What is Indrepta?

We are working hard to bring you products that have measurable benefits for the symptoms of cystic fibrosis

INDREPTA: A dietary supplement designed to promote lung heath

Dietary polyphenols are molecules found in abundance in brightly colored fruits and vegetables, and are associated with many of the health benefits of these foods. Diets rich in polyphenols are demonstrated to provide protection from a wide range of diseases including cancer, diabetes, osteoporosis and dementia.1 Food can indeed be medicine.

Some plant extracts take center stage in commercial products currently sold in drug stores. For example, the popular expectorant MucinexTM is simply a natural plant compound, guaifenesin, re-formulated as a time-release ‘drug’.

Natural compounds and cystic fibrosis research share a rich and intertwined history. Activation of the cystic fibrosis gene, CFTR, by the soybean-derived compound genistein was first reported in 1995.2,3 In 2004, another natural and food-derived compound generated much excitement in the CF community when it was shown that a component of a yellow curry spice, curcumin, could correct cystic fibrosis defects.4 In 2011, Yu and coauthors reported that genistein and curcumin, when used together, synergistically increase the function of G551D mutant CFTR to 50% of the wildtype level5 – that is, to the level of a heterozygous CF parent who has no CF symptoms. The observation that combinations of compounds may demonstrate superiority to any single compound for activation of residual CFTR function is important, however this fact may have held back widespread use of natural compounds for treatment of CF. When used alone, CF treatments that are powerful in combination may be overlooked or even initially dismissed, like curcumin, as ineffective.

Vertex Pharmaceutical’s CFTR corrector and potentiator drugs are synthetic polyphenolic molecules currently undergoing clinical trials in combinations to achieve improved efficacy across a wider range of CFTR mutations. There is increasing support for such use of combinations of polyphenolic correctors and potentiator molecules to achieve superior CFTR modulating activity, 6 and even evidence for improvement of efficacy of Vertex drugs by the co-administration of natural molecules. 7

Cystic Fibrosis patients often explore use of natural dietary polyphenols to treat their own CF symptoms. Some CF patients have obtained excellent results with ‘the GC combo’ (genistein and curcumin) and groups have formed on the internet to discuss health benefits to CF patients of rich plant sources of polyphenols such as Hawthorne (Crataegus) fruits, flowers and leaves. Many CF patients report health benefits of fresh fruit and vegetable smoothies, however delivering consistent levels of dietary polyphenols throughout the day and across seasons with smoothies is challenging; a standardized source of dietary polyphenols is needed.

Daily dietary polyphenol intake was found to vary considerably from 183 to 4854 mg/day in a Japanese study1 with an average of 1492 ± 665 mg/person/day of dietary polyphenols. In Poland, mean daily polyphenol intake is found to be slightly higher at 1756.5 ± 695.8 mg/day.2
Suppose you aim to obtain dietary polyphenols from smoothies or juicing. Total fruit smoothies ranged in polyphenol content from 1943±70.7 to 2692±21.6 mg/L.3 A second study averaged 1955.6±124.6 mg/0.7 L of smoothie. 4 You would be more likely to drink 500 ml smoothies, so estimate that you would achieve around 900 -1300 mg of total dietary polyphenols per smoothie. Some CF patients obtain excellent health results from smoothies and juicing and also reverse aquagenic palm wrinkling (this indicates CFTR is working better). Smoothies/juicing are a viable option for those who can commit to them.
Indrepta at the full dose of 9 capsules per day provides 3220 mg of total dietary polyphenols for Indrepta B and 3570 mg of total dietary polyphenols for Indrepta A. High daily consumers of fresh fruits and vegetables (including beverages with high polyphenolic content such as tea and coffee) can exceed the daily polyphenols provided in Indrepta. You can also get there by having three or four smoothies or extracted vegetable/fruit juices per day.
The specific polyphenols that are combined in Indrepta represent our current best understanding of what would most benefit CF patients.

Sourcing reliable high quality supplements available to all patients has also been challenging for CF patient groups who wish to study supplement benefits. The New York Attorney General’s office found in 2015 that few supplements offered by the largest US retailers contain ingredients listed on the label.8 By placing control of the formulation and manufacture of supplements within patient stakeholder organizations, quality concerns can be addressed. For example to create Indrepta, the Certificates of Analysis (COA’s) from multiple manufacturers were compared to select the best products regardless of cost. Ingredients used in Indrepta have each been subjected to individual analysis for quality and purity, and ingredients are standardized by HPLC to ensure consistency from batch to batch. Microbiology reports for ingredients are carefully reviewed.

Our bulk buying power allows us to create high quality supplements at lower cost than could be achieved by buying ingredients individually. The majority of Sharktank Research Foundation board members are CF stakeholders themselves, who developed this product with their own use in mind; and to benefit the larger CF community that they represent. International distribution centers established by overseas stakeholder-partners will help bring products to patients outside the US.

Indrepta was created to supply dietary polyphenols in a consistent, standardized formula three times a day. Indrepta combines several individual natural therapies with good literature support and positive feedback regarding benefit from patients. The goal of initial Indrepta formulations is to maximize the potential to successfully modulate a wide range of CFTR mutations. Further laboratory research and feedback from patients will allow further refinement of supplements.

We are releasing A and B versions of Indrepta, which share most of their ingredients but differ by substitution of Alpha Lipoic Acid and Naringin found in version A in with the B version herbal ingredients Amentoflavone and Forskolin. Amentoflavone and Forskolin are shown in vitro to activate CFTR through non-corrector/potentiator mechanisms described further below. Although specific health claims for supplements are prohibited, it is permissible to report independent third party research findings with regard to supplement activity and health benefits.

Each Indrepta ingredient is listed individually below with evidence to support its inclusion in the supplement. Supplement Information panels from product labels are also provided.

Curcumin – Archives of NACFC meetings indicate that in 2008, curcumin was listed as a pipeline CF drug.9 Curcumin, a well-studied food spice with multiple known health benefits, was given a small CF clinical trial. Lasting only 2 weeks and enrolling 14 subjects, 9 of whom completed the study, this curcumin trial did not pair oral administration of curcumin with any additives known to increase its systemic bioavailability. For example, a black pepper extract (piperine), included in Indrepta’ s formulation, is demonstrated to increase curcumin bioavailability by 20 fold.10 Oral curcumin is poorly absorbed from the gut without specific measures to improve its absorption. Piperine was not used in the curcumin clinical trials. Not surprisingly, undetectable levels of curcumin were found in serum of all but one CF patient in the trial, and levels were therefore insufficient to significantly impact the study endpoint, nasal potential difference (PD).11 For a compound to be effective, it must reach its target tissue at an adequate concentration. The single CF patient who achieved measurable blood levels of curcumin (83 ng/ml, lower level of detection=2.0 ng/ml) had forced vital capacity increased by 3.3%, enough to reach statistical significance (p=0.05). 11 Indrepta is formulated with curcumin and piperine, a combination reported by patients to produce desirable results in terms of reduction of sweat chlorides, reduced aquagenic wrinkling of the palms, weight gain and improved overall wellness. Curcumin is also reported to improve GI issues of patients with CF.
Resveratrol – Resveratrol is a promising CFTR corrector/potentiator12,13 already used by patients, with good response reported in particular by patients homozygous for dF508. However, resveratrol is poorly absorbed through the gut. Resveratrol is reported to receive enhancement in permeability when combined with quercetin (310%), curcumin (300%), and piperine (350%),14 all of which are included in Indrepta.
Naringin – Naringin is a flavone glycoside found naturally in citrus fruits. Naringin is structurally similar to apigenin, one of the most potent CFTR activating natural compounds used by researchers in drug screening experiments. 15, 16 Naringen demonstrates protective effects in diabetes and elevated oxidative stress,17, 18 and is believed to act, like apigenin, by increasing CFTR activity. 19
Quercetin – Quercetin is demonstrated to activate dF50820 and is also reported to increase ciliary beat frequency, suggesting its potential to help CF patients with chronic rhinosinusitis. 21 Quercetin is known to increase bioavailability of other co-administered supplements including resveratrol14 and green tea polyphenols which are components of the Indrepta formulation.
Bioperine™ – Bioperine is a registered trademark for a black pepper extract molecule known as piperine, which is demonstrated to increase oral bioavailability of some co-administered supplements. For example co-administration of 20 mg of piperine with 2 g curcumin (the Indrepta dose) caused 2000% increase in curcumin bioavailability in humans. 10 For this reason, modest doses of curcumin are used in Indrepta.
Silymarin – Silymarin from milk thistle has been administered for more than 2,000 years, primarily to treat liver dysfunction. 23 The German Commission E for natural compounds recommends milk thistle use for dyspeptic complaints, toxin-induced liver damage and as supportive therapy for chronic inflammatory liver conditions. 24 Silymarin is included in Indrepta to protect against cystic fibrosis liver disease and also toxic effects of pharmaceutical drugs.
EGCG – Epigallocatechin gallate (EGCG) is an antioxidant and herbal derivative of green tealeaves (Camellia sinensis). EGCG was tested in clinical trials to correct CFTR splicing defects 25 and also to enhance benefit of cysteamine administration; in this capacity, EGCG is proposed to act via autophagy-dependent rescue of class II-mutated CFTR. 26-27
Hawthorne – Hawthorne, also known by its botanical name Crataegus, is a flowering plant with berries. Crataegus preparations have been consistently proven to be well tolerated with low or negligible side effects. 28-30 Both flowers and leaves are rich sources of polyphenolic compounds. Since the fruits and plant parts of Hawthorne differ in their polyphenolic composition, 31,32 standardized extracts of both fruits and leaf/flower were included to increase polyphenolic diversity in the formulation.
Alpha Lipoic Acid – Alpha Lipoic Acid (ALA) is a potent antioxidant. As a supplement, it has shown benefit against oxidative stress and inflammation. In vivo and in vitro studies demonstrate that ALA exhibits ability to scavenge free radicals, regulate the detoxification of heavy metals, and modulate various pathways in pathological conditions. 33Lipoic acid is demonstrated to be highly effective in preventing cataract formation, 34 a reported side effect of Kalydeco.
Amentoflavone – Apigenin is one of the most potent natural CFTR potentiators.15,16 Amentoflavone is a biflavonoid of apigenin, and is also known as bis-apigenin. Amentoflavone is demonstrated to be a phosphodiesterase inhibitor35 (PDE) that can break down enzymes that destroy cyclic AMP (cAMP), a molecular activator of CFTR.
Forskolin – Forskolin is an herbal compound which directly activates the adenylate cyclase enzyme, thereby generating cAMP from ATP and raising intracellular cAMP Forskolin is a mainstay CFTR-activating drug used by laboratory researchers as well as an ancient remedy used to support lung, heart, and urinary health, among numerous other uses.36 As an oral supplement, forskolin has been used to treat asthma. 37 Forskolin increases cAMP, and then the other side of the coin, amentoflavone, is added to Indrepta B to prevent cAMP breakdown. The desired net effect of the combination of Amentoflavone and Forskolin is increased and extended overall CFTR activity.
Natural compounds used in Indrepta are time-tested for safety in humans, inexpensive, and act as potent modulators of CFTR function in laboratory experiments and for some but not all patients who use them as supplements. Currently it is impossible to predict without a cell biopsy which patients will respond most favorably to natural and/or synthetic polyphenolic compounds. There is likely a biological basis for variation in treatment effects, as primary airway epithelial cell lines obtained from different donors homozygous for dF508 demonstrate a wide range of activity in response to Vertex drugs. 38 This tells us two things. First, the remarkable variation reported by patients in perceived benefits and side-effects of Orkambi may have a sound biological basis. Second, treatment of CFTR by correction and potentiation, even among groups of patients sharing the same mutations may yield inconsistent efficacy. The individual genetic background of the patient is a factor that determines drug efficacy. Correction and potentiation of CFTR mutations is likely not one size fits all.

Because we have included powerful antioxidants in our supplements, we believe Indrepta will benefit the health of all patients with CF. For example, it has recently been demonstrated that dietary polyphenols are protective against drug induced hearing loss. 39,40

Sharktank is committed to continued research to develop and refine CFTR modulating therapies. We do this work in the first stakeholder funded and managed CF research laboratory we established in Research Triangle Park, North Carolina. Our goal is no CF patient left behind. You can join our effort by joining Sharktank and by making tax-deductible donations to Sharktank Research Foundation. Because each CF patient is unique, more available options for treating cystic fibrosis increase the likelihood that each patient will find therapies that work well for them.

1. Chie Taguchi,Yoichi Fukushima, Yoshimi Kishimoto, Norie Suzuki-Sugihara, Emi Saita, Yoshinari Takahashi, and Kazuo Kondo (2015). Estimated Dietary Polyphenol Intake and Major Food and Beverage Sources among Elderly Japanese. Nutrients. Dec; 7(12): 10269–10281.
2. Grosso G, Stepaniak U, Topor-Mądry R, Szafraniec K, Pająk A. (2014) Estimated dietary intake and major food sources of polyphenols in the Polish arm of the HAPIEE study. Nutrition. Nov-Dec;30(11-12):1398-403.
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