Tidlig undersøgelse af Tamoxifen-sikkerhed/tolerabilitet hos patienter med cystisk fibrose, der ikke kan bruge CFTR-modulatorer. (TMX)

Normal airways regulate the volume of airway surface liquid (ASL) through the activation of both cyclic adenosine monophosphate (cAMP) and Ca2+-dependent ion channels. In cystic fibrosis, the genetic defect causes a deficiency of cAMP-dependent CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) activity, leading to reduced Cl- and water secretion from airway epithelial cells and the consequent accumulation of mucus, facilitating bacterial and fungal infections. Women with CF have reduced survival compared with men with CF, although the mechanisms underlying this sex-related disadvantage are unknown. Despite the lack of CFTR, CF airways maintain a limited ability to regulate ASL volume, as ATP release, induced by breathing, activates purinergic pathways that increase intracellular Ca2+ concentration to stimulate an alternative Cl- secretion pathway. It has been hypothesized that estrogen might influence this pathway by reducing the ability of airway epithelia to adequately respond to nucleotides. They found that UTP-mediated Cl- secretion was reduced during periovulatory estrogen peaks in both CF and healthy women. Estrogen also inhibited Ca2+ signaling and ASL volume homeostasis in both non-CF and CF airway epithelia by attenuating Ca2+ influx. 17ß-estradiol inhibits the intracellular Ca2+ signaling, thus impairing the activity of calcium-activated chloride channels (CaCC). This suggests that antiestrogens, such as tamoxifen, could be beneficial in the treatment of CF lung diseases because they may increase Cl- secretion in the airways.

It has been demonstrated that TMX can restore CaCC function by inhibiting estrogen signaling. Furthermore, authors showed that TMX can directly activate CaCC regardless of estrogen signaling, therefore generating a significant amount of chloride current.

The results of these experiments indicate that:

• TMX can increase CaCC currents through two mechanisms:

  • Indirectly, as an antagonist of the negative effect of 17β-estradiol on the currents
  • Directly, regardless of the antiestrogen effect, by acting on CaCC, the alternative chloride transport pathway

• The action of TMX is not affected by the different class of CFTR mutations since it regulates CaCC

• The effect of TMX on CaCC currents is long-lasting and quantitatively significant, superior to the CFTR-dependent currents obtained from the combination of ivacaftor and lumacaftor

• Both women and men can benefit from TMX

• TMX antagonizes the inhibitory action of estradiol E2 on CaCC currents: TMX could counteract the negative effects of estrogens on CaCC currents during the periovulatory period (about 1 week per month) and acts directly on CaCC currents during all remaining days

• It can be used in combination with other therapeutic agents: given the complexity of intracellular trafficking and the short half-life of mutant CFTR proteins, it is conceivable that the currently available CFTR modulators will improve but not cure cystic fibrosis. Therefore, the treatment of cystic fibrosis may require the combination of different therapeutic agents. TMX treatment could be complementary and synergistic with CFTR modulators.

In conclusion, although effective therapies for CF have been already authorized in the European Union, the use of tamoxifen citrate is justified by the current scientific literature and preclinical data. Patients with CF should benefit from this treatment. Importantly, given its mechanism of action, TMX is expected to be beneficial for patients both with F508del CFTR mutation and other rare variants that still remain orphan of therapies. It follows that the European Commission has considered TMX treatment as a possible clinically relevant advantage for patients with CF.

Based on the results emerged from different studies, the European Commission has granted orphan designation (EU/3/17/1877) to GB Pharma S.r.l. for tamoxifen citrate for the treatment of cystic fibrosis.

Primary Objective The study aims to evaluate the safety and tolerability of TMX in patients with cystic fibrosis who do not have mutations currently eligible for therapy with modulator drugs.

Secondary Objectives

The study also aims to evaluate the effects of TMX on:

• lung function
• quality of life
• pulmonary exacerbations
• hospitalizations for pulmonary exacerbations
• antibiotic cycles
• BMI
• sputum microbiology
• sweat test