As we said in our September 10, 2014 article, we intended to post updates on companies that we had been following on our blog, and that have achieved significant progress in recent months. So far, we have covered Agios and Zafgen. Both of these companies were featured in Boston-area meetings in October—Zafgen in Xconomy Xchange: Boston’s Life Science Disruptors on October 8, and Agios in the New Approaches to Cancer Drug Discovery symposium at Harvard Medical School on October 14.

Now we turn to the small-molecule cystic fibrosis (CF) therapeutics program at Vertex Pharmaceuticals (Boston, MA).

We covered Vertex’ CF program in our articles of January 24, 2013 and February 15, 2013. As a result of the publication of these articles, I was interviewed for and quoted in an article in the March 11, 2013 issue of Elsevier Business Intelligence’s The Pink Sheet entitled “Cystic Fibrosis Market Snapshot: Disease-Modifying Drugs Elusive 24 Years After Discovery Of Root Cause”. (A subscription is required to view the full text of this article.)

To summarize our discussions of CF in these earlier articles, CF causes a suite of symptoms that affect the skin, the lungs and sinuses, and the digestive, endocrine, and reproductive systems. The most important results of CF is that patients accumulate thick, sticky mucus in the lungs. This results in clogging of the airways with mucus. This leads to inflammation and bacterial infections. Lung transplantation is often necessary as the disease worsens. With proper management, patients can live into their late 30s or 40s.

The gene that is affected in cystic fibrosis encodes the cystic fibrosis transmembrane conductance regulator (CFTR).  CFTR is an ion channel that regulates the movement of chloride and sodium ions across epithelial membranes, including the epithelia of lung alveoli. CF is an autosomal recessive disease, which is most common in Caucasians. The most common mutation that causes CF, ΔF508, is a deletion of three nucleotides that causes the loss of the amino acid phenylalanine at position 508 of the CFTR protein. The ΔF508 mutation accounts for approximately two-thirds of CF cases worldwide and 90% of cases in the United States. However, there are over 1500 other mutations that can cause CF.

Ion channels constitute an important class of drug targets, which are targeted by numerous currently marketed drugs. These compounds were developed empirically by traditional pharmacology before knowing anything about the molecular nature of their targets. However, discovery of novel ion channel modulators via modern molecular methods has proven to be challenging.

The ΔF508 mutation results in defective cellular processing, and the mutant CTFR protein is retained in the endoplasmic reticulum. Some other mutations in CTFR (which affect a small percentage of CF patients) result in mutant proteins that reach the cell membrane, but are ineffective in chloride-channel function.

After a long discovery and development program (which we outlined in our February 15, 2013 article), Vertex identified two types of candidate small-molecule CF therapeutics:

• CFTR potentiators, which potentiate the chloride channel activity of mutant CFTR molecules at the cell surface;
• CFTR correctors, which partially correct the folding and/or trafficking defect of such mutant CFTRs as ΔF508, thus enabling a portion of these mutant proteins to exit from the endoplasmic reticulum and to deposit in the cell membrane.

Vertex’ CTFR potentiator ivacaftor (Kalydeco, formerly known as VX-770) was approved by the FDA in January 2012, and approved in Europe in July 2012. At that time, ivacaftor was only indicated for treatment of CF patients age 6 and over carrying the CFTR G551D mutation (Gly551Asp). Although the G551D mutation only affects approximately 4% of CF patients, it is the most common CFTR gating mutation (i.e., a mutation that affects transport of sodium and chloride ions across epithelial membranes).

New indications for ivacaftor (Kalydeco)

On July 31, 2014, Vertex announced that the European Commission had approved ivacaftor for treatment of CF patients age 6 and over who have one of eight non-G551D gating mutations in the CFTR gene. The eight additional gating mutations included in the new approval affect approximately 250 people ages 6 and older in the European Union.

The approval was based on data from a Phase 3 randomized, double-blind, placebo-controlled study of 39 people with CF ages 6 and older who have a non-G551D gating mutation.

The European approval followed the February 21, 2014 announcement that the FDA had approved ivacaftor for treatment of CF patients 6 and older who have one of the same additional eight mutations in the CFTR gene. In the U.S., approximately 150 people ages 6 and older have one of the additional eight mutations.

On October 21, 2014, the FDA’s Pulmonary Allergy Drugs Advisory Committee (PADAC) voted 13-2 to recommend approval of ivacaftor in CF patients age 6 and older who have the R117H mutation in the CTFR gene. This new indication is now under review by the FDA.

Thus Vertex has been pursuing a strategy of testing and seeking approval of ivacaftor for treatment of CF patients with gating mutations in the CTFR gene other than the G551D mutation, in a systematic, step-by-step fashion. As a result of this strategy, ivacaftor is currently approved to treat over 2,600 people ages 6 and older in North America, Europe and Australia.

Vertex’ development of the CFTR correctors lumacaftor (VX-809) and VX-661

Meanwhile, Vertex has also been pursuing approval for its CFTR correctors lumacaftor (VX-809) and VX-661. We have discussed these agents in our February 15, 2013 blog article.

As we discussed in that article, as of February 2013 Vertex had completed Phase 2 studies of a combination of ivacaftor and lumacaftor in CF patients who were homozygous for the CFTR ΔF508 mutation. They then planned pivotal phase 3 trials of the combination therapy in this patient population. The rationale for the combination treatment was that VX-809 potentates the deposition of CFTR ΔF508 in the cell membrane, and invacaftor potentiates the function of cell-surface CFTR ΔF508.

As of February 2013, Vertex was also conducting Phase 2 trials of another CTFR corrector, VX-661, alone and in combination with ivacaftor in CF patients homozygous for CFTR ΔF508.

On June 24, 2014, Vertex announced that results from two Phase 3 studies of lumacaftor in combination with ivacaftor showed statistically significant improvements in lung function in people ages 12 and older with cystic fibrosis (CF) who were homozygous for CFTR ΔF508. All four 24-week combination treatment arms in the studies, known as TRAFFIC and TRANSPORT, met their primary endpoint of mean absolute improvement in lung function from baseline compared to placebo at the end of treatment. The combination treatments were also generally well tolerated.

Data from a pre-specified pooled analysis also showed improvements in multiple key secondary endpoints, including lowering pulmonary exacerbations.

On October 9, 2014, Vertex announced updates of the results of the TRAFFIC and TRANSPORT studies, in conjunction with the company’ presentations at the 28th Annual North American Cystic Fibrosis Conference (NACFC). Patients who completed 24 weeks of treatment in TRAFFIC or TRANSPORT were eligible to enter a Phase 3 rollover study to receive a combination regimen of lumacaftor and ivacaftor. The first interim data from the rollover study (presented at NACFC) showed that the improvements in lung function observed in the 24-week TRAFFIC and TRANSPORT studies were sustained through 48 weeks of treatment with the combination treatment. At the time of the interim analysis, safety and tolerability results were also consistent with those observed in the initial Phase 3 TRAFFIC and TRANSPORT studies.

In the October 9, 2014 press release, Vertex also announced the submission of an NDA in the U.S. and an MAA in Europe for the approval of ivacaftor in children with CF ages 2 to 5 with one of the same 9 CTFR gene mutations for which the drug is approved in patients 6 or older. These line extension submissions are based on further Phase 3 studies, which were also presented at the NACFC.

On November 5, 2014, the company announced that it had submitted an NDA to the FDA and an MAA to the European Medicines Agency (EMA) for a fully co-formulated combination of lumacaftor and ivacaftor for CF patients age 12 and older who are homozygous for CFTR ΔF508. There are approximately 22,000 people with CF ages 12 and older who are homozygous for CFTR ΔF508 in North America, Europe and Australia. This includes approximately 8,500 people in the United States and 12,000 people in Europe. These new submissions are based on data from TRAFFIC and TRANSPORT, and on the first interim data from the subsequent rollover study.

Meanwhile, as also announced on October 9, 2014, clinical studies of VX-661 are continuing. Vertex presented data from Phase 2 studies of VX-661 in combination with ivacaftor at the 2014 NACFC. In the October 9 press release, Vertex announced that it plans to initiate a pivotal Phase 3 development program for VX-661 in combination with ivacaftor in CF patients who have one or two copies of the CFTR ΔF508 mutation, including patients with a second CFTR mutation that causes a defect in the gating of the CFTR protein. The initiation of this study is pending regulatory discussions and data from a fully enrolled 12-week Phase 2b study of VX-661 in combination with ivacaftor in patients who are homozygous for CFTR ΔF508.

The high cost of Kalydeco causes controversy

Kalydeco (ivacaftor) costs nearly $300,000 a year. These costs are usually borne by insurers and governments, and Vertex has pledged to provide the drug free to any U.S. patient who is uninsured or whose insurance won’t cover it.

However, the high cost of this drug—and the anticipated higher cost of combination therapies for treatment of CF—has generated controversy in some circles. This issue has been discussed, for example, in 2013 articles in the M.I.T. Technology Review and in MedPage Today. (MedPage Today is a peer-reviewed online medical news service for clinicians, which provides breaking medical news, professional medical analysis and continuing medical education (CME) credits to its physician readers.)

According to the Technology Review article, by Barry Werth, doctors and patients enthusiastically welcomed Kalydeco because it offers life-saving health benefits and there is no other treatment. Insurers and governments readily paid the cost. However, commentators quoted in the MedPage Today article said that the price of Kalydeco is exorbitant, and the increasing numbers of high-priced life-saving drugs to treat rare diseases (although nor usually borne directly by patients themselves) is unsustainable. Vertex—as quoted in the MedPage Today article—said that the price of Kalydeco reflects its high degree of efficacy, the time and cost [and risk] it took to develop the drug, and the company’s commitment to reinvest in continued development of newer drugs to help other CF patients.

The discussions of the high cost of Kalydeco echoes the discussions of the cost of novel drugs for life-threatening cancers, as mentioned in our October 2, 2014 article, “Late-breaking cancer immunotherapy news”, on this blog.

With respect to the development of Kalydeco and other small-molecule CF drugs, the publicly-funded—and successful—research to determine the molecular cause of CF was of little help in enabling researchers to develop disease-modifying drugs. (See our January 24, 2013 blog article, “Determining the molecular cause of a disease does not necessarily enable researchers to develop disease-modifying drugs”.) As outlined in our February 15, 2013 blog article, Vertex’ own drug discovery and development program (partially funded by the nonprofit Cystic Fibrosis Foundation, which now receives royalties on sales of Kalydeco) was long (beginning in 1998), expensive, risky, and involved considerable ingenuity.

Given the high barrier between the knowledge of the molecular biology of CF and its use in discovering and developing safe and efficacious small-molecule drugs, the development of such agents as ivacaftor, lumacaftor, and VX-661 is almost miraculous. Vertex’ arguments that justify the high cost of the drug thus have considerable merit. However, discussions in the medical community and beyond on how the costs of novel life-saving drugs for rare diseases and cancer may be sustained will and should continue.

Conclusions

The goal of Vertex’ CF program as a whole is the development, approval and marketing of multiple combinations of small-molecule therapeutics that will have disease-modifying efficacy in the great majority of CF patients. Especially with the recent progress with clinical studies of the ivacaftor/lumacaftor combination in patients with CFTR ΔF508 mutations, and with line extensions of ivacaftor, Vertex appears to be well on its way to accomplishing this, pending regulatory approvals.

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