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.

    The Smackdown Becomes a CFF Milestone Donor

    CF Smackdown Commits Additional Funds to CF Research 

    The CF Smackdown has committed a new round of funds to the CFF. As a Milestone-level contributor, the Smackdown's impact on CF research continues to build.

    If you would like to contribute to our effort, please let us know. We'll even send you a lightning-bolt-adorned cape for your role in the ongoing Smackdown. 

    Announcing CF Smackdown grants

    Today we are announcing a unique new initiative, Smackdown grants.

    Smackdown grants are small grants ($500 - $5,000) available for specific projects that can improve the lives of those affected by CF, advance research toward better treatments or a cure, or lay the smackdown on cystic fibrosis in some other feisty way.

    Read more on our "Smackdown grants" page.


    CF Smackdown leads the way at local CFF event

    Congratulations to all-- the recent CFF Great Strides event in Chattanooga was a record-breaker. More than $130,000 raised overall, and the CF Smackdown team (a rookie who came out of nowhere) led the field with nearly $32,000 raised so far (nearly all through upstart partner nonprofit Causeway-- thank you, Causeway).  Hundreds of folks turned out, enjoyed music, walked around in circles, and overall, continued to pile on in the fight against cystic fibrosis.

    And did you see the sea of capes and lightning bolts? They were all with the CF Smackdown. Expect to see more where that came from. And let us know if you or your community would like to join the Smackdown and overwhelm your next event with capes and lightning bolts.

    Join us as we build momentum in a fight that will be won within this decade.


    Smackdown Helps Forge CFF-Funded Splice Mutation Research Collaboration

    Wow. Today, we are thrilled to announce that an international research collaboration, one which the Smackdown helped forge, has now launched and just received two years of funding from the CF Foundation.

    Details are confidential, but the project involves addressing a category of genetic mutations which, if successful, could help thousands of patients with CF, and potentially other diseases. It may take 10 years for this to bear fruit, but what was merely a “very, very long shot” in the beginning is now “game on”.

    This is a great example of how ordinary folks can make a huge difference for CF. Though this example took a whole lot of hustle, this was just a family from Chattanooga deciding it was going to help change things for the better, and then setting out to do so.


    Consider contributing to the CF Smackdown and join an underdog team who’s starting to rack up some victories.

    Calling all 5Ts: Update on the Kalydeco/Residual CFTR study in Denver

    Another significant step forward for the efforts of the Smackdown: After months of efforts lobbying for the addition of the IVS8-5T genotype to the Ivacaftor / Residual CFTR study in Denver, we were just notified that Vertex, and the study center, has agreed to recruit candidates with this genotype. 

    If you carry a major CF mutation and the 5T variant (TG11, TG12, or TG13) and otherwise qualify for this study, please contact us, and we'll help connect you.

    Disclaimer: While the fact that a daughter of a Smackdown founder carries the 5T obviously puts this variant on our radar, it is also carried by nearly 10% of the population, so we think it's worth paying some attention to. We will write a blog post later on the significant of the 5T, but suffice to say, if a drug like Kalydeco can potentiate residual 5T CFTR, there could be broad implications across a broad spectrum of disease.

    Kalydeco named "most important new drug of 2012"

    Kalydeco was just named "The Most Important New Drug of 2012" by Forbes Magazine (here), for three main reasons:

    • It is a genomics breakthrough, directly countering a genetic defect
    • It was driven, in large part, by the Cystic Fibrosis Foundation, who is absolutely leading patient advocacy groups by example.
    • It makes money for both the company who invented in it AND the CFF, who was visionary (and brave) enough to make the investment years ago.  The royalties from this drug will help fund future treatments-- this is innovation, and dare we say, capitalism, at its best.


    Pilot Study to Test Kalydeco/Ivacaftor in Subjects With CF and Residual CFTR Function

    A new pilot study to examine the effect of Kalydeco on patients with evidence of residual CFTR function launched this month.  The study sponsor is Vertex Pharma and the recruitment and study site is at National Jewish Health in Denver, Colorado.

    Here is the official description: "This study is a multiple within subject crossover study to evaluate the effect of ivacaftor on lung function in subjects aged 12 years and older with cystic fibrosis (CF) who have phenotypic or molecular evidence of residual CF transmembrane conductance regulator (CFTR) function."

    The layperson's key takeaway: if Ivacaftor/Kalydeco is shown to have a positive effect on lung function in patients with evidence of residual CFTR, this can potentially and significantly broaden the patient pool for whom Kalydeco could be of benefit. Our take: the study will show positive effects on lung function in patients with residual CFTR. We will have our eyes on the breakdown of effects by genotype.

    The official link to the pilot study is here.  They are recruiting candidates now, and if you qualify, and particularly if you are in the Denver area, contact Vertex at 617.444.6777 or medicalinfo@vrtx.com, or contact us, and we'll help you get in touch.

    In addition to encouraging as many qualified candidates to apply as possible, we are particularly interested in getting some IVS8-5T genotypes in the study, as this variant is carried by nearly 10% of the U.S. population and has a broad spectrum of phenotypic effects.  

    We will follow up later with a post on the significance of the 5T variant, as well as report on our progress trying to get the 5T added to the study. 


    The CF Smackdown Begins

    The CF Smackdown has begun.  Our goal is to help end cystic fibrosis this decade.  

     As a young family, like many other affected by this disease, this is not a fight we asked for. We also recognize this is not a fight we are alone in. Our conviction to combat this disease is one shared by so many who have fought before us, and who fight alongside us now. Anyone in this fight deserves our deepest respect, and our deepest gratitude.

    As recent events have shown, this is a time of breakthroughs in CF. Kalydeco was approved earlier this year (in fact, within two weeks of the birth of our daughter), and it changes everything. Momentum is building, CF is no longer invincible, and it is time to pile on.

    So while the CF Smackdown was launched by one family, it is not about one family. There are far too many families affected by this disease, and we’re all better off standing up against CF together. And doing something.

    That’s what the CF Smackdown is about. Patients, families, groups, companies, organizations, heroes– standing up, and doing something to help win this fight.

    So what are we going to do?

    Like everyone else touched by CF, we were initially thunderstruck by the news from our doctors, and for months, struggled to find our footing. Our daughter is doing well, and our plan is to not only regain our footing, but to start walking, then charging forward. We will start by working to help forge a new research collaboration on a certain class of CF mutations (splicing). Not to mention starting the CF Smackdown.

    CF used to be invincible. It's not looking so invincible anymore.

    It is time to pile on.