The paradox of Orkambi

[ethan508]

It has been a while since posting and I want to share my experience on Orkambi for the last 15 month (TL;DR version: Orkambi is helping my system when I don't have Orkambi in my system).

First some history. August 2015 I got my script for Orkambi, pre-Orkambi PFT was:
FEV1=94%,
FVC=101%
FEF25/75=75%.

So I started Orkambi in September 2015, noticed mild tightness and dyspnea. Essentially, I developed an audible wheeze that would occur a few hours after taking a dose. Aerobic exercise ability dropped a bit (30-45 seconds on my running pace, and pretty much developed exercise induced asthma enough that I carry a MDI and hit it prior to an aerobic event). But I did notice that colds and cough disappeared much quicker. Fast forward one year and Aug 2016 I get the following PFTs (w/ Orkambi in my system):
FEV1=90%
FVC=100%
FEF25/75 = 65%

So the drug appears to be not helping. My doctor doesn't want to give up on it just yet. So I added Breo (long lasting asthma treatment) and that took away the audible wheeze, but I didn't pick up any aerobic function and only the slightest measurable difference in PFTs.

So on my latest trip to clinic (a few weeks back) I did PFT without having Orkambi in my system (about 15 hours since last dose). PFTs look like this:
FEV1= 99%
FVC = 107%
FEF25/75 = 77%

These are the best numbers I've had in 3 years and the FVC match my high (May 2008).

So here is the paradox. Orkambi is helping my lungs as long as I don't have Orkambi in my system.

So now I'm trying a new drug (Triotropium) in attempt to control the asthma/tightness and will do another PFT in a few weeks. If PFTs don't show Triotropium helped, then the next trial period will be half a dose of Orkambi on the morning dose. I'm just trying to get to a point that I could get the benefits of Orkambi without it killing my ability to breath.

I know some of you have tolerated Orkambi well (do you truly have zero side effects), and some of you didn't tolerate it at all (never were able to breath easy on the drug). Are there a batch of those in my same shoes (I've heard more than a few people that take half doses)?

 

[Nell]

Hi, interesting post! I think your observations about Orkambi are valid - many have reported the same symptoms you have with Orkambi. As you know, Orkambi is designed to correct and potentiate CFTR. The molecules that make up Orkambi are both synthetic polyphenols. Indrepta is a natural supplement composed of multiple natural polyphenols known to activate CFTR through correction, potentiation and other means. The ingredients in Indrepta are also well known anti-inflammatory compounds. Indrepta may help you control your asthma symptoms and improve your tolerance for Orkambi. You may not be aware that Stanford University did clinincal trials on NAC (n-acetylcysteine) for CF and found that NAC three times a day in 900 mg doses (2700 mg total daily) prevented lung function decline in the treatment group, whereas controls declined. We believe NAC breaks up the sticky CF mucus and helps patient clear better, and that NAC and Indrepta are highly complementary. It is important to buy NAC in airtight packaging as it goes bad. PharmaNAC is what most people are using now. Sorry it is so expensive. It's great to see that your lung function is high.

 

[MissMe]

Here in Sweden we all more or less use what you call NAC in an efervescent tablet 1200 mg/day. I have used it since I was a child and I am now 44 and it is quite cheap too and sold in most pharmcies around Europe to combat colds (with lower dose). I cannot undertand why cf-doctors dont prescribe it in the US?? If I run out of them or forget just one days dose I can feel my mucus become thicker. But I have never heard of the airtight packages?

 

[desnot2]

Without access to data it is really difficult to know what is the wide spread effects of the drug on people. But with anecdotal evidence presented here in the forums, there at least seems to be some people who experience tightness in the chest and other issues.

After starting Orkambi a while ago, my PFT's were stable, and in fact had improved slightly. I have high PFT function studies like you, but was on a slow constant abnormal decline before taking the drug. We weren't sure what was going on.

I posted in another topic here, but essentially I experienced none of the problems others had regarding tightness or related issues. However, I experienced a different side effect over time. My liver enzyme levels increased to critical levels about 5 months after using it. I have been since taken off because my liver couldn't tolerate it.

A lot of the previously mentioned side effects have been on the drugs warning information, I just wonder how large the percentage of people are having problems with the drug.

 

[Nell]

The effervescent packages are sealed, air tight so the NAC does not spoil. This is important. All the effervescent tablets are in individual, air-tight packages. Otherwise they would not fizz. And the NAC stays fresh and works better, so this is definitely the way to go.

 

[Proteingirl]

Sorry, but VX-809, or Lumacaftor, the corrector in Orkambi is not a polyphenol. And "natural" polyphenols cannot take it's place or do the same job. A phenol is, by definition, a compound containing an hydroxyl group (OH-). A polyphenol is, by definition, a compound containing at least two or more hydroxyl groups. A simple search for Lumacaftor will bring up the chemical's structure and in that structure you will find only ONE hydroxyl group. So, while it is true to say that Indrepta contains polyphenols, it is absolutely untrue to say that Lumacaftor contains them or that Indrepta is in any way similar to known correctors.

 

[Nell]

Although Lumacaftor and Kalydeco are not ‘technically’ a polyphenols due to lacking one hydroxyl group, they do have multiple phenyl groups (6 carbon rings) like natural CFTR modulators and a single hydroxyl group whereas the naturals have two or more. Natural polyphenols are well known for their antioxidant protective effects, whereas Lumacaftor and Kalydeco have been associated with organ toxicity, damage to the lens of the eye and skin rashes. In this way (serious side effects) they are not similar to known natural correctors such as curcumin and resveratrol. Or to the many natural polyphenolic CFTR potentiators which also are known for their health benefits. Interestingly, VX-661, the Vertex drug intended to replace Lumacaftor, has three hydroxyl groups. Perhaps creating an artificial drug that is more like its natural counterparts can reduce drug toxicity. Indeed, VX-661 is reported to have fewer side effects.

Proteingirl, why would you think that natural polyphenols cannot take the place of man-made correctors or do the same job? Resveratrol is a demonstrated CFTR corrector, see the following references:
https://www.ncbi.nlm.nih.gov/pubmed/21366549
https://www.ncbi.nlm.nih.gov/pubmed/21480283
https://www.ncbi.nlm.nih.gov/pubmed/24282612
https://www.ncbi.nlm.nih.gov/pubmed/26092868

One paper arguing against resveratrol’s use as a CF therapy claims that adequate concentrations cannot be achieved by the oral route. However, it is known that combining resveratrol with other compounds such as quercetin, curcumin and piperine can increase resveratrol’s bioavailability by 350%: https://restorativemedicine.org/journal/combination-effects-of-quercetin-resveratrol-and-curcumin-on-in-vitro-intestinal-absorption/ . All these compounds were included in the Indrepta formulation for this and other reasons.

Here is an article demonstrating CFTR correction with curcumin: https://www.ncbi.nlm.nih.gov/pubmed/15105504 . Interestingly, curcumin is also shown to restore function to W1282X, a nonsense mutation: https://www.ncbi.nlm.nih.gov/pubmed/27007499 .
Again, poor bioavailability is thought to limit the usefulness of curcumin as an oral corrector drug. Liposomal/microsomal preparations are shown to overcome this problem in this study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815009/#R13 . Also it is known that combining curcumin with piperine enhances its bioavailability 2000%: https://www.ncbi.nlm.nih.gov/pubmed/9619120 . We combined curcumin with piperine in Indrepta.
Here is a paper demonstrating the synergistic effects of natural and pharmaceutical CFTR-modulating molecules. The natural compounds genistein and curcumin were found to be highly synergistic with Vertex drugs: https://www.ncbi.nlm.nih.gov/pubmed/27160424 . Here is a quote from this manuscript: “However, the strong synergistic potentiator effects observed here suggest that even low curcumin and genistein plasma levels may be sufficient to functionally repair CFTR-dependent fluid secretion either by duo-treatment or triple-treatment, including VX-770, especially if drugs would further accumulate in the affected tissues.” Another excellent point made in this and other research articles on the subject is that multiple correctors and potentiators seem to be superior. This is why so many companies are pursuing triple combination drugs. Because the natural compounds in Indrepta are already time-tested for safety (they are GRAS or generally recognized as safe by the FDA) we are able to use 7 or more CFTR modulating compounds in each Indrepta version.

Because some people object to taking phytoestrogen compounds, we substituted other excellent natural potentiators for genistein in Indrepta. Apigenin (in Indrepta A) is one of the best known CFTR potentiators, and was used in pharma drug screening as a positive control (the thing to beat). Amentoflavone (in Indrepta B and C) is actually bis-apigenin. EGCG is an excellent potentiator, as is quercetin. Why on earth this and other natural CFTR-modulating supplements were not made years ago into supplements for CF patients to help them stay healthy while they wait for great pharma drugs is beyond me. And now it appears that natural compounds may help existing pharma CFTR modulators work much better! It took cooperation of patient groups and a fundraiser by patients to get the Indrepta formulations manufactured. Although it is still early, we are receiving excellent news from patients who are using Indrepta. What everyone really cares about is what actually WORKS SAFELY. Each individual molecule should be considered on its merits, whether natural or synthetic.

We should all keep in mind that most drugs start out as some sort of plant-derived natural compound, and then modifications are made. These modifications create drugs that are patentable but they are not always improvements, particularly with regard to safety.