molecular basis of depression, which is not a firm foundation on which to build your financial future. So this is going to be one for the brave and for those with money that they can afford to lose. A lot of it is certainly being lost this morning.

33 comments on “Another Shot at Major Depression Fails”

  1. steve says:

    I’m wondering how the recent data with ketamine affect all these companies. Not my field but the press I’ve read seems to indicate that one treatment is sufficient to treat even refractory depression. I’d be interested in hearing opinions from people more versed in this area.

    1. No body says:

      Ketamine is an interesting beast. But getting it for MDD is tricky, even now that the FDA has signed off on it – see below:

    2. Adam Hallett says:

      You will notice quite a bit of press comes from promotions of local ketamine clinics masquerading as news stories.

    3. chemist says:

      Ketamine is a recreatonal drug, not a treatment for depression

      1. Druid says:

        Intravenous, low-dose?

  2. luysii says:

    We all know that clinically, antidepressants don’t work right away, so you can’t extrapolate from acute pharmacologic effects to chronic ones, otherwise we’d be using cocaine to treat it. In practice, I noted similar delayed effects of another monoamine neurotransmitter thought to be involved in mental states (dopamine).

    Starting L-DOPA for Parkinsonism, produced improvement, usually within the first week. What was really interesting, was that without ANY change in dose, patients continued to improve in subsequent weeks. I saw a fair amount of L-DOPA side effects, because people thought that ‘if a little is good, more is better’ and increased the dose pushing people into toxicity rather than waiting. This was back in the early days (9/70) before we really knew how to use it.

    1. NJBiologist says:

      Luysii, I’d be very careful about saying that because the monaminergic interventions take weeks to months to have an effect, therefore all interventions will take weeks to months to have an effect.

      1. luysii says:

        NJ Biologist — I agree. What I was pointing out was how the unusual time course of response is not confined to drugs for depression, but might be characteristic of some drugs affecting monoaminergic neurotransmission. Certainly not true of all when you consider the beta blockers.

        Hopefully other antidepressants will be found which have different mechanisms of action — the clinical response to ketamine has a much different time course. We are far from understanding how ketamine works, as two conflicting reports on its effects will show —

    2. aairfccha says:

      Opioids actually have a noticable antidepressant effect.

      Now, if only politicians would overcome their opiophobia and prohibitionism…

      1. Todd says:

        You’d need a Wellbutrin-style opioid to get it to market. It’s not impossible, but with fear of addiction going wild, you’d need to avoid dramatic spikes as much as possible.

        1. Scott says:

          Or something like Tramadol.

          And Schedule drugs are a pain in all the places: Creation, administration, paperwork…

          Not likely to fly, especially with the current opioid addiction problems.

      2. Simona says:

        Tianeptine has been available for years in some European countries.

  3. Barry says:

    Has anyone run a clinical on hydroxy-norketamine yet? Even if it must be administered by infusion, we’re already past that hurdle here.
    Or is there just no money for a Clinical trial of a compound that’s not patented?

    1. HNK says:

      WO2013056229A1 Is a patent application from the NIH folks on HNK. There are other.
      NCT03977675 Is a clinical study underway on The Role of HNKs in the Antidepressant Effect of Ketamine. There may be additional studies.

      Yes, CNS drug discovery is hard. However, not knowing everything doesn’t mean we don’t know anything. Different folks take differs approaches to move the field forward. Some have a more nuanced, hypothesis-driven strategy. Some are happy with poorly nuanced, opportunistic, shots-on-goal approach.

      As the genius that runs FB said, “read at your own peril”. Today’s blog opinion seems more like a high-level, bankers view of the issue that what may come from someone working deep in the area over the last 20 years trying to make things happen.

      Just saying…

  4. Dr. Andrea Price says:

    Lots of drugs produce an anti-depressant like effect. Almost the entire class of second generation atypicals will do some good. Ditto with the pain class. With all these drugs you would think there’s enough meds on the shelf that people wouldn’t have to waste $$$ developing new ones!

    1. metaphysician says:

      And how many of those drugs actually work for Patient A? How many of them continue to work 1, 5, 10 years later? How many of them have a lack of nasty side effects?

      Money is “wasted” in new anti-depressants because the currently available ones quite often suck. It doesn’t matter how many existing anti-depressants exist, if they all either don’t work for you, stopped working for you, are cause adverse effects so bad that untreated depression looks like a better deal for you.

  5. Magrinho says:

    It bears remembering that Prozac and other SSRIs failed a lot of Phase 3 trials. Patients in the placebo arm are regularly attended to by physicians, asked about their affect, health, etc. and that produces a modest benefit. One can draw a number of troubling conclusions from these results…

    1. Barry says:

      yes, our assays are noisy, “major depression” may turn out to be several diseases, our controls often show improvement, and our best drugs are not very effective

    2. loupgarous says:

      If you mean Hawthorne effect, it’s hard to control for that in a medical setting, especially if you’re a study center statistician who needs to fill clinical research forms consistently and accurately.

      Clinics that don’t give enrolled patients that kind of attention sometimes send CRFs to the sponsor that raise red flags (and sponsor has to “clean the data” – which isn’t as ominous as it sounds, mainly sending a team to chat with a study center’s statistician, questionable CRFs in hand, and going to patient charts to identify any discrepancies).

  6. In Betwivo says:

    Question about “Update: an an interesting side issue is that it appears that nearly 10% of the patients in the trial appear not to have been actually complying with the drug dosing, according to the blood work.”

    Speculating here, but might this be heterotypic metabolism / clearance rather than lack of compliance?

    1. Just asking says:

      The drug was statistically significantly active at earlier timepoints before day 15.
      Did the 9% patients stop taking the drug just after day 12?

    2. loupgarous says:

      Another odd pattern in response during a clinical trial was discussed here over 2 1/2 years ago, in the column “A Clinical Trial Torpedoed By Fraud and Incompetence” covering the story of the TOPCAT trial of spironolactone in 3445 participants who had heart failure with preserved ejection fraction in 6 countries.

      30% of the study’s patients enrolled in Russia and Georgia (the country) who didn’t show a dose-response relationship to the study drug didn’t have a known metabolite of that drug in their blood samples. According to a letter in the New England Journal of Medicine from the study organizers

      “Our findings suggest that the trial results obtained in Russia do not reflect the true therapeutic response to spironolactone“


      Before we talk about non-metabolizers in a study, maybe we ought to look for the horses in the paddock (patient not complying with the study protocol or othre study administration issues) before talking about zebras getting in there.

  7. Spingos Konstantinos says:

    High levels of placebo response just implies that the subjects in those trials were not severely ill.

  8. matt says:

    Is it true that psilocybin received a breakthrough therapy designation for both TRD and MDD?

    I wonder if there’s a receptor that both ketamine and psilocybin hit at some strength?

    1. Barry says:

      It’s likely that it is hydroxy-norketamine and not ketamine that is responsible for the anti-depressant activity. Ketamine’s activity at NMDA receptors may be irrelevant to anti-depressant activity

    2. Nick says:

      Yes. 5ht2a, and they may spur neurogenesis in hippocampus.

  9. Belgian PhD student says:

    How do they discover a compound like this for depression? Phenotypic screens? As far as I know the typical avenues are serotonin/dopamine/noradrenalin/NMDA oriented, right?

  10. goldfinch says:

    from other reading, the whole point of this compound was that it acted quickly and durably. I guess not.

  11. I’ve undertaken a good few valuation projections in CNS drug development over the last couple of years and, on starting out, did a double take over quoted success rates (7% chance of approval), until I understood the contributory factors- subject stratification, comorbidity, heterogeneity of response, high placebo response rates and the complexities of data capture.

    Putting unmet needs aside, I can’t blame the majors for abandoning CNS development in droves.

  12. Joseph says:

    As the Zulresso (brexanolone) launch is off, Sage Therapeutics has been focusing on certifying healthcare facilities to administer it under the REMS program, where more than 100 hospitals, infusion centers, wellness centers and fertility centers have been certified. The company is believed to pick up momentum by early 2020, as it prepares for the first ever treatment for postpartum depression.

    Most importantly, the company’s commercial experience gained during the launch of Zulresso is expected to boost its confidence when it launches its oral drug (SAGE-217) vs. IV treatment (Zulresso) for PPD and major depressive disorder.

    In short, these two novel depression drugs could potentially generate upto
    $5bn in revenues over time, where anxiety disorders and depression treatment estimated to reach $18.6bn.

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