Hopes rest on causal therapy

The development of new causal therapies in cystic fibrosis is progressing rapidly. New correctors are currently being tested. In the foreseeable future, a causal therapy should be available for 90% of all patients.

In past decades, cystic fibrosis was primarily addressed by treating symptoms: mucolytic inhalations, antibiotics, physical therapy. This certainly had its success: from a disease with a pre-school mortality, medicine transformed cystic fibrosis into a disease with a life expectancy into early middle adulthood. However, it also had to be noted that the survival curve flattened out in the 1980s. While life expectancy has increased since the 1940s from infancy to about 25 years, only about 10 more years have been added in recent decades. The future now lies in causal therapies with CFTR(Cystic Fibrosis Transmembrane Conductance Regulator) modulators.

The basis for making it possible to repair the CFTR protein pharmacologically at all is to understand the molecular defects. “We know of more than 2,000 mutations in this protein and can divide them into five defect classes,” explained Prof. Dr. Marcus A. Mall, head of the Department of Pediatrics with a focus on pneumology and immunology with intensive care medicine at Charité – Universitätsmedizin Berlin, in his presentation at the 60th DGP Congress in Munich. These include defects that result in no protein being formed at all, protein maturation not functioning properly, CFTR chloride channels being incorporated into the membrane but not functioning as channels per se, or decreased channel activity. “What we’ve learned in the last 10 years is to translate the understanding of this into principles or concepts for causal therapies.”

Missing CFTR chloride channels are root of the evil

The core of the problem: If the CFTR chloride channels are missing at the surface, the end result is a dehydrated and thus highly viscous mucus, and mucociliary clearance does not work. This occurs because there are no CFTR chloride channels at the membrane, which is called a minimal function (MF) mutation. This includes the most common mutation F508del. Alternatively, the channels are incorporated but do not function as a channel or have only residual function, which is known as a gating mutation or residual function (RF) mutation. These mutations are treated with enhancers called potentiators, which have the effect of increasing the activity of channels that are already in the membrane. However, this type of mutation first requires a corrector that causes the protein to reach the surface in the first place, where activity is then further enhanced by a potentiator.

The first drugs with CFTR modulators are already in the clinic. A breakthrough was the approval of the first amplifier ivacaftor in 2011, initially for the gating mutation G551D. “What we saw there was a really resounding improvement in lung function,” recalls Prof. Mall. “However, only in a relatively small proportion of patients. That’s why it was important that we then got a first corrector/potentiator combination therapy in 2015, with which we can also treat the patients with the F508del mutation.” However, it must be noted with reservation that this therapy has so far only worked in homozygous patients, who make up about 50%. Of course, the expert went on to say, it would be ideal if it were sufficient to treat only one F508del allele, since about 90% of the CF population carries an allele with this mutation. A new corrector/potentiator combination, tezacaftor/ivacaftor, has been available since the end of 2018, but so far it also only works homozygously.

Resounding success with Ivacaftor

The effects of this modulator therapy on lung function and also on the sweat test as a biomarker of CFTR function show a resounding success of ivacaftor with a 10.6% improvement in _FEV1 and a drop in sweat chloride of nearly 50 mmol/l. Patients thus come close to the upper limit of a normal sweat test under ivacaftor. In contrast, the effect on lung function with the two available corrector/potentiator combinations is statistically significant but comparably moderate, and the decrease in sweat chloride is even less pronounced. “This means that, on the one hand, we have a highly effective correction of these gating and residual function mutations, but on the other hand, we have an ‘efficacy ceiling’ when it comes to the pharmacological correction of this common F508del mutation with the existing correctors,” Prof. Mall summarized.

The question of why the function of this mutation cannot be further improved has been addressed by several basic studies in recent years, with revealing answers. The reason for the efficacy limit of CFTR correctors was found to be that F508del interferes with CFTR folding at several sites, so in principle there are two biochemical defects here. “It’s only logical that you also need at least two correctors to effectively solve this problem.” This has led to the search for – and discovery of – new correctors in addition to the first-generation lumacaftor and ivacaftor with high-throughput methods.

New correctors for the future

Prof. Mall presented data from the testing of three new correctors, made on the airway epithelial cells of patients with one F508del allele and a second severe mutation. Using tezacaftor/ivacaftor as an example, it has been shown how the addition of a next-generation corrector increases the effect in vivo and on average to more than 50% of wild-type function (Fig. 1). Four of these correctors have been tested in Phase II studies, two of which (compounds 659 and 445) have recently been published. This showed the effect on the biochemical maturation of the protein: in both heterozygous and homozygous patients, there was a marked improvement with the addition of this third corrector, and thus a marked increase in function, which in this study was again in the range of 50% of wild-type function.

Phase III studies on this are ongoing, and initial results of this analysis also show an improvement in lung function in the heterozygous patients after four weeks of therapy. In addition, the effect was investigated in delF homozygous patients already on tezacaftor/ivacaftor therapy, here an add-on effect of 10% is obtained. “As I said, 90% of patients carry an F508del allele, so this is really very hopeful data that we will be able to effectively treat nine out of ten CF patients in this way in the near future,” Prof. Mall concluded.

Summary

There is a rapid development of new causal therapies for cystic fibrosis.
In Phase II trials: proof-of-concept that causal therapy may be available in the foreseeable future for approximately 90% of all patients.
Great potential in preventive treatment to prevent irreversible lung damage with CTFR modulators.

Source: Symposium “Therapies of the Future” as part of the 60th Congress of the German Society of Pneumology and Respiratory Medicine on 15.03.2019 in Munich (D)

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