Kalydeco/Ivacaftor Need Not Be A $300,000 Orphan Drug: The Case For Mild Cystic Fibrosis Mutations, A Preventative Approach To CFTR-Related Diseases, And Expanding The Market To Decrease Prices By 99%

Note: Original post appeared November 28, 2013; Updated: March 27, 2015 and July 20, 2015This is not a peer reviewed post, it expresses opinions, and it is primarily presented to help further the discussion on the issues covered.

The Market is Bigger Than People Think. This Is Good News for All, Fans and Critics of Big Pharma Alike.

Kalydeco, in oversimplified terms, improves the function of CFTR. If you have any functioning CFTR, which helps facilitate the transfer of chloride and thiocyanate across cell membranes, Kalydeco will make it function even more efficiently. This matters, a lot, when a patient does not have "enough" functioning CFTR due to a disease like cystic fibrosis (CF). It also matters in less severe situations, where CFTR dysfunction leads to milder symptoms across a broad spectrum ranging from atypical CF to common rhino-sinusitis.

“Mild” CFTR mutations and variants, including the 5T variant, unlike "classic" CF mutations which often leave no functioning CFTR, cause varying decreases in CFTR that lead to just such a broad array of symptoms. Such mild mutations and variants are often less studied, and less understood, than classic mutations. However, mounting evidence suggests that greater attention to mild mutations and residual CFTR could yield significant medical, scientific, and financial benefits to multiple constituencies, from patients to clinicians to drug developers.

Case in Point: the IVS8-5T variant

There are thousands of milder CF mutations and variants. One useful example is the IVS8-5T, also known as the poly(TG)n(T)5, or "5T", for short. Research is beginning to suggest that successfully potentiating the function of its residual CFTR, or correcting the 5T’s imperfect CFTR synthesis (more to come here), could improve lives in a much broader swath of the population than currently envisioned.

In plain terms, a potentiator drug like Kalydeco/Ivacaftor, in a patient with residual CFTR function, could potentially:

  1. address a broader spectrum of diseases than originally assumed - from classic cystic fibrosis, to COPD (third largest cause of death in U.S., tens of millions affected), to sinusitis (much less serious, but many millions more affected).
  2. be successfully applied to this broader spectrum of diseases in a more preventative way than currently practiced.

We'll try to at least get started making the case here.

Making the case for mild mutations (using the 5T example)

  1. The gray area of “atypical CF” is getting bigger.

    1. The "cystic fibrosis" label is no longer as clear as it once was. The spectrum has broadened, causing discrepancies in diagnosis and treatment. For example, the 5T variant, and its array of TG-repeat sequences such as 5T(TG)12 and 5T(TG)13, is considered “CF-causing” by some groups, but not by others.

    2. Instead of asking if a gene is “CF-causing or not?” perhaps the discussion should factor in an additional question like “does it cause CFTR-related symptoms or not?”, and even “is it specifically treatable or not?”

    3. Most clinicians who have dealt with symptomatic 5T TG12 and TG13 patients have little doubt that mild mutations like the 5T, when paired in trans with a major CF mutation, can cause CF symptoms, whether “typical” or “atypical”, “mild” or “classic”, CRMS or a CFTR related disorder.

  2. There are 30 Million carriers of the 5T in the U.S., and 250,000 with 5T/M genotypes. It is the world's most common CFTR-related disease mutation.

    1. The 5T is more prevalent in the U.S. population than all other CF mutations combined. Most estimates indicate that up to 10% of the U.S. population carries the 5T variant -- potentially more than 30 million people, with more than 250,000 people carrying both the 5T and a major CF mutation.

    2. While mild mutations like the highly penetrant 5T(TG)13 are considered “CF-causing” in Europe, some fly largely under the radar in the United States. But with the surge in newborn screening (NBS), particularly in California, the identified 5T and “mild mutation” population will surge as well.

  3. Kalydeco / Ivacaftor need not be a $300,000/yr orphan drug.

    1. As mentioned, a growing body of research indicates that the presence of mild mutations, particularly those like the 5T that yield residual CFTR, can contribute to a broad range of treatable phenotypic manifestations.

    2. Such symptoms, whether or not they meet classic or even atypical CF thresholds, nevertheless remain symptoms of CFTR-related disease.

    3. A broad spectrum of patients with CFTR-related disease (who have symptoms that could be improved with improved CFTR function), ranging from classic CF to COPD to sinusitis, are likely treatable by CFTR potentiators like Kalydeco / Ivacaftor.

    4. Economics takes over. A larger patient pool with infinite potential supply could allow prices to ease, with companies like Vertex remaining healthily profitable, and more patients benefiting. Prices can become much more moderate well before Kalydeco goes off-patent in 2027. Kalydeco would stand to lose little, if anything (and perhaps gain), and many new patients could stand to gain a lot.

  4. Fitness for Trial: mild mutations have the potential for demonstrably clear response to treatment.

    1. Given the levels of residual CFTR in patients with certain milder mutations, the response from some of these patients will likely be clinically significant. Moreover, mutations like the 5T may respond with delineable measurability, given a relatively uniquely reproducible gradation / delineation in CFTR yield per TG repeat level (potentially helpful in accurately assessing potentiation "leverage" on markers like FEV, sweat chloride, etc. per level/range of expressed CFTR).

    2. In 2013, in Denver, a pilot n-of-1 study was conducted to test the effects of Ivacaftor on patients with residual CFTR function (including both non-classic mutations like 5T and classic mutations like 3849+10kb C->T, and even 621+1G>T).

  5. The market size, in potential patient benefit - and in potential dollars - merits attention.

    1. The addressable market is broad, with the pain ranging from relatively shallow to deep. As mentioned, the IVS8-5T alone is carried by approximately 10% of the greater population with a full range of manifestations, likely treatable with existing and future potentiators like Kalydeco.

    2. Mild mutations are at risk of remaining clinically marginalized in the US, making drugs like Kalydeco more difficult to prescribe for affected patients with residual CFTR function (whether CF, CRMS, potential other conditions like COPD, etc). One result is treating fewer patients and charging higher prices.

    3. Given the range of symptoms caused by CFTR dysfunction, and the relatively nascent understanding of significance of milder mutations, it is not unlikely that numerous treatable patients are incorrectly diagnosed who could otherwise benefit. In this way, the situation is like that of hemochromatosis (see below), except that emerging CF treatments (unlike simple phlebotomies in hemochromatosis) can be lucrative to innovative companies. And they may also be able to play a preventative role, further broadening the population to those at risk (more below).


Making the Case for Preventing CF: The onset of many symptoms of cystic fibrosis may be preventable.

  1. Yes, we are getting a little ahead of ourselves.

    1. It is on purpose. We’re talking about preventative treatment, whose whole point is to get ahead of ourselves.

    2. With that said, given the dynamics of Ivacaftor and the often delayed onset of atypical CF and CFTR-related diseases, the prospect of using Kalydeco and other potentiators in a more preventative fashion is intriguing, and relatively unexplored. As such, while many of these symptoms are treatable with new CF drugs like Kalydeco, many of these patients may fall through diagnostic cracks, or get identified too late, after permanent damage.

    3. When studies like the pilot study in Denver show that residual CFTR is potentiated to clinical effect in patients with residual CFTR, one can envision the potential use of Ivacaftor (and other potentiators or correctors) as preventative treatments vs largely reactive ones. The implications here are admittedly large, which makes a conversation all the more necessary.

  2. The hemochromatosis analogy: The relatively untracked but high population frequency of mutations affecting CFTR levels, coupled with their relatively unaddressed, spectral, and progressive array of symptoms, recalls an equally neglected patient population with another condition: hemochromatosis.

    1. Hemochromatosis is the most common hereditary disorder in the US, ahead of cystic fibrosis, and among the least diagnosed. It is also nearly fully treatable if diagnosed early.

    2. The difference between investing in hemochromatosis research vs CF research (from a business perspective) is that the potential treatment of mild mutations like the 5T (again, vs simple phlebotomy therapy for hemochromatosis) offers a substantial financial argument for exploration.

    3. As patients treated early for hemochromatosis, certain CF or CFTR-related disease patients could arguably be pushed into completely (or preventatively) asymptomatic territory, and, arguably, to stay.

  3. Preventing “silent progression": the nature and timing of disease penetrance in CFTR-decreasing genotypes often begins subtly - even subclinically.

    1. Disease associated with mild genotypes like the 5T may progress silently for years. As research shows, cases (symptomatic and otherwise) can go completely undocumented or incorrectly diagnosed for decades.

    2. Most researchers and clinicians familiar with mild genotypes like 5T appear to believe, primarily with the most severe 5T(TG)13, that symptoms are a matter of “when, not if”.

  4. Focusing on a goal of pre-emptive / preventative treatment makes sense.

    1. The potential exists for a safe and reasonable way to treat the underlying cause of CFTR-related disease pre-emptively with a potentiator like Kalydeco (proverbially maintaining the gutters vs waiting for them to get clogged).

    2. While expanded use of potentiators like Ivacaftor will be easier when off-patent (2027 for Kalydeco), expanding treatment to "mild" CF, pre-CF, COPD, recovering smokers, etc., would allow price declines for patients and insurance companies, while mitigating profit loss for drug companies through a vastly expanded market.

    3. As price becomes less an obstacle, preventative doses could be more easily considered and/or prescribed.  

  5. The Role of "silent progression" in the argument for preventative approaches

    1. While most clinicians agree there is a "silent progression" element to early disease, no one agrees on how "silent" is "silent"-- for example, whether irreversible bronchiectasis in CF requires single or repeated episodes of infection and inflammation (presumably with at least some telltale elements like cough or episodic bronchitis), or whether mucus plugging alone can create it without infection or other telltale signs.

    2. Evidence is mounting that CRMS-type cases may mask subtle progression of lung disease that, even while clinically asymptomatic, could be mitigated by pre-emptive therapies such as Kalydeco.  See this excerpt below from the Journal of Family Practice:

      1. When to suspect atypical cystic fibrosis - The Journal of Family Practice

        1. Early Detection May Translate Into Better Treatment

          1. Although patients diagnosed with cystic fibrosis as adults are less likely to present with classic clinical features, they may develop bronchiectasis and advanced lung disease.10,11Those who are identified early on—including those who are asymptomatic and have normal lung function—may benefit from respiratory therapy to prevent or delay lung disease.12 Several studies have shown that patients with mild cystic fibrosis disease and stable spirometry results have evidence of bronchiectasis on their x-rays and advanced lung disease that appears on high-resolution CT.13,14

          2. Judge et al have suggested that mucus plugging occurs early in cystic fibrosis lung disease and at a milder stage of lung function impairment, and that bronchiectasis may be an end result of such abnormalities.14 Nonclassic cystic fibrosis patients often have episodes of “bronchitis,” and once the practitioner becomes concerned, the radiographic image may already show evidence of bronchiectasis. Once again, this emphasizes the importance of early detection and prompt treatment.15  (reference here)

    3. While few would argue for aggressive treatment with medications like Kalydeco in asymptomatic cases, in the presence of other indicators, such as biochemical markers or high-resolution CT-based evidence, preventative treatment should arguably be a consideration.

  6. Certain genotypes don’t play by the rules. The Cold War vs GWOT.

    1. The days of only classic CF were like the Cold War; the current world of NBS is more like GWOT. Classic CFTR mutations are severe and clearly identified, with behavior that is somewhat easily classified. The new "enemies" are much less identifiable or predictable, even from patient to patient. Yet with proper strategies and attention, their effects are often more readily treatable, and, better yet, potentially preventable.

    2. There are many examples of how certain genotypes don’t play by the “classic” rules. Splicing mutations like the 5T or even 3849+10kbc- t often lead to misleadingly “normal” or equivocal sweat tests; the 5T (TG)13 variant, when combined with a severe mutation, can exhibit normal sweat chloride tests but CF-like lung disease penetrance. There are numerous documented cases and examples where normal sweat chloride results "do not provide much guidance as to what to expect for disease manifestations in other organ systems over time," since "splicing mutations tend to be quite variable in their effects, both from patient to patient, and also within a given patient over time."

  7. On the ground: prescription challenges for “CRMS” and “off-the radar” variants:

    1. Many milder mutations (more are discovered every year) will remain under the radar, and, from a patient and clinician perspective, potentially hard to prescribe for, even though Ivacaftor is proven to help patients with a wide array of mutations with residual CFTR. 

    2. More of these mutations likely need to be "on-label", possibly with dose adjustments, for the situation to improve. CFTR-compromised genotypes including the 5T(TG)13 could potentially be given a more legitimate "paper trail" (e.g., listed in clinical trial/study recruitment and results, such as Denver's). As one benefit among many, such a paper trial could have value In the eyes of insurance adjusters who have little incentive to be agreeable upon first review, and who generally like paper, and trails.

      1. Misdiagnosis and under-diagnosis of CF-related symptoms remains a risk. Both the broader symptom spectrum and the lack of inclusion of milder mutations like the 5T in most sequencing likely result in under-reporting into databases such as CFTR2.

      2. European guidelines have increasingly moved mutations like 5T TG13 to the list of CF-causing mutations/variants, while in the U.S., attention often depends on whether a particular physician or researcher has had experience with it (recall the hemochromatosis analogy above).  

      3. When it comes to considering drugs like Kalydeco for milder mutations and preventative approaches, there is a risk of over-aggressive treatment. 


    Summary: A way to improve lives, save lives, and, yes, make money.

    1. CFTR-related diseases are widely prevalent, but likely underdiagnosed and undertreated.
    2. Drugs like Kalydeco can likely help treat many of these diseases.
    3. While drugs like Kalydeco are expensive, pricing could ease as larger treatable populations and other applications like preventative treatment are recognized.
    4. Companies like Vertex and their shareholders should take special note that certain common genetic variants, like the 5T, cause a broad spectrum of symptoms, are largely addressable by drugs like Ivacaftor, and are prevalent in large percentages of the population. Symptomatic cases likely occur in numbers that are many multiples larger than traditionally measured CF populations.
    5. This discussion touches only a small part of a larger discussion to be had amongst the research, medical, and financial communities, among others. CFTR-related diseases comprise both a medical and market opportunity potentially larger than currently assumed. The opportunity is one where more diseases could potentially be treated with existing drugs, more patients could be served at a lower cost per patient, and drug companies could preserve their financial rewards and incentives.  As such, it is an opportunity that merits additional attention, and an opportunity that may be as good, and certainly as meaningful, as they come.