Download pdf - The cystic fibrosis drug market

FROM THE ANALYSTrsquoS COUCH

The cystic fibrosis drug marketBasharut A Syed and Bashar Hamad Green fashion couch image from ArchideaphotoAlamy

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 2500 live birthsWorldwide over 75000 people are affected by the condition

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

infection particularly with the bacterium Pseudomonas aeruginosa In the pancreas hyperviscous mucus obstructs the movement of digestive enzymes

To date more than 1700 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 position 508 (ΔPhe508) resulting in the expression of a defective CFTR protein

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

pancreatic enzyme replacement therapy (PERT) optimal nutrition and an active lifestyle

Pharmacotherapy includes dornase alfa (Pulmozyme GenentechRoche) 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

Ivacaftor (Kalydeco Vertex PharmaceuticalsCystic Fibrosis Foundation (CFF)) was approved by the US Food and Drug Administration (FDA) in 2012 for patients with the G551D CFTR mutation which accounts for 4ndash5 cases of CF Ivacaftor is the first drug that treats the underlying cause of the disease however at over US$300000 per year it remains very expensive

Table 1 | Selected cystic fibrosis therapies in late-stage development

Drug (alternative name) Developers Modes of action Highest development stage

Bronchitol Central Sydney Area Health ServicePharmaxis

Osmotic agent Marketed in UK Germany Austria and Australia Registered in EU Phase III in USA Canada New Zealand and Argentina

Ataluren (Translarna) PTC Therapeutics Facilitates read-through of stop-codons Phase III (worldwide)

Ivacaftor (Kalydeco) in combination with lumacaftor

Vertex PharmaceuticalsCFF Fixed combination of CFTR activators Phase III (North America and EU)

Lumacaftor (VX-809) Vertex PharmaceuticalsCFF CFTR corrector Phase II (North America and EU)

VX-661 Vertex PharmaceuticalsCFF CFTR activator Phase II (USA)

CFTR gene therapy CFGTC Gene therapy Phase II (UK)

N-6022 N30 Pharmaceuticals GSNOR inhibitor Phase IIa (USA)

Lynovex (NM-001) NovaBiotics Antibacterial mucolytic Phase IIa (UK)

OligoG AlgiPharma Antibiotic oligosaccharide Phase IIb (UK and Ireland)

Alpha-1 antitrypsin Grifols Anti-inflammatory proteinase inhibitor Phase II (USA)

KB001-A KaloBios PharmaceuticalsCFF Anti-inflammatory monoclonal Fab fragment

Phase II (USA and France)

Sildenafil (Revatio) CFF Anti-inflammatory phosphodiesterase inhibitor

Phase II (USA)

Levofloxacin (Aeroquin or MP-376)

Aptalis PharmaCFF Anti-infective Phase III (USA)

Arikace (inhaled amikacin) InsmedCFF Anti-infective Phase III (EU and Canada)

AeroVanc (inhaled vancomycin)

Savara PharmaceuticalsCFF Anti-infective Phase II (USA)

Liprotamase Eli Lilly PERT Phase III (worldwide)

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

N E W S amp A N A LY S I S

NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | OCTOBER 2014 | 721

copy 2014 Macmillan Publishers Limited All rights reserved

Nature Reviews | Drug Discovery

Mucolytics

Anti-infectivesCFTR modulators

PERT

Total$16

billion

$168million

$626million

$530million

$288million


More recently an inhaled dry-powder form of mannitol (Bronchitol Pharmaxis) mdash an osmotic agent thought to help rehydrate CF secretions mdash became available in certain markets (TABLE 1) as an add-on therapy to the best standard of care

Emerging therapiesA number of promising CF products with different modes of action are in development (TABLE 1) One of the most advanced is ataluren (Translarna PTC Therapeutics) a small-molecule agent that putatively makes ribosomes less sensitive to stop-codons Phase III clinical trials are currently in progress in Europe and in the United States In May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use at the European Medicines Agency

Vertex Pharmaceuticals in collaboration with the CFF is developing lumacaftor (also known as VX-809 now in Phase III) and VX-661 (in Phase II) both alone and in combination with ivacaftor for the ΔPhe508 CFTR mutation Two Phase III trials (lsquoTRAFFICrsquo and lsquoTRANSPORTrsquo) of lumacaftor in combination with ivacaftor reported positive data Vertex plans to file for FDA approval by the end of 2014

In March 2012 the UK Cystic Fibrosis Gene Therapy Consortium initiated a Phase II trial of a gene therapy (GL67ApGM169) The product which is delivered via an aerosol device is a combination of a cationic liposome (GL67A) and plasmid DNA encoding CFTR (pGM169) The results so far are positive and indicate no serious safety concerns

N-6022 (N30 Pharmaceuticals) a small-molecule agent that inhibits S-nitrosoglutathione reductase (GSNOR) is in Phase IIa 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

NM-001 (Lynovex NovaBiotics) a biologically active oral antibacterialndashmucolytic peptide is in Phase IIa 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

OligoG (AlgiPharma) is currently being assessed in Phase IIb studies as a dry-powder formulation Derived from Norwegian seaweed the alginate oligomer works by

chelating the calcium that is found in the mucus of individuals with CF and which in part accounts for the mucus hyperviscosity

Three anti-inflammatory agents are currently in Phase II 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 A Phase II trial has been completed in the United States

KB001-A (KaloBios PharmaceuticalsCFF) is a humanized monoclonal antigen-binding (Fab) fragment that targets a P aeruginosa virulence factor (the Type III secretion system of the bacteria) A Phase II trial began enrolment in late 2012 with a primary end point focused on inflammation And sildenafil (Revatio CFF) a phosphodiesterase inhibitor has completed a Phase II study the results are pending

Three inhaled anti-infectives are also in late-stage development Levofloxacin (Aeroquin Aptalis PharmaCFF) has completed Phase III trials in patients with CF A Phase IIb trial of the drug demonstrated reduction of P aeruginosa in the sputum and improvements in lung function Arikace (InsmedCFF) a liposomal formulation of the antibiotic amikacin has successfully completed a Phase III trial in Europe and Canada in individuals with CF who had been colonized with P aeruginosa A Phase III trial of the drug for the treatment of nontuberculous mycobacteria is currently underway in the United States And a Phase II trial of AeroVanc (Savara PharmaceuticalsCFF) an inhaled dry-powder form of vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) airway infection in individuals with CF is currently enrolling

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

Market indicatorsThe current CF drug market is worth ~$16 billion (FIG 1) (IMS Health IMS Midas 2014) It has more than doubled in the past 4 years with a compound annual growth rate (CAGR) of 237 Anti-infectives dominate the CF market with sales of tobramycin (Tobi Novartis) estimated at $445 million over the 12 months to Q1 2014 accounting for 711 of sales in this class Mucolytics with dornase alfa being the only approved

drug in this class generated $530 million during the same time PERT sales were led by pancrelipase (Creon AbbVie) with sales of $260 million and the CFTR modulator ivacaftor achieved $168 million The United States remains the dominant national market for CF therapies accounting for 741 of the total sales

The CF drug market is projected to reach $39 billion by 2019 (CAGR 195 2014ndash2019) 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 40 years

Basharut A Syed PhD and Bashar Hamad PhD are at IMS Health Ltd 210 Pentonville Road

London N1 9JY UKe-mails bsyedukimshealthcom

bhamadukimshealthcom

doi101038nrd4434

Competing interests statements The authors declare no competing interests

FURTHER INFORMATIONIMS Health httpwwwimshealthcom

ALL LINKS ARE ACTIVE IN THE ONLINE PDF

Figure 1 | Global sales of cystic fibrosis drugs Sales in US$ over the 12 months to Q1 2014 CFTR cystic fibrosis transmembrane conductance regulator PERT pancreatic enzyme replacement therapy


722 | OCTOBER 2014 | VOLUME 13 wwwnaturecomreviewsdrugdisc


Nature Reviews | Drug Discovery

Mucolytics

Anti-infectivesCFTR modulators

PERT

Total$16

billion

$168million

$626million

$530million

$288million


More recently an inhaled dry-powder form of mannitol (Bronchitol Pharmaxis) mdash an osmotic agent thought to help rehydrate CF secretions mdash became available in certain markets (TABLE 1) as an add-on therapy to the best standard of care

Emerging therapiesA number of promising CF products with different modes of action are in development (TABLE 1) One of the most advanced is ataluren (Translarna PTC Therapeutics) a small-molecule agent that putatively makes ribosomes less sensitive to stop-codons Phase III clinical trials are currently in progress in Europe and in the United States In May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use at the European Medicines Agency

Vertex Pharmaceuticals in collaboration with the CFF is developing lumacaftor (also known as VX-809 now in Phase III) and VX-661 (in Phase II) both alone and in combination with ivacaftor for the ΔPhe508 CFTR mutation Two Phase III trials (lsquoTRAFFICrsquo and lsquoTRANSPORTrsquo) of lumacaftor in combination with ivacaftor reported positive data Vertex plans to file for FDA approval by the end of 2014

In March 2012 the UK Cystic Fibrosis Gene Therapy Consortium initiated a Phase II trial of a gene therapy (GL67ApGM169) The product which is delivered via an aerosol device is a combination of a cationic liposome (GL67A) and plasmid DNA encoding CFTR (pGM169) The results so far are positive and indicate no serious safety concerns

N-6022 (N30 Pharmaceuticals) a small-molecule agent that inhibits S-nitrosoglutathione reductase (GSNOR) is in Phase IIa 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

NM-001 (Lynovex NovaBiotics) a biologically active oral antibacterialndashmucolytic peptide is in Phase IIa 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

OligoG (AlgiPharma) is currently being assessed in Phase IIb studies as a dry-powder formulation Derived from Norwegian seaweed the alginate oligomer works by

chelating the calcium that is found in the mucus of individuals with CF and which in part accounts for the mucus hyperviscosity

Three anti-inflammatory agents are currently in Phase II 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 A Phase II trial has been completed in the United States

KB001-A (KaloBios PharmaceuticalsCFF) is a humanized monoclonal antigen-binding (Fab) fragment that targets a P aeruginosa virulence factor (the Type III secretion system of the bacteria) A Phase II trial began enrolment in late 2012 with a primary end point focused on inflammation And sildenafil (Revatio CFF) a phosphodiesterase inhibitor has completed a Phase II study the results are pending

Three inhaled anti-infectives are also in late-stage development Levofloxacin (Aeroquin Aptalis PharmaCFF) has completed Phase III trials in patients with CF A Phase IIb trial of the drug demonstrated reduction of P aeruginosa in the sputum and improvements in lung function Arikace (InsmedCFF) a liposomal formulation of the antibiotic amikacin has successfully completed a Phase III trial in Europe and Canada in individuals with CF who had been colonized with P aeruginosa A Phase III trial of the drug for the treatment of nontuberculous mycobacteria is currently underway in the United States And a Phase II trial of AeroVanc (Savara PharmaceuticalsCFF) an inhaled dry-powder form of vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) airway infection in individuals with CF is currently enrolling

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

Market indicatorsThe current CF drug market is worth ~$16 billion (FIG 1) (IMS Health IMS Midas 2014) It has more than doubled in the past 4 years with a compound annual growth rate (CAGR) of 237 Anti-infectives dominate the CF market with sales of tobramycin (Tobi Novartis) estimated at $445 million over the 12 months to Q1 2014 accounting for 711 of sales in this class Mucolytics with dornase alfa being the only approved

drug in this class generated $530 million during the same time PERT sales were led by pancrelipase (Creon AbbVie) with sales of $260 million and the CFTR modulator ivacaftor achieved $168 million The United States remains the dominant national market for CF therapies accounting for 741 of the total sales

The CF drug market is projected to reach $39 billion by 2019 (CAGR 195 2014ndash2019) 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 40 years

Basharut A Syed PhD and Bashar Hamad PhD are at IMS Health Ltd 210 Pentonville Road

London N1 9JY UKe-mails bsyedukimshealthcom

bhamadukimshealthcom

doi101038nrd4434

Competing interests statements The authors declare no competing interests

FURTHER INFORMATIONIMS Health httpwwwimshealthcom

ALL LINKS ARE ACTIVE IN THE ONLINE PDF

Figure 1 | Global sales of cystic fibrosis drugs Sales in US$ over the 12 months to Q1 2014 CFTR cystic fibrosis transmembrane conductance regulator PERT pancreatic enzyme replacement therapy


722 | OCTOBER 2014 | VOLUME 13 wwwnaturecomreviewsdrugdisc
