SAGE Therapeutics — CNS Disorders

[Nick47]

It surprised me that they measure tinnitus loudness. Might be the GABA part.

I think their aim is simply getting a tinnitus approved indication since there is nothing formally approved for us. I guess it will result in a similar outcome as if Amitriptyline/Mirtazapine was trialed for tinnitus which would surely give a statistically significant outcome versus placebo. You can get an antidepressant approved for 1000s of chronic disorders. So it is more a "strategic" trial to get some market share in an untouched market. Especially because there is no published rationale or mentioning of tinnitus anywhere in their report.

I'm speculating but I'm not interested in this one.

@InNeedOfHelp, yes, it's surprising they don't have any background rationale at all, let alone discovery science. Same can be said for Pimozide, where they boldly claim a discovery of a dopamine pathway. Although the later also works as a 5-HT7 antagonist, which are present in the DCN. I think Pimozide also acts as an H4 antagonist, and there is some discussion in scientific papers of that receptor's involvement.

 

[Nick47]

I wonder if SAGE Therapeutics could be an underdog surprise here. Their stock has gone up 43% in 6 months and looking back up the thread, they've had a few tinnitus patents in the pipeline. I was motivated to have another look at this after @Jorge P. Simoes's comments a few days ago. It's already being used for other conditions, although if not covered by insurance, I hear it's very expensive.

Again it's the lack of scientific lead-in that's strange, as treatments are normally developed after clinical findings.

 

[Josh59]

There has been a recent update on this study, with a start date in May and an end date in October 2023.

An Open-Label Study Evaluating Brexanolone in Adults With Tinnitus - Full Text View - ClinicalTrials.gov

Could this help us reduce our symptoms?

 

[lapidus]

There has been a recent update on this study, with a start date in May and an end date in October 2023.

An Open-Label Study Evaluating Brexanolone in Adults With Tinnitus - Full Text View - ClinicalTrials.gov

Could this help us reduce our symptoms?

I find it a bit odd that they are excluding somatic tinnitus since approximately 60-80% of all tinnitus sufferers have somatic components despite not having a somatic cause.

Participant's tinnitus can be modulated by maneuvers of the temporomandibular joint, head and neck, eyes, or limbs, or otherwise attributed to somatosensory cause or has had prior otoscopic surgeries or cholesteatoma.

 

[Nick47]

find it a bit odd that they are excluding somatic tinnitus since approximately 60-80% of all tinnitus sufferers have somatic components despite not having a somatic cause.

I think they mean somatosensory i.e. much rarer cases like TMJ or cervical issues rather than somatic (modulated) forms which are common. In other words, it's inner ear damage induced common tinnitus they want.

 

[Josh59]

The study should be completed shortly.

I don't know how long it will take for the results to be published?

In any case, let's not lose sight of this study!

 

[SarahMLFlemmer]

I think they mean somatosensory i.e. much rarer cases like TMJ or cervical issues rather than somatic (modulated) forms which are common. In other words, it's inner ear damage induced common tinnitus they want.

This is great news for someone like me, who has one to no somatic components. The only time my tinnitus changes is when I open my mouth in front of a fan or running water, the left ear only goes from a pure tone to a "shhh" and after I close my mouth, it's back to a pure tone. It only does this on occasion but it's only if I am in front of a fan or running water. But besides that, it doesn't change, not one bit, no matter what I do.

Pretty sure I have inner ear damage from ototoxicity.

Seems like not too many researchers/scientists care about medication-induced tinnitus, but I could be wrong!

 

[Josh59]

There was a new update on 2 October. Recruitment is still underway. The trial is due to finish in May 2024, not this month.

An Open-Label Study Evaluating Brexanolone in Adults With Tinnitus - Full Text View - ClinicalTrials.gov

Can anyone here contact SAGE Therapeutics to find out more?

 

[Christiaan]

There has been a recent update on this study, with a start date in May and an end date in October 2023.

An Open-Label Study Evaluating Brexanolone in Adults With Tinnitus - Full Text View - ClinicalTrials.gov

Could this help us reduce our symptoms?

Can GABAkines Quiet the Noise? The GABAA Receptor Neurobiology and Pharmacology of Tinnitus (Witkin et al., 2022)

Abstract
Tinnitus is a highly prevalent and disabling disorder in which sound is perceived in the absence of an external auditory energy source. The disorder is complex and can arise from multiple etiologies. Co-morbid symptoms of anxiety, depression, and sleep loss are prevalent. There are no approved medications and the treatments that have been studied produce marginal improvements in symptoms.

A major hypothesis of the etiology and maintenance of tinnitus is that inhibitory input mechanisms become compromised where impairedγ-aminobutyric acid (GABA) synaptic transmission has been implicated. This general idea lends support to the potential for enhanced inhibition by drugs that enhance GABA function (GABAkines) to dampen symptoms of tinnitus. Convergent evidence from neurochemical, anatomical, physiological, and pharmacological studies support the GABAA hypothesis.

Although there is surprising a relatively sparse data set, examples of therapeutic efficacy have been reported with GABAkines. These studies have relied primarily on classical benzodiazepine anxiolytics like alprazolam and clonazepam.

However, the possibility that novel GABAkines with unique activities might be effective have yet to be intensively explored. For example, data implicating extrasynaptic GABAA receptors in the control of tinnitus suggests the potential for extrasynaptic GABAA receptor modulators.

The large medical need, a basis for further testing of the GABAA hypothesis, and the recent reinvigoration of the drug development pipeline of new GABAkines, combine to give impetus and promise for further inquiry.

 

[SarahMLFlemmer]

This trial is still recruiting in Atlanta, Georgia and Iowa City, Iowa!

An Open-Label Study Evaluating Brexanolone in Adults With Tinnitus

 

[Note]

Does Brexanolone target tinnitus loudness or tinnitus related depression?

 

[ma7555]

Study completed, no results posted yet.

 

[BuzzyBee]

Does Brexanolone target tinnitus loudness or tinnitus related depression?

I'm going to guess it targets the tinnitus itself. I am not smart enough to explain scientifically, but I can explain where my dumb hunch comes from.

Women who are cycling and have tinnitus can often predict moods and tinnitus spikes based on times of the cycle. Generally speaking, estrogen has an excitatory effect on neurotransmitters while progesterone is inhibitory. Often, the tinnitus is quieter during times when when the hormones are in balance or when progesterone is slightly higher. As I understand it, Brexanolone is allopregnanolone. Allopregnanolone is "a naturally occurring neurosteroid which is made in the body from the hormone progesterone."

Progesterone is generally thought to be a calming hormone which is why perimenopausal women might use it in creams to help sleep.

So my guess is Brexanolone targets tinnitus by calming the excited cartwheel cells or whatever those cells are in the dorsal cochlear nucleus that are overactive and cause tinnitus. Or maybe it potentiates calming neurotransmitters that do this job.

If I were eligible, I would get into this study ASAP, but there are too many exclusions, including hearing loss. I don't even know how they are going to find people who meet all their criteria. Maybe a mother who was treated for postpartum depression might anecdotally report it helped her tinnitus.

 

[Nick47]

Does Brexanolone target tinnitus loudness or tinnitus related depression?

Tinnitus loudness is the primary endpoint.

I'm going to guess it targets the tinnitus itself. I am not smart enough to explain scientifically, but I can explain where my dumb hunch comes from.

Women who are cycling and have tinnitus can often predict moods and tinnitus spikes based on times of the cycle. Generally speaking, estrogen has an excitatory effect on neurotransmitters while progesterone is inhibitory. Often, the tinnitus is quieter during times when when the hormones are in balance or when progesterone is slightly higher. As I understand it, Brexanolone is allopregnanolone. Allopregnanolone is "a naturally occurring neurosteroid which is made in the body from the hormone progesterone."

Progesterone is generally thought to be a calming hormone which is why perimenopausal women might use it in creams to help sleep.

So my guess is Brexanolone targets tinnitus by calming the excited cartwheel cells or whatever those cells are in the dorsal cochlear nucleus that are overactive and cause tinnitus. Or maybe it potentiates calming neurotransmitters that do this job.

If I were eligible, I would get into this study ASAP, but there are too many exclusions, including hearing loss. I don't even know how they are going to find people who meet all their criteria. Maybe a mother who was treated for postpartum depression might anecdotally report it helped her tinnitus.

You realise the trial was open to both sexes?

 

[IndyMLVC]

I'm going to guess it targets the tinnitus itself. I am not smart enough to explain scientifically, but I can explain where my dumb hunch comes from.

Women who are cycling and have tinnitus can often predict moods and tinnitus spikes based on times of the cycle. Generally speaking, estrogen has an excitatory effect on neurotransmitters while progesterone is inhibitory. Often, the tinnitus is quieter during times when when the hormones are in balance or when progesterone is slightly higher. As I understand it, Brexanolone is allopregnanolone. Allopregnanolone is "a naturally occurring neurosteroid which is made in the body from the hormone progesterone."

Progesterone is generally thought to be a calming hormone which is why perimenopausal women might use it in creams to help sleep.

So my guess is Brexanolone targets tinnitus by calming the excited cartwheel cells or whatever those cells are in the dorsal cochlear nucleus that are overactive and cause tinnitus. Or maybe it potentiates calming neurotransmitters that do this job.

If I were eligible, I would get into this study ASAP, but there are too many exclusions, including hearing loss. I don't even know how they are going to find people who meet all their criteria. Maybe a mother who was treated for postpartum depression might anecdotally report it helped her tinnitus.

Awesome. I'm on both estrogen and progesterone. No difference.

 

[BuzzyBee]

Tinnitus loudness is the primary endpoint.

You realise the trial was open to both sexes?

Of course, because they are testing the drug on tinnitus. But to actually GET the drug without being in a trial, you have to be a female with postpartum depression. I don't think any psychiatrist can just send a patient, male or female, to the local university or wherever that's using Brexanolone and ask them to treat a male or female patient's tinnitus. Insurance wouldn't cover it, that's for sure.

So the only way a male could try the drug, as far I know at least, would be in the trial. And here's what I mean about long exclusion list:

1. Participant has history or presence of any neurologic disease or condition, including, but not limited to, unexplained loss of consciousness, seizure disorder including a prior nonfebrile seizure, and closed head trauma with clinically significant sequelae
2. Participant has a history of sleep apnea or any clinically significant respiratory conditions that may predispose the participant to hypoxia during the infusion
3. Participant intends to start or discontinue a pharmacological or nonpharmacological therapy (e.g., psychotherapy, sound therapy, masking, transcranial magnetic stimulation [TMS]) for tinnitus during the course of the study
4. Participant has currently active and medically significant or uncontrolled hepatic, renal, cardiovascular, pulmonary, gastrointestinal, hematological, immunologic, metabolic disease (hypothyroidism with stable thyroid replacement is acceptable)
5. Participant's tinnitus can be modulated by maneuvers of the temporomandibular joint, head and neck, eyes, or limbs, or otherwise attributed to somatosensory cause or has had prior otoscopic surgeries or cholesteatoma
6. Participants has current unilateral or bilateral hearing loss of 30 decibel (dB) or greater (mild hearing loss) in one or more tested frequencies (500 Hertz [Hz], 1000 Hz, 2000 Hz, and 4000 Hz), 60 dB or greater at 6000 Hz and 8000 Hz, asymmetry of 30 dB or greater in two or more tested frequencies, or uses a cochlear implant or hearing aid
7. Participant has history of chronic otitis media (>3 per year during past 5 years)
8. Participant has a total score of 15 or greater (i.e., moderately severe) on the Patient Health Questionnaire-9 (PHQ-9) at Screening
9. Participant has diagnosis of moderate or severe substance use disorder (excluding nicotine dependence) within 12 months of Screening, has a positive screen for drugs of abuse including tetrahydrocannabinol (THC) on Day 1 prior to dosing, or has a positive screen for alcohol on Day 1 prior to dosing
10. Participant has a known allergy to progesterone, allopregnanolone, or any IP excipient
11. Participant has had exposure to another investigational drug or device within 30 days or 5 half-lives of the investigational drug, whichever is longer, prior to the Day 1 visit
12. Participant has a history of suicidal behavior within 2 years or answers "YES" to Questions 3, 4, or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening or at Day 1 or is currently at risk of suicide in the opinion of the investigator
13. Participant has donated 1 or more units (1 unit = 450 milliliter [mL]) of blood or experienced acute loss of an equivalent amount of blood within 60 days prior to Day 1
14. Participant has any condition, comorbidity, or lifestyle consideration that in the opinion of the investigator would limit or interfere with the participant's ability to complete or partake in the study
15. Participant is unwilling or unable to comply with study procedures and the required training during the Baseline Period. The participant must complete 10 VAS assessments remotely prior to Day 1
16. Participant is unable to complete participation in the study, e.g., due to preplanned event including elective surgery

 

[grate_biff]

Of course, because they are testing the drug on tinnitus. But to actually GET the drug without being in a trial, you have to be a female with postpartum depression. I don't think any psychiatrist can just send a patient, male or female, to the local university or wherever that's using Brexanolone and ask them to treat a male or female patient's tinnitus. Insurance wouldn't cover it, that's for sure.

So the only way a male could try the drug, as far I know at least, would be in the trial. And here's what I mean about long exclusion list:

1. Participant has history or presence of any neurologic disease or condition, including, but not limited to, unexplained loss of consciousness, seizure disorder including a prior nonfebrile seizure, and closed head trauma with clinically significant sequelae
2. Participant has a history of sleep apnea or any clinically significant respiratory conditions that may predispose the participant to hypoxia during the infusion
3. Participant intends to start or discontinue a pharmacological or nonpharmacological therapy (e.g., psychotherapy, sound therapy, masking, transcranial magnetic stimulation [TMS]) for tinnitus during the course of the study
4. Participant has currently active and medically significant or uncontrolled hepatic, renal, cardiovascular, pulmonary, gastrointestinal, hematological, immunologic, metabolic disease (hypothyroidism with stable thyroid replacement is acceptable)
5. Participant's tinnitus can be modulated by maneuvers of the temporomandibular joint, head and neck, eyes, or limbs, or otherwise attributed to somatosensory cause or has had prior otoscopic surgeries or cholesteatoma
6. Participants has current unilateral or bilateral hearing loss of 30 decibel (dB) or greater (mild hearing loss) in one or more tested frequencies (500 Hertz [Hz], 1000 Hz, 2000 Hz, and 4000 Hz), 60 dB or greater at 6000 Hz and 8000 Hz, asymmetry of 30 dB or greater in two or more tested frequencies, or uses a cochlear implant or hearing aid
7. Participant has history of chronic otitis media (>3 per year during past 5 years)
8. Participant has a total score of 15 or greater (i.e., moderately severe) on the Patient Health Questionnaire-9 (PHQ-9) at Screening
9. Participant has diagnosis of moderate or severe substance use disorder (excluding nicotine dependence) within 12 months of Screening, has a positive screen for drugs of abuse including tetrahydrocannabinol (THC) on Day 1 prior to dosing, or has a positive screen for alcohol on Day 1 prior to dosing
10. Participant has a known allergy to progesterone, allopregnanolone, or any IP excipient
11. Participant has had exposure to another investigational drug or device within 30 days or 5 half-lives of the investigational drug, whichever is longer, prior to the Day 1 visit
12. Participant has a history of suicidal behavior within 2 years or answers "YES" to Questions 3, 4, or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening or at Day 1 or is currently at risk of suicide in the opinion of the investigator
13. Participant has donated 1 or more units (1 unit = 450 milliliter [mL]) of blood or experienced acute loss of an equivalent amount of blood within 60 days prior to Day 1
14. Participant has any condition, comorbidity, or lifestyle consideration that in the opinion of the investigator would limit or interfere with the participant's ability to complete or partake in the study
15. Participant is unwilling or unable to comply with study procedures and the required training during the Baseline Period. The participant must complete 10 VAS assessments remotely prior to Day 1
16. Participant is unable to complete participation in the study, e.g., due to preplanned event including elective surgery

6, 9 and 12 would exclude me and I´m guessing many of us

 

[Nick47]

This clinical trial was completed 4 months ago. Still no results.