Update to Medications Currently in Trials for Schizophrenia (Spring 2021)

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Medications in development, phase 2/3

Spring 2021

This list does not include medications that do not have current trials underway, even though they may be in development. It does not include phase 1 trials or drugs in preclinical testing (not enough info to be worthwhile). It does not include supplements, or already approved medications being repurposed (like levetiracetam, telmisartan) or reformulations of existing medication as an injectable or sublingual. It does not include other therapies like rTMS. Maybe I will try to do a list of those later.

These studies are currently listed on clinicaltrials.gov as: 1. Active, not recruiting, 2. Enrolling by invitation, 3. Recruiting, or 4. Not yet recruiting.

Drug name: SEP-363856
Mechanism of action: a novel trace amine associated receptor-1 (TAAR1)/5-HT1A agonist with no dopamine-D2/5-HT2A antagonist activity
Proposed to treat: Acute psychosis
Phase: 3
Estimated study end date(s): October 2021, March 2022, November 2022, June 30, 2025 (multiple studies)
Notes: The results from the phase 2 study were good.

The primary analysis showed a significant reduction in LS mean PANSS total score for SEP-363856 vs. placebo at week 4 (-17.2 vs. -9.7; P=0.001; effect size = 0.45). Significant reduction for SEP-363856 was also observed on the CGI-S (clinical global impression) and BNSS (Brief Negative Symptom Scale) total score. Effects on weight, lipids, glucose, prolactin, ECG and extrapyramidal symptoms were similar to placebo. Adverse events occurring with an incidence ≥2% on SEP-363856 vs. placebo were: somnolence (6.7% vs. 4.8%), agitation (5.0% vs. 4.8%), nausea (5.0% vs. 3.2%), diarrhea (2.5% vs. 0.8%), and dyspepsia (2.5% vs. 0%).

Drug name: Pimavanserin
Mechanism of action: selective inverse agonist of the serotonin 5-HT2A receptor
Proposed to treat: Negative symptoms of schizophrenia
Phase: 3
Estimated study end date(s): March 2023, March 2024, January 2025
Notes: Pimavanerin is approved for Parkinson’s psychosis, but was recently rejected for dementia related psychosis. (The FDA said it was not statistically significant in some dementia subgroups). The results of the phase 2 schizophrenia study showed significant improvement in the NSA-16 (negative symptom assessment) but no significant change in the Personal and Social Performance Scale score. One analyst says of the drug that is is at the “low end of the range” for efficacy as an atypical anti-psychotic.

Treatment-emergent adverse events occurred among 39.8% and 35.1% of patients in the pimavanserin and placebo groups, respectively, with headache and somnolence as the most common.

Drug name: NaBen
Mechanism of action: Enhances the glutamate-NDMA receptor function by inhibiting the degredation of D-serine by DAAO (D-amino acid oxidase)
Proposed to treat: As an add on to current medication, the primary measurement of the study is PANSS (Positive and Negative Syndrome Scale)
Phase: 2/3
Estimated study end date: December 2021
Notes: The company website says that they have preliminary clinical data showing NaBen can improve negative symptoms, cognitive symptoms, and further reduce positive symptoms. There is another study running concurrently on NaBen with clozapine. http://www.syneurx.com/en/snd13/

Drug name: KarXT (Xanomeline and Trospium Chloride)
Mechanism of action: M-1-M4 muscarinic agonist
Proposed to treat: Schizophrenic psychosis. The drug is also being developed for negative and cognitive symptoms, it is in an earlier phase.
Phase: 3
Estimated study end date(s): January 2022, February 2022, June 2023, July 2023
Notes: Most common side effects in the phase 2 study were nausea and constipation, which largely resolved after the first week. The phase 2 study found a larger improvement in cognition in those who had more severe cognitive impairments.

Drug name: AVP-786 , a deuterated, second-generation version of AVP-923/Nuedexta
Mechanism of action: a weak antagonist of NMDA receptors, and an agonist of sigma 1 receptors
Proposed to treat: Negative symptoms of schizophrenia
Phase: 2/3
Estimated study end date: Feb 2022
Notes: Previous failure for this drug for agitation in Alzheimer’s patients.

Drug name: MK-8189
Mechanism of action: PDE10A inhibitor
Proposed to treat: Acute schizophrenia
Phase: 2
Estimated study end date: July 2022
Notes: Drug is being compared to placebo as well as risperidone

Drug name: Cannabidiol
Mechanism of action: undetermined/possibly anandamide regulation
Proposed to treat: One study is of cannabidiol as a maintenance treatment of schizophrenia as an add-on to antipsychotic, the other compares it to olanzapine and to placebo. There is an additional study of cannabidiol in early psychosis ending Dec 2021, and another ending June 2023.
Phase: 2
Estimated study end date(s): December 2021 March 2023
Notes: This might be considered a supplement but I am going to go ahead and include it as a drug.

Drug name: BI-425809 + cognitive training
Mechanism of action: Gly-T1 inhibitor
Proposed to treat: Cognitive impairment
Phase: 2
Estimated study end date: April 2022
Notes: Study tests the drug plus cognitive training vs placebo plus cognitive training. All patients are required to be stable on 1-2 antipsychotics, excluding clozapine.

There were 2 studies, the first study, 1346.9 was a study of the drug as an add-on to exisiting medication, but without cognitive training. The earlier study is reported to have met its primary endpoint, improvement in cognition.

Five of six dose–response models showed a statistically significant benefit of BI 425809 over placebo

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30513-7/fulltext

The second (this one) is study 1346.38 and includes the addition of cognitive training.

Drug name: BI-409306
Mechanism of action: PDE9A inhibitor / glutamatergic neurotransmission
Proposed to treat: Prevention of relapse in schizophrenia, prevention of conversion to psychosis in attenuated psychosis syndrome
Phase: 2
Estimated study end date(s): March 2021, April 2021
Notes: The same drug did not improve cognitive impairment in schizophrenia in an earlier trial.

Drug name: RO6889450 Ralmitaront
Mechanism of action: Partial TAAR1 agonist
Proposed to treat: Acute Exacerbation of Schizophrenia or Schizoaffective Disorder, negative symptoms
Phase: 2
Estimated study end date(s): December 2022, April 2023
Notes: studies for acute exacerbation and negative symptoms are separate trials but running concurrently.

Drug name: RL-007
Mechanism of action: modulator of cholinergic, NMDA and GABA type B receptor systems
Proposed to treat: Cognitive impairment – this study is a safety and biomarker study
Phase: 2
Estimated study end date: September 2021
Notes: atai Life Sciences Acquires Majority Stake in Recognify Life Sciences to Develop Novel Treatment for Cognitive Impairment Associated with Schizophrenia

RL-007 preliminarily exhibited pro-cognitive effects on exploratory endpoints in pain patients, an experimental cognitive paradigm, and healthy volunteers. Preclinically, it demonstrated pro-cognitive effects in healthy young animals, age-associated memory loss, and models of cholinergic-deficits. RL-007 also showed anxiolytic properties in animal models of unconditioned anxiety. Finally, it has been shown to enhance long term potentiation in rat hippocampal slices, indicating a direct action on mechanisms and brain regions involved with learning and memory processes.

Drug name: BIIB-104 , also known as PF-04958242
Mechanism of action: Positive allosteric modulator (PAM) of the AMPA receptor, glyicine reuptake inhibitor
Proposed to treat: Cognitive impairment
Phase: 2
Estimated study end date: June 2021
Notes: –

Drug name: PF-03463275
Mechanism of action: Glycine transporter 1 (GlyT1) inhibitor
Proposed to treat: Cognitive impairment
Phase: 2
Estimated study end date: December 2021
Notes: –

Follow ups from my May 2019 list that are not already covered above:

Lumateperone/Caplyta/ITI-007 was approved and is available in many markets. Lumateperone is a 5-HT2A receptor antagonist, partial agonist of presynaptic D2 receptors and an antagonist of postsynaptic D2 receptors, serotonin transporter blocker with affinity for the D1 receptor and lower affinity for the Alpha-1A_adrenergic_receptor and Alpha-1B_adrenergic_receptor 5-HT2C receptor and D4 receptor, with indirect glutamatergic modulation. It is said to have a better side effect profile than most D2 antipsychotics.

Roluperidone/MIN-101 did not meet its endpoints in it’s phase 3 study ended June 2020. Minerva counters that the combination of the phase 2 and 3 studies show effectiveness and warrants an NDA submission. However, the phase 2 study did not use the commercial formulation of roluperidone, and there were problems with at least one of the study sites. At this time it is down, but not necessarily out. Roluperidone is being studied as a monotherapy for primarily negative symptoms of schizophrenia.

FDA acknowledged that the data from the Phase 2b and Phase 3 studies appear to show promising signals and encouraged Minerva to continue the development of roluperidone for treatment of negative symptoms in schizophrenia, which FDA confirmed is an unmet need.

Minerva intends to continue development and NDA activities consistent with FDA’s December 2019 draft guidance.

Evenamide. Newron successfully completed an additional safety study requested by the FDA.

[Evenamide] has a unique mechanism of action: glutamate modulation and voltage-gated sodium channel blockade. Evenamide modulates sustained repetitive firing, without inducing impairment of normal neuronal excitability. It normalizes glutamate release induced by aberrant sodium channel activity. In a Phase IIa clinical study, Newron demonstrated evenamide’s evidence of efficacy in significantly improving symptoms of psychosis compared with placebo when added to two of the most commonly prescribed atypical antipsychotics in patients with chronic schizophrenia.

No patient on evenamide discontinued from the study due to adverse events, and there were no significant adverse events relating to evenamide. No symptoms were observed suggestive of severe CNS events, symptoms/signs of seizures, EEG diagnosis of seizure like activity, or cardiac events in patients with evenamide. There were no differences in laboratory, ECG or vital signs abnormalities between evenamide and placebo-treated patients. The most frequent adverse events reported (greater than 5%) were headache and somnolence, which were equally distributed between evenamide and placebo.

ASP-4345 a dopamine D1 receptor modulator for cognitive impairment. The phase 2 trial was completed, CTG Labs - NCBI Astellas pharma does not appear to list the drug on their website.

TAK-831 did not meet its primary endpoints for treatment of adults with negative symptoms of schizophrenia. TAK-831 is a D amino acid oxidase inhibitor.

CTP692 phase 2 trial did not meet endpoints. CTP-692 is a deuterated form of D-serine, an endogenous amino acid that is a co-agonist of the NMDA receptor.

TAK-063 Phase 2 study did not meet primary endpoint, but secondary endpoints were suggestive of antipsychotic activity. TAK-063 is a PDE10A inhibitor.

TAK-041 for anhedonia/motivation. CTG Labs - NCBI

Lu AF11167 development discontinued

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Thanks for posting this @twinklestars

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They don’t accept ppl with a BMI of over 35 for the NaBen study :slightly_frowning_face:

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I enjoyed sodium benzoate. It worked.

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I always thought it was bad before reading about its effects on sz. Its a preservative I think? Anyways I read it improved negative symptoms by 21% according to studies. I read vape liquid contains sodium benzoate.

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From where did you take it? Supplements?

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Amazon supplement.

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Glycine helps me a bit. I am taking it now. Ldopa helped a lot but caused psychotic symptoms, it reduces meds effects as meds reduce dopamine and ldopa increases dopamine.

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We’re you prescribed ldopa @Aziz?
That stuff triggers psychosis.

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No I took it from a supplement that has 15% L-Dopa, its called Mucuna Pruriens.

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Yes it did when I took too much. I had to manually increase my Risperdal dosage to 6mg for one day to go back to normal. 4mg wasnt enough. Yea its dangerous. I stopped it.

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I don’t want to sound critical. But, research should focus on the prevention of schizophrenia, not its aftermath. I think once one becomes ill, it is hard to recover. I think prevention should be a priority.

All these medications make the pharmaceutical companies richer. I see the reason for developing these medications- profit. If these companies had any compassion, they would put their profits into researching the prevention of schizophrenia.

Yes, newer medications make a lot of money. New patents are profitable for 20 years or so. But, these new medications all have side effects and some are just modified versions of previous medications. Money is the motivation, not our well-being.

I don’t want to be a walking pharmacy. I am disgusted by the perspective that making newer medication is key to our recovery. There are many medications now on the market. More medication does not mean that we will have success with all of them. After awhile, there will be a candy store variety of medications for psychosis. Are you kidding me?

I am critical because I used to take many medications without much success. Now, I take one- only one- and am doing fine. I don’t believe that these newer medications are that much different from the previous ones.

Stop this nonsense!

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Thanks for all the work you did on this. I did something like this many years ago and created a Google “sites” free website with the info.

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Thats much harder as we need need genetic trearment to prevent sz from happening. Thats treating sz from its roots.

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Like imagine if Drs can detect sz genes using a test very early and then treat the genetic defects.

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I know it is harder but not much has been done about preventing the disease. I benefit from medication too. However, it seems each year new medications are on the market. I I do hope that there is more research into preventing psychosis too in the future. Medications help. But we should also find out the reasons of why we become psychotic and develop schizophrenia as well. That is all I am asking. I know our genes play a role in developing the disease. But, which genes and why some of us become schizophrenic have never been researched thoroughly. If we could put as much money into the roots of the cause of psychosis, may be, some of us would have better outcomes by prevention of the disease. I ramble. But I mean well for all of us who have schizophrenia.

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I think that there is a fair amount (not really enough, but some anyway) of research into prevention of schizophrenia.

There’s some of it at the prenatal level.

In adolescents and young adults there are a couple trials using things like NAC, sulforaphane, cognitive training, omega 3 fatty acids, and levetiracetam as possibilities for either the prevention of psychosis, or studying changes to the brain around the time of the onset of psychosis to figure out what’s going wrong and how to alter it. BI-409306 is the closest on this list, as they are testing it to see if it keeps people with attenuated psychosis syndrome from becoming worse.

In preclinical, there is research in rats on applying TDCS or other stimulation to certain areas of the brain in adolecence - and it works in SZ model rats, but the problem is it isn’t good for healthy rats. And in people you just don’t know - yet. So there will probably not be human trials until they can say “this person is almost certainly going to develop schizophrenia, and so it is worthwhile to take the risk of treatment.”

I think that there will be some possibility there after they have very accurate testing. I do think it is only a matter of time before there is a lab test for schizophrenia. To be really accurate it might have to combine different tests, like blood and MRI/EEG, but I think it’s gonna happen by 2030 or before. If it does, I expect they will also be able to predict the onset of schizophrenia before it happens, and then they will really be able to study prevention in adults/teens, and maybe even preteens.

I also think there will eventually be real disease modifying treatments. Perhaps stem cells, or gene therapy or drugs that increase or decrease the activity of certain genes, combined with functional therapy, brain stimulation and other tech. Unfortunately there is nothing like that on this list, the best we can do now is to stay as well as possible until that is a real thing. They are pursuing it - there will be papers published in animal models on a monthly basis. But it’s still not something they’re willing to do on people yet.

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Thank you for the update!

I hope there is more research like this.

I know there is not much research being done for the prevention of schizophrenia. But, we have to start somewhere.

I do hope the newer medications work for some people. I think if the cause of schizophenia is found, we can target this and do something dramatic.

I find that medications now are hit or miss. Some people with schizophrenia benefit whereas others don’t from medication. Producing more medications without understanding the cause of the disease is not helpful for those with schizophenia or psychosis. Medications are like bandages. What is the cause/ the source should be investigated thoroughly instead of making more medications.

The best we as people with schizophrenia can do is to take our medications for the rest of our lives. This is profitable for the pharmaceutical companies. But it is a life-long sentence for those with schizophrenia.

These are the reasons I am dissatisfied when I hear there are more medications on the market each year but not much research into the cause/ prevention of schizophrenia.

My hope is that one day schizophrenia is preventable and more manageable. All I see now is medication advertisements everywhere but no real answers of preventing it. Schizophrenia causes severe disability. The cost of people’s lives destroyed by this disease is immeasurable. We continually suffer from the illness or from side effects of medication. Medication is not a panacea but just a temporary fix. Truthfully,I wish I did not have to take medication to prevent psychosis. I know many others who feel the same. I wish there were healthier alternatives to medication. So, much can be done in schizophrenia research besides developing new medications.

Thank you again for this information about testing for schizophrenia and disease -modifying treatments.

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I thought you might be interested in this news, on an existing drug called fenofibrate.

To boost synaptic function—a well-documented problem in people with schizophrenia—the team gave mice a drug called fenofibrate, which activates PPARα. Fenofibrate is already taken by millions of people every day to help control cholesterol and fat levels in the blood. The researchers showed that the drug helped alleviate brain and behavioral abnormalities in various mouse models of schizophrenia.

Unfortunately, they can’t just use fenofibrate at human-safe doses because:

However, because fenofibrate does not readily cross the blood–brain barrier, the scientists had to administer very high doses of the drug. That approach would be risky in people, says Maekawa, since fenofibrate can sometimes seriously damage muscle tissue. To avoid that potential side effect, drug developers may have to refine the chemistry of fenofibrate or discover new agents that activate PPARα. “To test the therapeutic strategy in people, we need more drugs that penetrate the brain for clinical trials,” Maekawa says.

But I think this sort of research at least shows that they are working on, and there is the possibility of, drugs that actually change the brain and help it have a more normal connectivity. Although I am sure it is a long way out, there are new technologies to deliver drugs more directly to the brain, and new ways to predict with computers what properties new chemical structures might have. So I expect something like this will eventually be developed in people.

This is the full paper.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30506-5/fulltext

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I also wanted to add that there are a couple of natural PPARα activators which are safe in moderation: green tea, reservatrol (present in grapes, blueberries and dark chocolate) and sesame seeds and oils. While it is unlikely they would have as much effect as a drug, it still may be an explanation for their health benefits.

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