I mentioned in my previous post on my experiments with cystagon that I was going to try Orkambi, the drug designed to correct the CFTR channels in the cells of CF people with two deltaF508 mutations. Well, I did try it. And I'm not on it now. That should give you a hint of my general take on the whole experience. I'm back on cystagon and plan to stay on it indefinitely, or until Vertex comes up with a better drug for me to try. First, I'll give you a little summary of what it is and what it did for (or to) me, and then I will discuss the significance of its pharmacology.
What is Orkambi?
Orkambi is a drug made by the Vertex corporation, approved by the FDA in July 2015. It costs approximately $259,000 a year [jumps up and down in a fit of rage over the greed of the pharmaceutical industrial complex]. I will resist the temptation to rant about the prohibitive cost of this drug, as that's probably not what you're hear to read about. Moving on...
Orkambi is actually a combination drug made from two drugs: ivacaftor (i.e. Kalydeco, used for the potentiation of the G551D mutation) and lumacaftor (a corrector). Even though it's been on the FDA fast track, it's been in trials for years. It is meant both to correct the faulty deltaF508 protein and potentiate it. What this means is essentially that it gets the CFTR protein to the right place in the membranes of our epithelial cells, and opens that protein to allow ions to flow across the membrane effectively. In theory, this would "fix" the problem of low extracellular electrolytes, which causes the sticky mucus issue that CF is known for. It is approved for use in CFers with two copies of the deltaF508 genetic mutation (homozygous).
What it did for (or to) me
I gave Orkambi a month-long trial and then weaned off of it over 1.5 weeks. Overall, I did notice that by the end of the trial my lungs did feel a little bit clearer (not as clear as on cystagon), I had better energy and exercise tolerance, and my sinuses felt more moist. On the other hand, I had significant shortness of breath in the beginning that subsided after the first 4 days but never completely went away, I had a mild depression settle on me, my poops were irregular and too soft (they are usually perfect), and my blood sugar was completely out of control (peaks and crashes so extreme that I had to avoid carbs altogether). Towards the end, I also experienced a bad bout of pleural pain on my right side, and I am 90% sure it was a small pneumothorax (but there was nothing I could do about it anyway and it healed in less than a week). The other stupid thing was that I caught a cold for the first several days upon starting Orkambi, which made me pissed off that my experiment had been contaminated with compounding variables! I also lost a few pounds on Orkambi, mostly because it obliterated my appetite, which could have been related to the depression.
After I got off of Orkambi I noticed that I had postural orthostatic tachycardia syndrome (POTS) that lasted for a couple of weeks, and worst of all, on the 3rd night after I had stopped Orkambi completely (after the weaning period) I coughed up a very large amount of blood in the middle of the night, about 1/3 cup. Not ok. I immediately took a Yunnan Baiyao and continued to take it for the next 4 days. Luckily, I didn't have any more bleeding. I also noticed it took my finger pricks longer to clot than usual. The clotting time went back to normal after a few weeks off of Orkambi, as did the rest of the post-Orkambi symptoms. In addition, I had my triglycerides tested 2 weeks after I stopped Orkambi and they were sky high! Like 527 (normal is 35-150 mg/dL)! That was obviously alarming, so 2 weeks later I retested and it was back down within the normal range, at 129. The super high test result could have been an error (my sister hypothesized the lab tech was probably eating cheetos and forgot to wash his hands). If it wasn't an error, then my theory on this strange occurrence is that since Orkambi had caused my blood sugars to go crazy (and my A1c actually increased during that time too, up to 6.1) all that excess glucose had been turned into fat to store in my adipose tissue, causing my blood fat (triglycerides) to increase.
After one month on Orkambi full dose I weaned off of it. I weaned off of it instead of stopping it cold turkey because of the increased risk of hemoptysis that has been reported after abruptly stopping Orkambi. This has something to do with its effects on liver metabolism of hormones, as I will discuss below. I did one week at a half dose (taking 1 pill twice a day instead of the normal dose of 2 pills twice a day), then for 4 days I took one pill once a day. For the last two days of this I restarted low dose cystagon because I was starting to feel mucusy and feverish again. I was planning on using a quarter dose of Orkambi for a week, but I was getting impatient and really wanted to be done with the side effects. It is clear to me now, in hindsight, that I did not wean off slowly enough to prevent the post-Orkambi bleeds that are so commonly reported. I probably should have done two weeks at the half dose and two weeks at the quarter dose, to be extra safe.
In summary, I did notice that Orkambi cleared up some of the mucus in my lungs and gave me a bit more energy than usual. My quantitative lung functions did not improve at all during this time; in fact, they declined by a few points (probably due to shortness of breath). If I had stayed on it for a few more months I predict that it would have further reduced my mucus load and may have even improved my FEV1. However, I wanted to get off of it ASAP because I knew that, due to the nature of its pharmacology, many of the side effects would get worse with time, and I didn't want to dig myself a hole that I couldn't climb out of. Overall, the risks outweighed the benefits. Cystagon is a far superior drug, in my opinion, and I feel so lucky to have it so that I don't feel the desperation of having no option other than Orkambi.
Pharmacology
This is a complicated subject and I've barely scratched the surface of the truth here, but from what I can gather from research and from my CF research-colleagues, here's what I know. Ivacaftor is a great drug. Simple (relatively), effective (for the G551D mutation), with a relatively uncomplicated metabolism pathway that causes relatively few side effects. Ivacaftor/Kalydeco has some pretty remarkable success stories attached to its use. This gave the next Vertex drug in the pipeline a ton of hype, especially since Orkambi is meant to treat people with the two copies of the deltaF508 mutation (homozygous deltaF508), which makes up about half of the CF population in the US.
But Orkambi is anything but simple. Lumacaftor is a seriously complex drug with a complicated metabolism pathway, which actually interferes with the metabolism of its partner, ivacaftor. As a result, it has many side effects, some of them potentially dangerous. There have been no studies on the long-term use of Orkambi, since it was fast-tracked, but this drug is designed for long-term use (uh... like a lifetime). So we, as the first generation of users, are acting as guinea pigs. Now, some of us are quite desperate in the search for anything that can help. I totally get that. CF is scary and there are few solutions, especially if our lung functions are low enough. Orkambi has even worked, and worked well, for a handful of people in the trials (or so they reported). But Orkambi is not an ideal treatment, at least not in my opinion. And the next drug in Vertex's pipeline is a few years away and is also targeting the double deltaF508 mutation, with insider reports saying it is a way better drug than Orkambi is. Is it safer to wait it out and hope that the next drug is better? I know where I stand. But here's a little more info to help others make a more informed decision.
The main issue with Lumacaftor is that it seriously messes with liver metabolism. The liver is where the majority of drug, hormone, toxin, and plant constituent metabolism takes place. The liver metabolizes drugs mainly through the use of cytochrome P450 enzymes, or the CYP450 system for short. There are many CYP450 enzymes, and certain drugs are metabolized by one or more of these enzymes. Of these enzymes, CYP3A4 is responsible for the majority of drug metabolism in the liver. Another twist to this situation is that drugs, toxins, or plant constituents (together called xenobiotics) can affect the rate at which specific enzymes act to metabolize other xenobiotics. For example, St. John's wort is a strong inducer of CYP3A4, which means that it increases the activity of CYP3A4, which would reduce the blood levels of a drug that is processed through 3A4 (because metabolism is increased, it is cleared through the system faster, reducing blood levels of the drug). On the other hand, some xenobiotics can act as inhibitors of a specific enzyme, which means that it reduces the activity of that enzyme and can cause elevated levels of a drug metabolized by that enzyme. For example, naringenin in grapefruit is a 3A4 inhibitor, so if someone is taking a drug metabolized through 3A4, drinking a lot of grapefruit juice can lead to high blood levels of the drug, which could potentially lead to an overdose. A xenobiotic that is metabolized by a specific enzyme is called a substrate of that enzyme.
The crazy thing about Orkambi is that it is both a substrate and a strong inducer of CYP3A4. Ivacaftor is a 3A4 substrate, and lumacaftor is a strong inducer. This means that in formulation, the dose of ivacaftor needs to compensate for its rapid metabolism induced by lumacaftor. But that's not all. Our sex hormones (estrogen, testosterone, and other cholesterol-based hormones like vitamin D) and some of our stress hormones (like cortisol) are metabolized through 3A4. Testosterone is also partially metabolized through CYP2D6, so its blood levels may be less disrupted by a strong 3A4 inducer compared to the blood levels of estrogen. Both males and females produce both estrogen and testosterone, in different proportions. By inducing 3A4, this can lead to significant imbalances in sex hormones and adrenal hormones that can have some pretty serious side effects, both during and immediately after Orkambi use. These side effects can include: vitamin D deficiency, disregulation of testosterone and estrogen levels, fatigue, increased risk of bleeding (especially hemoptysis), blood sugar disregulation, disregulation of blood lipids, postural orthostatic tachycardia syndrome (POTS), interactions with other drugs, and mood swings. The most common side effect is shortness of breath (as if we need more of this in our lives?) but I don't know if this is related to liver metabolism.
The most frightening side effect seems to be an increased risk of hemoptysis or general bleeding in the first week or so after stopping Orkambi. We are trying to figure out why exactly this happens, but it is likely due to Orkambi's powerful effect on liver metabolism. It could be related to abnormalities in estrogen levels (estrogen induces coagulation) or it may be related more directly to the metabolism of proteins involved in the clotting cascade. Either way, it is a side effect that few doctors are aware of (since it happens after and not during Orkambi use), so if you experience this please make sure to report it to your doctor and your pharmacist. We MUST document all cases of when this happens so that the FDA becomes aware of this issue and investigates it further.
Conclusion
Overall, I was not impressed with Orkambi and would not recommend it to others. There are other options out there currently (like cystagon) and some better drugs coming down the pipeline for those with deltaF508 mutations. For people desperate for any kind of help, I think that cystagon may be safer to try first before Orkambi, but if you must try Orkambi, then start slowly and cautiously. It has been said that those with an FEV1 lower than 40% should start at a half dose, due to the shortness of breath that a full dose can induce.
Orkambi is not the wonder drug that the media makes it out to be, so I advise CFers and parents of CFers to use caution when considering whether or not to try it.
Orkambi is a drug made by the Vertex corporation, approved by the FDA in July 2015. It costs approximately $259,000 a year [jumps up and down in a fit of rage over the greed of the pharmaceutical industrial complex]. I will resist the temptation to rant about the prohibitive cost of this drug, as that's probably not what you're hear to read about. Moving on...
Orkambi is actually a combination drug made from two drugs: ivacaftor (i.e. Kalydeco, used for the potentiation of the G551D mutation) and lumacaftor (a corrector). Even though it's been on the FDA fast track, it's been in trials for years. It is meant both to correct the faulty deltaF508 protein and potentiate it. What this means is essentially that it gets the CFTR protein to the right place in the membranes of our epithelial cells, and opens that protein to allow ions to flow across the membrane effectively. In theory, this would "fix" the problem of low extracellular electrolytes, which causes the sticky mucus issue that CF is known for. It is approved for use in CFers with two copies of the deltaF508 genetic mutation (homozygous).
What it did for (or to) me
I gave Orkambi a month-long trial and then weaned off of it over 1.5 weeks. Overall, I did notice that by the end of the trial my lungs did feel a little bit clearer (not as clear as on cystagon), I had better energy and exercise tolerance, and my sinuses felt more moist. On the other hand, I had significant shortness of breath in the beginning that subsided after the first 4 days but never completely went away, I had a mild depression settle on me, my poops were irregular and too soft (they are usually perfect), and my blood sugar was completely out of control (peaks and crashes so extreme that I had to avoid carbs altogether). Towards the end, I also experienced a bad bout of pleural pain on my right side, and I am 90% sure it was a small pneumothorax (but there was nothing I could do about it anyway and it healed in less than a week). The other stupid thing was that I caught a cold for the first several days upon starting Orkambi, which made me pissed off that my experiment had been contaminated with compounding variables! I also lost a few pounds on Orkambi, mostly because it obliterated my appetite, which could have been related to the depression.
After I got off of Orkambi I noticed that I had postural orthostatic tachycardia syndrome (POTS) that lasted for a couple of weeks, and worst of all, on the 3rd night after I had stopped Orkambi completely (after the weaning period) I coughed up a very large amount of blood in the middle of the night, about 1/3 cup. Not ok. I immediately took a Yunnan Baiyao and continued to take it for the next 4 days. Luckily, I didn't have any more bleeding. I also noticed it took my finger pricks longer to clot than usual. The clotting time went back to normal after a few weeks off of Orkambi, as did the rest of the post-Orkambi symptoms. In addition, I had my triglycerides tested 2 weeks after I stopped Orkambi and they were sky high! Like 527 (normal is 35-150 mg/dL)! That was obviously alarming, so 2 weeks later I retested and it was back down within the normal range, at 129. The super high test result could have been an error (my sister hypothesized the lab tech was probably eating cheetos and forgot to wash his hands). If it wasn't an error, then my theory on this strange occurrence is that since Orkambi had caused my blood sugars to go crazy (and my A1c actually increased during that time too, up to 6.1) all that excess glucose had been turned into fat to store in my adipose tissue, causing my blood fat (triglycerides) to increase.
After one month on Orkambi full dose I weaned off of it. I weaned off of it instead of stopping it cold turkey because of the increased risk of hemoptysis that has been reported after abruptly stopping Orkambi. This has something to do with its effects on liver metabolism of hormones, as I will discuss below. I did one week at a half dose (taking 1 pill twice a day instead of the normal dose of 2 pills twice a day), then for 4 days I took one pill once a day. For the last two days of this I restarted low dose cystagon because I was starting to feel mucusy and feverish again. I was planning on using a quarter dose of Orkambi for a week, but I was getting impatient and really wanted to be done with the side effects. It is clear to me now, in hindsight, that I did not wean off slowly enough to prevent the post-Orkambi bleeds that are so commonly reported. I probably should have done two weeks at the half dose and two weeks at the quarter dose, to be extra safe.
In summary, I did notice that Orkambi cleared up some of the mucus in my lungs and gave me a bit more energy than usual. My quantitative lung functions did not improve at all during this time; in fact, they declined by a few points (probably due to shortness of breath). If I had stayed on it for a few more months I predict that it would have further reduced my mucus load and may have even improved my FEV1. However, I wanted to get off of it ASAP because I knew that, due to the nature of its pharmacology, many of the side effects would get worse with time, and I didn't want to dig myself a hole that I couldn't climb out of. Overall, the risks outweighed the benefits. Cystagon is a far superior drug, in my opinion, and I feel so lucky to have it so that I don't feel the desperation of having no option other than Orkambi.
Pharmacology
This is a complicated subject and I've barely scratched the surface of the truth here, but from what I can gather from research and from my CF research-colleagues, here's what I know. Ivacaftor is a great drug. Simple (relatively), effective (for the G551D mutation), with a relatively uncomplicated metabolism pathway that causes relatively few side effects. Ivacaftor/Kalydeco has some pretty remarkable success stories attached to its use. This gave the next Vertex drug in the pipeline a ton of hype, especially since Orkambi is meant to treat people with the two copies of the deltaF508 mutation (homozygous deltaF508), which makes up about half of the CF population in the US.
But Orkambi is anything but simple. Lumacaftor is a seriously complex drug with a complicated metabolism pathway, which actually interferes with the metabolism of its partner, ivacaftor. As a result, it has many side effects, some of them potentially dangerous. There have been no studies on the long-term use of Orkambi, since it was fast-tracked, but this drug is designed for long-term use (uh... like a lifetime). So we, as the first generation of users, are acting as guinea pigs. Now, some of us are quite desperate in the search for anything that can help. I totally get that. CF is scary and there are few solutions, especially if our lung functions are low enough. Orkambi has even worked, and worked well, for a handful of people in the trials (or so they reported). But Orkambi is not an ideal treatment, at least not in my opinion. And the next drug in Vertex's pipeline is a few years away and is also targeting the double deltaF508 mutation, with insider reports saying it is a way better drug than Orkambi is. Is it safer to wait it out and hope that the next drug is better? I know where I stand. But here's a little more info to help others make a more informed decision.
The main issue with Lumacaftor is that it seriously messes with liver metabolism. The liver is where the majority of drug, hormone, toxin, and plant constituent metabolism takes place. The liver metabolizes drugs mainly through the use of cytochrome P450 enzymes, or the CYP450 system for short. There are many CYP450 enzymes, and certain drugs are metabolized by one or more of these enzymes. Of these enzymes, CYP3A4 is responsible for the majority of drug metabolism in the liver. Another twist to this situation is that drugs, toxins, or plant constituents (together called xenobiotics) can affect the rate at which specific enzymes act to metabolize other xenobiotics. For example, St. John's wort is a strong inducer of CYP3A4, which means that it increases the activity of CYP3A4, which would reduce the blood levels of a drug that is processed through 3A4 (because metabolism is increased, it is cleared through the system faster, reducing blood levels of the drug). On the other hand, some xenobiotics can act as inhibitors of a specific enzyme, which means that it reduces the activity of that enzyme and can cause elevated levels of a drug metabolized by that enzyme. For example, naringenin in grapefruit is a 3A4 inhibitor, so if someone is taking a drug metabolized through 3A4, drinking a lot of grapefruit juice can lead to high blood levels of the drug, which could potentially lead to an overdose. A xenobiotic that is metabolized by a specific enzyme is called a substrate of that enzyme.
The crazy thing about Orkambi is that it is both a substrate and a strong inducer of CYP3A4. Ivacaftor is a 3A4 substrate, and lumacaftor is a strong inducer. This means that in formulation, the dose of ivacaftor needs to compensate for its rapid metabolism induced by lumacaftor. But that's not all. Our sex hormones (estrogen, testosterone, and other cholesterol-based hormones like vitamin D) and some of our stress hormones (like cortisol) are metabolized through 3A4. Testosterone is also partially metabolized through CYP2D6, so its blood levels may be less disrupted by a strong 3A4 inducer compared to the blood levels of estrogen. Both males and females produce both estrogen and testosterone, in different proportions. By inducing 3A4, this can lead to significant imbalances in sex hormones and adrenal hormones that can have some pretty serious side effects, both during and immediately after Orkambi use. These side effects can include: vitamin D deficiency, disregulation of testosterone and estrogen levels, fatigue, increased risk of bleeding (especially hemoptysis), blood sugar disregulation, disregulation of blood lipids, postural orthostatic tachycardia syndrome (POTS), interactions with other drugs, and mood swings. The most common side effect is shortness of breath (as if we need more of this in our lives?) but I don't know if this is related to liver metabolism.
The most frightening side effect seems to be an increased risk of hemoptysis or general bleeding in the first week or so after stopping Orkambi. We are trying to figure out why exactly this happens, but it is likely due to Orkambi's powerful effect on liver metabolism. It could be related to abnormalities in estrogen levels (estrogen induces coagulation) or it may be related more directly to the metabolism of proteins involved in the clotting cascade. Either way, it is a side effect that few doctors are aware of (since it happens after and not during Orkambi use), so if you experience this please make sure to report it to your doctor and your pharmacist. We MUST document all cases of when this happens so that the FDA becomes aware of this issue and investigates it further.
Conclusion
Overall, I was not impressed with Orkambi and would not recommend it to others. There are other options out there currently (like cystagon) and some better drugs coming down the pipeline for those with deltaF508 mutations. For people desperate for any kind of help, I think that cystagon may be safer to try first before Orkambi, but if you must try Orkambi, then start slowly and cautiously. It has been said that those with an FEV1 lower than 40% should start at a half dose, due to the shortness of breath that a full dose can induce.
Orkambi is not the wonder drug that the media makes it out to be, so I advise CFers and parents of CFers to use caution when considering whether or not to try it.
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