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  "documentTitle": "Harmony Biosciences (HRMY)",
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      "text": "The ex-Abbott scientist indicated that the bioavailability problems are inherent to all drugs in the class due to first-pass metabolism by CYP3A4, an enzyme that degrades the drug in the gut and liver before it enters general circulation or the brain – “metabolism is the biggest problem you have here.”",
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      "text": "Bioavailability is caused by drugs in the class (like pitolisant) being metabolized by CYP3A4, which degrades the drug into metabolites before it can enter the plasma and brain",
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      "text": "The ex-Abbott scientist indicated that the bioavailability problems are inherent to all drugs in the class due to first-pass metabolism by CYP3A4, an enzyme that degrades the drug in the gut and liver before it enters general circulation or the brain – “metabolism is the biggest problem you have here.” We note pitolisant is specifically indicated as being metabolized by CYP3A4. He shared data indicating that “the bioavailability...is between 1 and 3% in blood and the fraction in the brain is less than 0.2%,” meaning that there is basically no unmetabolized drug left for a therapeutic effect as “90% of this drug just goes into the urine after all.”",
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      "text": "A: “The biggest problem with this class is with the CYP3A4 having a very narrow therapeutic margin, and metabolism is the biggest problem you have here. That's the enzyme that actually degrades it. That's actually the pathway in which the product is degraded, so it's in metabolites.”",
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      "text": "A: “And that's why you will see with these products, even pitolisant, they are very sensitive for any enzyme co-administration because all of these things are going on the same pathway.” – Senior pharmaceutical executive/scientist, previously at Abbott and now at another major pharma company",
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      "text": "A: “As I said, the bioavailability is anything between 1 and 3% in the blood, and the fraction in the brain is less than 0.2%.”",
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      "text": "A: “The most important thing is where the active metabolite. And do you have enough concentration for the active metabolite to really saturate the receptor? Because the problem with H3 receptors is they are everywhere. The H3 receptor exists in many places. The most important one is the brain, but you need a certain level of saturation to really reach the point that you're going to see an effect, that this patient starts waking up again or keeping enough attention.”",
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      "text": "A: “Yes. And then 90% of this drug just goes into the urine after all. And that main metabolite pathways are ones like CYP3A4.” – Senior pharmaceutical executive/scientist, previously at Abbott and now at another major pharma company",
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      "text": "“The biggest problem with this class is with the CYP3A4 having a very narrow therapeutic margin, and metabolism is the biggest problem you have here. That's the enzyme that actually degrades it.” — Senior pharmaceutical executive/scientist, previously at Abbott and now at another major pharma company",
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      "text": "Source: Scorpion Capital consultation calls with experts",
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