The cystic fibrosis drug market

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<ul><li><p>FROM THE ANALYSTS COUCH</p><p>The cystic fibrosis drug marketBasharut A. Syed and Bashar Hamad Green fashion couch, image from Archideaphoto/Alamy</p><p>Cystic fibrosis (CF), also known as mucoviscidosis, is a lethal common autosomal-recessive disorder. The highest incidence of CF is among Caucasians of northern European descent, occurring in approximately 1 in 2,500 live births.Worldwide, over 75,000 people are affected by the condition.</p><p>The disease is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), an anion channel that helps maintain fluid- and electrolyte-homeostasis in multiple organs, including the lungs and pancreas. In individuals with CF this homeostasis is disrupted, leading to the accumulation of hyperviscous mucus. In the lung, this blocks the airways, resulting in a cycle of inflammation and chronic </p><p>infection, particularly with the bacterium Pseudomonas aeruginosa. In the pancreas, hyperviscous mucus obstructs the movement of digestive enzymes. </p><p>To date, more than 1,700 different CFTR mutations have been described. The most common mutation, found in almost 70% of individuals with CF, is a deletion of three nucleotides encoding phenylalanine at position508 (Phe508), resulting in the expression of a defective CFTR protein. </p><p>Current treatmentsThough a cure for CF has yet to be developed, patients with CF have a number of options to treat their symptoms. These include: airway-clearance techniques and medications to clear mucus from the lungs; proactive treatment of infections; </p><p>pancreatic enzyme replacement therapy (PERT); optimal nutrition; and an active lifestyle. </p><p>Pharmacotherapy includes dornase alfa (Pulmozyme; Genentech/Roche), a recombinant human DNase that acts as a potent aerosolized mucolytic agent. However, only ~10% of individuals with CF respond to the drug and there are no reliable markers to predict response.</p><p>Ivacaftor (Kalydeco; Vertex Pharmaceuticals/Cystic Fibrosis Foundation (CFF)) was approved by the USFood and Drug Administration (FDA) in 2012 for patients with the G551D CFTR mutation, which accounts for 45% cases of CF. Ivacaftor is the first drug that treats the underlying cause of the disease; however, at over US$300,000 per year, it remains very expensive. </p><p>Table 1 | Selected cystic fibrosis therapies in late-stage development</p><p>Drug (alternative name) Developers Modes of action Highest development stage</p><p>Bronchitol Central Sydney Area Health Service/Pharmaxis</p><p>Osmotic agent Marketed in UK, Germany, Austria and Australia; Registered in EU; PhaseIII in USA, Canada, New Zealand and Argentina</p><p>Ataluren (Translarna) PTC Therapeutics Facilitates read-through of stop-codons PhaseIII (worldwide)</p><p>Ivacaftor (Kalydeco) in combination with lumacaftor</p><p>Vertex Pharmaceuticals/CFF Fixed combination of CFTR activators PhaseIII (North America and EU)</p><p>Lumacaftor (VX-809) Vertex Pharmaceuticals/CFF CFTR corrector PhaseII (North America and EU)</p><p>VX-661 Vertex Pharmaceuticals/CFF CFTR activator PhaseII (USA)</p><p>CFTR gene therapy CFGTC Gene therapy PhaseII (UK)</p><p>N-6022 N30Pharmaceuticals GSNOR inhibitor PhaseIIa (USA)</p><p>Lynovex (NM-001) NovaBiotics Antibacterial, mucolytic PhaseIIa (UK)</p><p>OligoG AlgiPharma Antibiotic oligosaccharide PhaseIIb (UK and Ireland)</p><p>Alpha-1 antitrypsin Grifols Anti-inflammatory, proteinase inhibitor PhaseII (USA)</p><p>KB001-A KaloBios Pharmaceuticals/CFF Anti-inflammatory, monoclonal Fab fragment</p><p>PhaseII (USA and France)</p><p>Sildenafil (Revatio) CFF Anti-inflammatory, phosphodiesterase inhibitor</p><p>PhaseII (USA)</p><p>Levofloxacin (Aeroquin or MP-376)</p><p>Aptalis Pharma/CFF Anti-infective PhaseIII (USA)</p><p>Arikace (inhaled amikacin) Insmed/CFF Anti-infective PhaseIII (EU and Canada)</p><p>AeroVanc (inhaled vancomycin)</p><p>Savara Pharmaceuticals/CFF Anti-infective PhaseII (USA)</p><p>Liprotamase EliLilly PERT PhaseIII (worldwide)</p><p>CFF, Cystic Fibrosis Foundation; CFGTC, UK Cystic Fibrosis Gene Therapy Consortium; CFTR, cystic fibrosis transmembrane conductance regulator; EU, European Union; Fab, antigen-binding fragment; GSNOR, S-nitrosoglutathione reductase; PERT, pancreatic enzyme replacement therapy.</p><p>N E W S &amp; A N A LY S I S</p><p>NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | OCTOBER 2014 | 721</p><p> 2014 Macmillan Publishers Limited. All rights reserved</p></li><li><p>Nature Reviews | Drug Discovery</p><p>Mucolytics </p><p>Anti-infectivesCFTR modulators</p><p>PERT</p><p>Total$1.6</p><p>billion</p><p>$168million</p><p>$626million</p><p>$530million</p><p>$288million</p><p>FROM THE ANALYSTS COUCH</p><p> More recently, an inhaled dry-powder form of mannitol (Bronchitol; Pharmaxis) an osmotic agent thought to help rehydrate CF secretions became available in certain markets (TABLE1) as an add-on therapy to the best standard of care. </p><p>Emerging therapiesA number of promising CF products with different modes of action are in development (TABLE1). One of the most advanced is ataluren (Translarna; PTC Therapeutics), asmall-molecule agent that putatively makes ribosomes less sensitive to stop-codons. PhaseIII clinical trials are currently in progress in Europe and in the United States. InMay 2014, ataluren received a positive opinion from the Committee for Medicinal Products for Human Use at the European Medicines Agency.</p><p>Vertex Pharmaceuticals, in collaboration with the CFF, is developing lumacaftor (also known as VX-809, now in PhaseIII) and VX-661 (in PhaseII), both alone and in combination with ivacaftor for the Phe508 CFTR mutation. Two PhaseIII trials (TRAFFIC and TRANSPORT) of lumacaftor in combination with ivacaftor reported positive data. Vertex plans to file for FDA approval by the end of 2014. </p><p>In March 2012, the UK Cystic Fibrosis Gene Therapy Consortium initiated a PhaseII trial of a gene therapy (GL67A/pGM169). The product, which is delivered via an aerosol device,is a combination of a cationic liposome (GL67A) and plasmid DNA encodingCFTR(pGM169). The results so far are positive and indicate no serious safety concerns. </p><p>N-6022 (N30Pharmaceuticals), a small-molecule agent that inhibits S-nitrosoglutathione reductase (GSNOR), is in PhaseIIa development. GSNOR is key regulator of organ repair, regeneration, and healing. Its substrate, GSNO, acts through nitric oxide signalling and is essential for the normal function of CFTR.</p><p>NM-001 (Lynovex; NovaBiotics), a biologically active oral antibacterialmucolytic peptide is in PhaseIIa development as an orphan drug treatment for CF. It is also being formulated for inhalation to enable longer-term, better-targeted delivery of the drug.</p><p>OligoG (AlgiPharma) is currently being assessed in PhaseIIb studies as a dry-powder formulation. Derived from Norwegian seaweed, the alginate oligomer works by </p><p>chelating the calcium that is found in the mucus of individuals with CF, and which in part accounts for the mucus hyperviscosity. </p><p>Three anti-inflammatory agents are currently in PhaseII development. Alpha-1 antitrypsin (developed by Grifols) is an inhaled formulation of an alpha-1 proteinase inhibitor with anti-inflammatory properties that is derived from human plasma. APhaseII trial hasbeen completed in the United States.</p><p>KB001-A (KaloBios Pharmaceuticals/CFF) is a humanized monoclonal antigen-binding (Fab) fragment that targets a P.aeruginosa virulence factor (the TypeIII secretion system of the bacteria). A PhaseII trial began enrolment in late 2012 with a primary end point focused on inflammation. And sildenafil (Revatio; CFF), a phosphodiesterase inhibitor, has completed a PhaseII study; the results are pending.</p><p>Three inhaled anti-infectives are also in late-stage development. Levofloxacin (Aeroquin; Aptalis Pharma/CFF) has completed PhaseIII trials in patients with CF. A PhaseIIb trial of the drug demonstrated reduction of P.aeruginosa in the sputum and improvements in lung function. Arikace (Insmed/CFF), a liposomal formulation of the antibiotic amikacin, has successfully completed a PhaseIII trial in Europe and Canada in individuals with CF who had been colonized withP.aeruginosa. APhaseIII trial of the drug for the treatment of nontuberculous mycobacteria is currently underway in the United States. And a PhaseII trial of AeroVanc (Savara Pharmaceuticals/CFF), an inhaled dry-powder form of vancomycin, for the treatment of methicillin-resistantStaphylococcus aureus (MRSA) airway infection in individuals with CF is currently enrolling.</p><p>Another pipeline therapy is liprotamase (Sollpura; Alnara (a subsidiary of Eli Lilly)), which is in Phase III trials for the treatment of exocrine pancreatic insufficiency.</p><p>Market indicatorsThe current CF drug market is worth ~$1.6billion (FIG.1) (IMS Health, IMS Midas; 2014). It has more than doubled in the past 4years with a compound annual growth rate (CAGR) of 23.7%. Anti-infectives dominate the CF market, with sales of tobramycin (Tobi; Novartis) estimated at $445million over the 12months to Q12014 accounting for 71.1% of sales in this class. Mucolytics, with dornase alfa being the only approved </p><p>drug in this class, generated $530million during the same time. PERT sales were led by pancrelipase (Creon; AbbVie), with sales of $260million, and the CFTR modulator ivacaftor achieved $168million. The United States remains the dominant national market for CF therapies, accounting for 74.1% of the total sales. </p><p>The CF drug market is projected to reach $3.9billion by 2019 (CAGR 19.5%, 20142019), driven by the potential of disease-modifying agents and the rising numbers of individuals with CF in Caucasian populations, as well as an increasing diagnosis rate of the disease in non-Caucasian populations. The prognosis for CF has improved owing to earlier diagnosis through screening, and better treatment and access to health care. However, continued demand persists for novel and efficacious treatments to make the disease more manageable and to help patients live beyond their current life expectancy of 40years.</p><p>Basharut A. Syed, Ph.D. and Bashar Hamad, Ph.D. are at IMS Health Ltd, 210 Pentonville Road, </p><p>London N19JY, UK.e-mails:; </p><p></p><p>doi:10.1038/nrd4434</p><p>Competing interests statements The authors declare no competing interests.</p><p>FURTHER INFORMATIONIMS Health: http:/</p><p>ALL LINKS ARE ACTIVE IN THE ONLINE PDF</p><p>Figure 1 | Global sales of cystic fibrosis drugs. Sales in US$ over the 12months to Q12014. CFTR, cystic fibrosis transmembrane conductance regulator; PERT, pancreatic enzyme replacement therapy.</p><p>N E W S &amp; A N A LY S I S</p><p>722 | OCTOBER 2014 | VOLUME 13</p><p> 2014 Macmillan Publishers Limited. All rights reserved</p><p>mailto:bsyed@uk.imshealth.commailto:bhamad@uk.imshealth.comhttp:/</p></li></ul>