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Early last year, Roche Pharmaceuticals announced they were conducting a clinical trial study of their drug basmisanil for young children with Dup15q Syndrome called the Quindecim studies. I assumed the drug is similar to flumazanil, an antidote for overdosing on Lorazapam (Ativan) but later found that although they are both reversal agents for benzodiapazines, their mechanism and receptor targets are different. Basmisanil is a type of anti-benzodiazapine but unlike flumazanil, basmasinil was touted as being more selective to the target site of a protein, GABAa receptor encoded within the Dup15q chromosome (15q11.2-13.1) thus, hopefully leading to improved cognition and behavioral abilities. At least, this was what was being advertised to the dup15q community. Not long after the start of the clinical trial, Roche decided to pull the rug on the study leaving many participants confused and upset, From the beginning, I questioned why basmisanil, a drug that failed to show improved abilities in both Downs Syndrome and schizophrenic populations was being repurposed for Dup15q Syndrome. Since Roche's patent on flumazanil was ending soon were they trying to capitalize on patenting another drug for profit? One distinguishing phenotype of Dup15q Syndrome is the presence of a clear biomarker by way of an EEG tracing showing distinct beta waves which mimics that found in individuals taking benzodiapines. Would it be logical then to consider a drug such as flumazanil, an antidote for overdosing on benzodiazapines such as Lorazapam, could be the target of the Dup15q biomarker. Couldn't flumazanil, an already FDA approved drug on the market, be trialed on our kiddos? The receptor targets differ between the two drugs, and it is found that basmisanil has more specificity to the gene targets of Dup15q than flumazanil as will be explained below. If that is the case, why did researchers use basmisanil for Down's and Schizophrenics who don't share the same duplicated chromosomal duplicated region of 15q11.2-13.1 found in Dup15q Syndrome? Was there even a shared biomarker target from Chromosome 23 (triplicate among individuals with Downs Syndrome) and 15 (duplicated among individuals with Dup15q Syndrome)? That seems a bit far-fetched to me. I am impressed and surprised that some pharmaceutical companies are even tackling rare diseases as the market is miniscule compared to more prevalent health conditions such as cardiovascular diseases or cancer. Will they recoup the money spent on R&D for rare diseases such as Dup15q Syndrome? Could this concern be the reason why big pharma companies are buying up smaller pharmaceutical companies that already invested a lot of money in drug discovery so as to reduce the cost of starting from the ground up?
Within less than a year of advertising basmisanil for clinical trial for the Dup15 population, Roche pharmaceuticals decided to terminate their study for financial reasons (click for details). Many families who signed up for the study were left devastated and their hopes dashed for a potential cure or at least improvement in cognition, communication and daily living skills. This may be way out there and a very unorthodox suggestion but has anyone considered administering flumazanil, a benzodiapapine antidote, specifically lorazapam (Ativan), for seizure control? It would definitely be an off-label use of it. But given the EEG biomarker for the syndrome being unusual beta waves that mimic people on benozo's, I wonder if it could actually reduce seizure frequency and intensity and improved cognition? Researchers were hesitant to trial flumazenil for risk of increased seizure as that is one of the adverse effects in the "normal" population. But I wonder if such a detrimental side effect could paradoxically turn out to improve seizures in the Dup15q population as they have different biology to the normal population. Basmisanil’s mechanisms of action differs from flumazanil in that the former works as a selective negative allosteric modulator of the GABA alpha 5 receptor, meaning it binds to the GABA alpha five receptor and inhibits its function, primarily impacting cognitive processes and affective symptoms such as depression; whereas, the latter works as a “potent benzodiazepine receptor antagonist that competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepine on the central nervous system.” Does flumazanil only work in the presence of a benzodiazepine and has no effect in its absence? Since Roche gave up on the basmisanil clinical trial and we already have flumazanil on the market, I wonder if any doctor would be willing to prescribe it for seizure reduction or for improved cognition. Saniona did a preclinical study that showed that selective modulation of GABAa between flumazanil and basmisanil at similar concentrations was about the same and it was not very impressive. see Time stamp 13:20
Ovid Therapeutics is another biopharmaceutical company "dedicated to developing medicines for brain conditions with deep unmet needs". Ovid is developing a pipeline of potential small molecule medicines that seek to meaningfully improve the lives of those affected by diseases of the central nervous system." Researchers at Ovid were trialing a small molecule, TAK-OV935, for seizure reduction in a small cohort of individuals with Dup15q Syndrome. One parent of a son in his 30's said they trialed it for 8 months but showed little to no change in seizure reduction and had abandoned the study. Some families who participated in the study decided to "remain on the drug in an open label extension as they saw other benefits." Ovid then sold the drug to a bigger global pharmaceutical company headquartered in Japan called Takeda Pharmaceuticals whose company website states that they "aim to transform lives, helping patients with limited or no treatment options including rare diseases among many others." I wonder if Takeda is still considering a treatment for Dup15q Syndrome.
An international pharmaceutical company headquartered in Denmark called Saniona that specializes in finding drugs for neurodegenerative diseases, announced they are considering starting phase 1 clinical trials in 2026 on their compound SAN2465, a novel potential first-in-class rapid onset GABAa alpha 5 negative allosteric modulator indicated for depressive disorders but also positioned for "rare diseases". It targets the same GABAa receptor clusters similar to basmisanil and duplicated in the15q11.2-13.1 region but has a 1000-fold greater specificity to the dup15q targeted gene product than either flumazanil or basmisanil. Since researchers believe excessive GABAa activation in the duplicated 15q region causes the unique beta wave biomarker found in EEG tracings in Dup15q, they hope the drug will reverse this increased beta power by inhibiting the GABA alpha 5 receptors as stated in their presentation (time stamp 11:50). They don't come out and say explicitly that this reduction will result in improved cognition but given that was the desired outcome from the basmasinil study, I am assuming that reduced beta wave activity results in improved cognition. I am also hypothesizing that there may be a reduction in anxiety and depression, affective symptoms very prevalent among Dup15q, especially anxiety, as this compound is also being studied for depressive disorders. Why not also look into seizure reduction as another variable to monitor along with improved cognition and affective behavior? Who's to say that decreased beta waves wouldn't improve seizures? Their rat study data using deprivation of sucrose as a stressor and ketamine, an MDNA antagonist, as the positive control shows the compound "fully reversed" stress-induced anxiety and cognitive impairment. (see time stamp 16:30) I asked a few Duper parents what their children's response to ketamine was and most said there was no adverse reactions noted except for some sedation. However, one parent stated that ketamine made all four limbs shake for their child and the doctor explained to her that this sometimes happens. Perhaps this is a general side effect common to most people and not a concern of contraindication for Dup15q individuals. Saniona's CSO, Karin Sandager Nielson, remarked on Dup15q Syndrome, "There is no FDA approved treatment for this syndrome. Epilepsy is just treated with standard antiepileptic drugs and the psychiatric symptoms are treated with SSRIs and antipsychotics and that is really not a good option for these kids. So, there is a significant medical need, in particular, for the psychiatric symptoms including intellectual disability. There is a very direct link to the GABA a 5 target in that part of the genes that are duplicated in this syndrome comprise the genes that encode for the alpha 5 protein. The extra gene numbers result in excess alpha 5 in the brain and can be demonstrated by the enhanced beta wave activity [on an] EEG. The clinical value property for this drug is we want to normalize this hyper-inhibitory GABAa activation through the GABAa 5 negative modulation". In layman's terms, it's like plugging up these extra receptors with the experimental compound. I would assume dosing will be a very critical variable to study in the clinical trial because we need to find the right dose, just enough to plug up the extra receptors but not too much to plug up more than needed. Wrong dosing amount could lead to inaccurate results of its efficacy. But how do they know how much is enough? Would adequate reduction in beta wave activity on an EEG be a sign of right dosing?
Did Roche drop their basmisanil study because they knew another company was studying a compound that was 2 orders of magnitude greater in potency to their product? Roche dropping their basmisanil study left many families upset and with dashed hopes, but I am learning that one setback doesn't necessarily mean the game is over. Pharma companies want to make money and survive, and their strategic decisions may seem callous on the surface but there is always something else brewing in the backdrop that we don't necessarily have privy to know. In the end, rather than being swayed by heavy emotions, it is best to just trust in the process, be patient and have faith that someone somewhere is working on the problem, and the solution will eventually come to light. Saniona also has two other compounds ready for Phase 1 trial, SAN2355 and SAN2219 that target focalized and generalized pediatric epilepsy and acute rare seizures "with opportunities in rare and severe epilepsy", respectively. There is another product, a "GABA Program" in the preclinical stage also indicated for epilepsy and positioned for "rare pediatric epilepsy syndrome." Could they be implying a Dup15q cohort study or are they thinking of another rare disease? I have a feeling they are thinking of my son's syndrome.
On a side topic, there is another study promoting Bexicaserin (click for info) , centrally acting serotonin 5-HT 2C receptor super-agonist which is a Phen fen analog (what???) study to reduce seizures. Yes, a Phen fen analog to treat seizures on my kiddo! Are we willing to potentially destroy healthy heart valves in exchange for the peace we get from seizure reduction? A word of caution: In our desperate pursuit for finding a cure we must be careful not to get exploited. Their trial stopped prematurely citing financial reasons. The company that was doing the drug trials, Longboards Pharmaceuticals a company based in San Diego, was bought out by Lundbeck, a Danish pharmaceutical company! I wonder if this is why Lundbeck got interested in Dup15q and more specifically, Lennox-Gestault Syndrome. Per their press release, "Longboard's 5-HT 2C receptor super-agonist Bexicaserin for seizures associated with rare forms of epilepsy [they are referring to Dup15q specifically], which is due to start phase 3 within the next few months, will round out the quartet – assuming of course the takeover completes as expected." It makes sense that Lundbeck would buy out Longboards as both companies are looking at the same 5-HT class of receptor targets for neurologic disorders. At the end of January of this year, they announced positive results for their bexicaserin study (Click for link to study).
Interestingly, Lundbeck has a patent on the antidepressant, vortioxetine aka Brintellix/Trintellix. This is an antidepressant via SSRI/5-HT1a Receptor partial agonist; serotonin 5-HT3 receptor antagonist, serotonin 5-HT3 and serotonin modulator (LexiDrug). Lundbeck's website states, " No other MDD medication is thought to work exactly like Trintellix.... The mechanism of the antidepressant effect of Trintellix is not fully understood, but it is thought to be related to its enhancement of serotonergic activity in the central nervous system through inhibition of the reuptake of serotonin (5-HT),....The contribution of these activities to the antidepressant effect of Trintellix has not been established." -Leslie Citrome, MD, MPH
One of the scientific advisors to the Dup15q Alliance, Dr. Larry Reiter of the University of Tennessee has been studying the effects of 5-HT (5-hydroxytryptamine) class of receptors in seizure reduction in drosophila fly Dup15q models. The results of this study (click for details) showed that among various SSRI's, Trintellix (vortioxetine) showed promising reduction in seizures followed by mirtazapine (remeron), wellbutrin and pregabalin (Lyrica). The paper states, "Recently, our group identified an EEG biomarker in children with Dup15q syndrome, which has now been confirmed in other cohorts by high density EEG analysis. This biomarker could potentially be used to assess the effects of treating children with Dup15q syndrome with 5-HT1A agonists like vortioxetine, an antidepressant, in an offlabel trial for seizure suppression in these children. Preliminary studies presented here show that vortioxetine is just as efficient in suppression of seizures as serotonin and more efficient than commonly used AEDs felbamate and valproic acid in our fly model (Figure S9)." I was almost tempted to supplement Lucas with 5HTP to see if any seizure reductions occurred. Either that or feed him turkey everyday. The SSRI link made me wonder if there is a connection to why so many people with the syndrome have GI issues, notably severe constipation. About 70% of serotonin is generated in the gastrointestinal system and is primarily linked in the "gut-brain axis" click for link; so if there is a pathology with the serotonin receptors along with hypotonia causing weak peristalsis of the abdominal muscles could they possibly contribute, or be the cause of severe constipation so prevalent in Dup15q Syndrome? Also, I wonder if Dr. Reiter can get sponsorship from Lundbeck to continue his study or, would that be a conflict of interest due to his position in academia?
Is it a coincidence that Dr. Reiter's study on the SSRI's that affect 5-HT class of receptors, notably the promising results of Vortioxetine (Trintellix) and Lundbeck, makers of Trintellix and their acquisition of Longboard pharmaceuticals who also were studying the promising effects of 5-HT 2C receptor superagonist for seizures related to "rare forms of epilepsy all lead back to a class of SSRI's that target 5-HT receptors? These don't seem coincidental but orchestrated around the same target for drug discovery. The question I have is, are they looking at the right target and is it specific enough to target the overexpressed genes of the 15q region duplicated in the Dup15q Syndrome? Only further studies will tell if it is or isn't.
Acadia Pharmaceuticals is another company that has a clinical trial pipeline for a drug to treat Rhett Syndrome (click for more info.) and Prader-Willi Syndrome The latter is promising as it is in the same duplicated chromosome region as Dup15q Syndrome. The company already has an FDA approved drug DayBue (trofinetide) to treat Rhetts. Another company named Neurogene, started by Rachel McMinn,whose sibling has Rhett Syndrome, focuses on "genetic medicine". This company has been in contact with the Dup15q Alliance for a possible collaboration with our families. How exciting would it be to have a drug personalized for Dup15q, also! And shout out to all the amazing siblings affected by rare syndromes!
Karin Sandager, CSO of Saniona, was absolutely right when she said giving generic anti-epileptic drugs and antipsychotics to our children is not acceptable. If we could give just two pills, one that is a negative allosteric modulator of the GABAa alpha 5 receptor and another drug targeting 5 – HT receptors instead of 5 antiepileptic drugs and 4 antipsychotic drugs, it would be a godsend!
I found no pharmaceutical companies studying the effects of amplified UBE3a gene products, a protein which was the buzz topic among Dup15q Alliance and assumed to be implicated in autistic features. Whatever happened to UBE3a studies?
A successful drug discovery process requires many good players dedicated to getting the drug to market from pharmaceutical companies with its vast resources to the brains of academics but at the heart is the patient and their advocacy groups who must remain vigilant and dedicated to making sure the other players are working in good faith and for the benefit and safety of the patient because while the motivation for the other parties may be financial gain, advocacy groups are the ones truly vested in the patient's welfare for its own sake and not swayed by other more worldly incentives.
