Available drugs – Progress 2016

Anti-Infectives

SHOW MORE

ATP12A RX

Company: Research

Reducing the acidity in airways helps fighting infections

Pre-clinical

Genotype

All


Comment

New research from the University of Iowa answers a question that has vexed cystic fibrosis (CF) researchers for almost 25 years: Why don’t mice with CF gene mutations develop the life-threatening lung disease that affects most people with CF?

Michael Welsh, MD,
Michael Welsh

The research team, led by Michael Welsh, discovered an answer to this long-standing scientific puzzle, and in doing so, identified a proton pump that could be a target for new CF therapies. They published their results Jan. 29 in the journal Science.

“Since the first CF mouse was reported in 1992, I have been asked hundreds of times, ‘Why don’t CF mice have respiratory host-defense defects and develop lung infections?’” says Welsh, who is a professor of internal medicine, molecular physiology, and biophysics; a Howard Hughes Medical Institute Investigator; and director of the Pappajohn Biomedical Institute at the UI.

In answering this question, Viral Shah, first author on the study and a student in the Medical Scientist Training Program at the UI Carver College of Medicine, homed in on the thin layer of liquid that covers the mice’s airways, i.e., the tracheal and bronchial passages. Shah and his colleagues studied the liquid’s acidity, the importance of which was revealed in earlier UI studies using pigs with CF. That work showed that the CF pigs had an abnormally acidic airway liquid, and that increased acidity impaired the ability of their airways to fight off infection.

bacteria (Pseudomonas aeruginosa) on the surface of a CF-affect airway.
Bacteria (Pseudomonas aeruginosa) are shown on the surface of a CF-affected airway. Image courtesy of Viral Shah.

Shah explains that, normally, two opposing processes control airway acidity. The cystic fibrosis transmembrane conductance regulator (CFTR) channel secretes bicarbonate, a base. That process is countered by the secretion of protons—an acid. The balance tightly controls the acidity of liquid in the airways.

In people, pigs, and mice with CF, the CFTR channel is lost, stopping the flow of bicarbonate into the airways. When that happens in people and pigs, their airway liquid becomes more acidic, reducing their ability to fight infection. But in mice, the airway liquid does not become more acidic, and they are not prone to infection. That fact led the scientists to ask what secretes acid into the airways of people and pigs that is missing in the mice. They discovered that a proton pump called ATP12A is responsible.

Viral Shah, University of Iowa MSTP student
Viral Shah

Shah and his colleagues made the discovery by comparing airway tissue from humans, pigs, and mice. The scientists showed that blocking ATP12A in airway tissue from pigs and humans with CF reduces the acidity of their airway liquid and restores their airways’ defenses against infection. Conversely, putting the ATP12A proton pump into the airways of CF mice increases the acidity of the liquid and predisposes the CF mice to bacterial infections.

“This discovery helps us understand the cause of lung disease in people with CF. It may also identify ATP12A as a new therapeutic target,” Shah says. “We wonder if blocking ATP12A in people with CF could halt the progression of lung disease.”

Shah adds that targeting ATP12A could potentially be helpful for all forms of CF, regardless of a patient’s CFTR mutation, because ATP12A is independent of CFTR.

The CF pig model was developed in 2008 by Welsh and his research team at the UI, with colleagues from the University of Missouri. The CF pig closely mimics human CF disease, including the lung problems absent from CF mice, and has proven very useful in advancing our understanding of CF lung problems.

In addition to Shah and Welsh, the research team on the Science study included David Meyerholz, Xiao-Xiao Tang, Leah Reznikov, Mahmoud Abou Alaiwa, Sarah Ernst, Philip Karp, Christine Wohlford-Lenane, Kristopher Heilmann, Mariah Leidinger, Patrick Allen, Joseph Zabner, Paul McCray, Lynda Ostedgaard, David Stoltz, and Christoph Randak.

The research was funded in part by grants from the National Institutes of Health, the Cystic Fibrosis Foundation, and the Roy J. Carver Charitable Trust.


Administration

Not known


Science and clinical information

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390761/

 


Worth reading

Jane O`Briens private trial, inhaling bicarb soda

 

SHOW MORE

QUINSAIR (MP-376)

Company: Raptor Pharmaceuticals

MP-376 is an inhaled formulation of levofloxacin, a fluoroquinolone antibiotic.

To patients

Genotype

P. aeruginosa


Comment

QUINSAIR is an inhaled formulation of levofloxacin, a fluoroquinolone antibiotic, for the management of chronic pulmonary infections caused by P. aeruginosa in adult patients with cystic fibrosis. The fluoroquinolones rapidly inhibit replication and transcription of bacterial DNA, which leads to bacterial cell death.8 Administration of MP-376 with a high-efficiency nebulizer allows for the delivery of high concentrations of active drug directly to the site of infection in approximately five minutes

 

QUINSAIR is contraindicated in patients with hypersensitivity to levofloxacin, a history of tendon disorders related to fluoroquinolones, epilepsy, or who may be pregnant or breast feeding. The safety profile of QUINSAIR has been evaluated in two double-blind, placebo-controlled studies and in an active comparator study in which the most frequently reported adverse reactions were cough/productive cough, dysgeusia, and fatigue/asthenia.


Website

http://www.raptorpharma.com


Administration

Inhalation


Science and clinical information

A study that compared levoflaxacin versus tobramycin showed that treatment led to less incident of exacerbations compared to those taking tobramycin


SHOW MORE

Lynovex® (NM001 cysteamine)

Company: NovaBiotics

Lynovex kills Gram-negative and -positive respiratory bacteria and disrupts formation of biofilms while disrupting mucus more effective than current mucoactive agents

Phase 2

Genotype

All


Comment

NM001 (Lynovex®) has a unique, dual antibacterial-mucoactive mode of action which aggressively tackles both of the major clinical features responsible for progressive lung deterioration in cystic fibrosis.

NM001 not only kills Gram-negative and Gram-positive respiratory bacteria (including Pseudomonas aeruginosa and Burkholderia cepacia) but prevents and disrupts formation of the slimy biofilms which these pathogens create in order to establish long-term, antibiotic insensitive infections/colonies in the cystic fibrosis lung environment. Experiments with sputum from cystic fibrosis patients have demonstrated NM001 is active against the panel of multi-drug resistant cystic fibrosis pathogens within the complex and challenging matrix of cystic fibrosis sputum and that NM001 reverses resistance/insensitivity to antibiotics in these microbes.

NM001 (Lynovex®) is also mucolytic; acting to disrupt the mucus in cystic fibrosis patients’ airways. In vitro and ex vivo tests have shown NM001 to be more effective than currently available mucoactive agents.


Website

http://www.novabiotics.co.uk


Administration

dry powder inhalation


Science and clinical information

http://www.novabiotics.co.uk/blog/2015/08/lynovex-activity-in-cf-sputum-against-the-emerging-cf-pathogen-mycobacterium-abscessus

 

 

 

 


Worth reading

SHOW MORE

Mul-1867

Company: TGV-inhalonix

Mul-1867 is being developed against multidrug-resistant bacteria and fungi. Initial testing indicates Mul-1867 to be a significant breakthrough in the war on lung infections in patients with cystic fibrosis.

Pre-clinical

Genotype

All


Comment

Mul-1867 is a promising antimicrobial for the treatment and prevention of several pathogens, including P.aeruginosa, S. aureus & B. cepacia. First pre-clinical test show promising results compared to available drugs.


Website

http://tgv-inhalonix.com


Administration

Inhalation


Science and clinical information

Mul-1867 Novel Drug Candidate Shows Significant Promises Against Rare Pathogens that Cause Life-Threatening Lung Infections In Cystic Fibrosis Patients


Worth reading

SHOW MORE

AeroVanc

Company: Savara Pharma

AeroVanc™ is a inhaled version of Vancomycin for battling MRSA

Phase 2

Comment

AeroVanc™ (vancomycin hydrochloride inhalation powder) is a proprietary inhaled dry powder form of vancomycin in a capsule-based device designed for convenient self-administration. Vancomycin, administered by injection into a vein (also called intravenous or IV administration), is the antibiotic of choice for MRSA-related bronchopneumonia, however, the inconvenience of IV administration, poor penetration into the lungs and systemic toxicities limit its use in a chronic setting. By delivering vancomycin directly to the site of infection in the lungs, the hope is that AeroVanc will improve clinical efficacy and reduce adverse effects due to systemic drug exposure. AeroVanc has been granted orphan drug status (link) by the U.S. Food and Drug Administration (FDA).


Website

http://www.savarapharma.com


Administration

Inhalation


Science and clinical information

Savara Pharmaceuticals Completes $20 Million Round of Financing – Savara Pharmaceuticals


SHOW MORE

POL7080

Company: Polyphor

POL7080 is a Pseudomonas specific antibiotic with a novel mode of action

Phase 1

Comment

POL7080 is a Pseudomonas specific antibiotic with a novel mode of action. Pseudomonas aeruginosa is a bacterium commonly found in the environment which can give rise to serious, life-threatening infections in humans and animals. Pseudomonas aeruginosa is regarded as an opportunistic pathogen and serious infections in various types of tissue develop in patients with compromised or reduced immune system, e.g. in case of AIDS or cancer treatment.

The Infectious Diseases Society of America (IDSA) listed Pseudomonas aeruginosa as one of the six most dangerous drug-resistant microbes. Pseudomonas like other Gram-negative bacteria is difficult to treat with existing antibiotics and many bacteria develop resistance after unsuccessful treatment. Thus, therapy of Pseudomonas infections is increasingly difficult.

POL7080 is the first of a new class of antibiotics derived from the PEM Technology platform. In preclinical studies the compound was highly active on a broad panel of clinical isolates including multi-drug resistant Pseudomonas bacteria with outstanding in vivo efficacy in septicemia, lung and thigh infection models. Its novel mode of action has been published in Science (2010, 327, 1010-1013, DOI). Phase I clinical trial in healthy volunteers in Europe was successfully completed demonstrating the clinical safety and tolerability of POL7080. All primary study objectives were achieved in this Phase I trial.


Website

http://www.polyphor.com


SHOW MORE

SNSP113

Company: Synspira

A therapy that could revolutionize the battle against antibiotic-resistant lung infections  eliminated resistant Staphylococcus aureus in a lab, a study reports.

Phase 1

Comment

A new treatment to alter the progression of CF

Synspira is developing proprietary modified polysaccharide molecules that facilitate mucus expectoration and biofilm disruption, thereby rendering otherwise protected bacteria susceptible to antibiotics. Synspira’s lead molecule, SNSP113, seeks to treat pulmonary exacerbations in cystic fibrosis by controlling infection and inflammation. SNSP113 reduces mucus adhesion and viscosity, breaking up bacterial biofilms, and potentiating antibiotic activity, improving lung function.

How SNSP113 works at the lung surface

On the lung’s surface, mucus is moved up and out of the airways by structures known as cilia to keep inhaled bacteria and harmful substances from remaining in the respiratory system. In cystic fibrosis (CF), the mucus is thick and viscous, preventing free movement of the cilia and allowing bacterial colonies to form biofilms. Inhaled SNSP113 interacts with native glycoproteins in mucus and polysaccharides in bacterial biofilms to loosen the mucus and disrupt the biofilms. In doing so, SNSP113 allows normal clearance to occur and exposes bacteria previously protected by biofilms and mucus, making them more susceptible to antibiotics.


Website

http://www.synspira.com


Science and clinical information


Anti-Inflammatory

SHOW MORE

Acebilustat (CTX-4430)

Company: Celtaxsys

blocks Leukotriene B4 (LTB4) and thereby reduces inflammation

Phase 2

Genotype

All


Comment

Acebilustat is a small-molecule drug that works by blocking production of an inflammatory biochemical called Leukotriene B4 (LTB4).

From Cystic Fibrosis News today:

Acebilustat is administered as a daily-oral dose of 50 mg and 100 mg for a period of over 48 weeks and compared to placebo control group. The drug acts by blocking the production of an inflammatory factor — the Leukotriene B4 (LTB4) — that activates inflammatory responses in a group of immune cells called white blood cells (or leukocytes), including neutrophilsmacrophages and monocytes. LTB4 also serves as potent attractant signal to recruit inflammatory cells.

A particularly important point in the design of the small-molecule acebilustat is that it was engineered to specifically target the enzyme LTA4H (short for leukotriene A4 hydrolase), a crucial player in the synthesis of LTB4. Therefore, acebilustat has a specific action and does not affect other cells in the body or related enzymes.

Acebilustat received orphan drug status for the treatment of CF in the US and the EU. In previous clinical trials, acebilustat reduced inflammatory responses in CF patients — researchers discovered a 65% reduction on neutrophils burden in patients’ lungs and in neutrophil-related damages to lung tissue. Results were obtained with only two weeks of treatment. Of note, acebilustat efficacy is independent on the type of mutations CF patients carry in their Cftr gene and can be administered on top of other therapies, including Kalydeco and Orkambi.


Website

http://www.celtaxsys.com


SHOW MORE

Resunab

Company: Corbus Pharmaceuticals

Resunab is designed to turn inflammation off by activation the CB2 receptor

Phase 2

Genotype

All


Comment

Resunab is designed to trigger the resolution of chronic inflammation by binding to and activating the CB2 receptor on immune cells (in effect, turning inflammation “off”).

 

Airway inflammation begins early in the disease course, with increased neutrophil infiltration present in infants as young as 4 weeks of age. The inflammatory process persists throughout the patient’s life, gradually leading to bronchiectasis, irreversibly damages the airways, and progressive decline in lung function. Pulmonary disease accounts for most of the morbidity and mortality in patients with cystic fibrosis although other organs, such as the pancreas and liver, are also affected by inflammatory damage in cystic fibrosis.

The importance of inflammation (both underlying and infection-derived) is universally accepted as contributing to the disease progression, but current anti-inflammatory treatments present a paradox: while treatment with systemic steroids and high doses of ibuprofen (a common NSAID) are effective at improving the symptoms of the disease, the side effects associated with these drugs are severe, and as a result, are infrequently used.

There is a strong consensus that a safe, effective chronic anti-inflammatory therapy will be of tremendous value to patients potentially impacting the quality of their lives as well as extending it.

 

Resunab™ is a first in class, synthetic oral endocannabinoid-mimetic drug that preferentially binds to the CB2 receptor expressed on activated immune cells and fibroblasts. CB2 activation triggers endogenous pathways that resolve inflammation and halt fibrosis. Resunab has the potential to be a safe and potent anti-inflammatory drug with a unique mechanism of action to treat a range of chronic inflammatory diseases.

 

SS 2016-01-18 kl. 22.37.55 SS 2016-01-18 kl. 22.38.12 SS 2016-01-18 kl. 22.37.47

*Bacterial CFU (colony-forming unit –CFU) is a measure of viable bacterial or fungal cells.CFU measures only viable cells. For convenience the results are given as CFU/mL (colony-forming units per milliliter) for liquids, and CFU/g (colony-forming units per gram) for solids.


Website

http://www.corbuspharma.com


Administration

Oral daily dosage


Science and clinical information

Phase 2 running and data readout Q4 2016
Next study Q3 2017
NDA 2021

Pre-clinical and Phase 1 clinical studies (123 subjects) have shown Resunab to have a favorable safety, tolerability and pharmacokinetic profile. It has also demonstrated promising potency in pre-clinical models of inflammation and fibrosis. Resunab triggers the production of “Specialized Pro-resolving Lipid Mediators” (SPMs) that activate an endogenous cascade responsible for the resolution of inflammation and fibrosis, while reducing production of pro-inflammatory eicosanoids and cytokines. Resunab has direct effects on fibroblasts to halt tissue scarring. In effect, Resunab triggers endogenous pathways to turn “off” chronic inflammation and fibrotic processes, without causing immunosuppression.

Resunab has demonstrated promising efficacy data in several pre-clinical models including ones specific to cystic fibrosis and scleroderma. Patient ex-vivo data showed similar promise.

Resunab is currently being evaluated in three separate Phase 2 clinical trials for the treatment of cystic fibrosis, diffuse cutaneous systemic sclerosis and dermatomyositis. To learn more about Corbus’ ongoing clinical trials, please click on one of the below links or visit clinicaltrials.gov.


Worth reading

Latest investor information ( January 2016)

http://content.stockpr.com/corbuspharma/db/184/1394/pdf/Corbus+Investor+Presentation+Jan+2016+.pdf

SHOW MORE

LAU-7b

Company: Laurent pharma

LAU-7b has been shown to correct the lipid imbalance resulting in reduced lung inflammation and a considerable decrease in the severity of pulmonary infections with Pseudomonas aeruginosa

Phase 1

Comment

LAU-7b is a reformulation of fenretinide, a semi-synthetic retinoid derivative. LAU-7b is administrated orally and is under clinical development for the treatment of cystic fibrosis (CF) as a potential disease-modifier addressing the immuno-inflammatory pathway. Oral administration of fenretinide was shown to correct the lipid imbalance in lungs and plasma of specific animal models of CF, resulting in reduced lung inflammation and dramatic decrease in the severity of pulmonary infections with Pseudomonas aeruginosa, a bacterium involved in perpetuating the inflammation-infection vicious cycle in CF. Patients with CF have an innate imbalance of essential fatty acids with increased arachidonic acid (AA) levels and decreased docosahexanoic acid (DHA) levels. An increasing amount of evidence suggests that this lipid imbalance is a very early effect in CF associated with the mutations in the CFTR gene and playing a major role in the infection-inflammation vicious cycle that leads to respiratory failure.

Fenretinide, an orally-available semi-synthetic retinoid, is an investigational drug candidate that was explored extensively for its potential therapeutic use in various indications including cancer, obesity, type 2 diabetes, rheumatoid arthritis, dry age-related macular degeneration, and more recently cystic fibrosis. Fenretinide was never commercialized.

Although the complete mechanism of action in CF is not yet elucidated, it is proposed that fenretinide corrects the AA/DHA imbalance and inhibits macrophage inflammatory mediators via the extracellular signal-regulated kinase (ERK) pathway. Fenretinide was also shown to inhibit the activation of the pro-inflammatory transcriptional nuclear factor (NF)-kappaB, as well as inhibit the downregulation of peroxisome proliferator-activated receptor gamma (PPARγ). The proinflammatory response and altered fatty acid metabolism in CF are linked to decreased expression of PPARγ in epithelial cells and PPARα in macrophages.

The innate lipid imbalance, known for decades as one of the hallmarks of CF, is emerging as a new target with the potential to address the link between the genetic defect and the altered immuno-inflammatory response, which remains an enigmatic pathogenic pathway in CF. The observed fatty acid abnormalities could play a major role in the initiation, maintenance and degree of progression of the infection-inflammation vicious cycle. Thus, the concept of modulating lipids in CF is an innovative therapeutic approach that can complement current therapies and has the potential to improve CF patients’ immuno-inflammatory response.


Website

http://www.laurentpharma.com/


Administration

Oral


Science and clinical information


SHOW MORE

PB01 - recombinant human follistatin

Company: Paranta

Follistatin modulates inflammatory processes and prevents accompanying fibrosis.

Phase 1

Comment

One of the advantages of follistatin as a therapeutic for inflammatory and fibrotic disorders is that it is a naturally occurring glycoprotein expressed by many cells in the body. Its primary function is to bind to and neutralize activins. Activins are a critical component of the innate immune response and in the development of fibrosis. Numerous studies have shown activin levels increase in the serum and various tissues in acute and chronic inflammatory diseases. Activins are also known to stimulate fibrosis and tissue repair and also mediate the fibrotic actions of other key growth factors. Follistatin therefore offers great potential for modulating inflammatory processes and preventing or resolving accompanying fibrosis.

We have demonstrated excellent anti-inflammatory and antifibrotic properties of PB01 in preclinical studies. Importantly, in non-clinical safety studies we have also shown that PB01 is a very safe and well-tolerated compound possessing an exceptionally benign toxicological profile. Based on our preclinical efficacy and safety data, PB01 has the potential to be a major advance for the management and treatment of cystic fibrosis lung disease.”


Website

http://parantabio.com


Administration

Inhalation


Science and clinical information

Preclinical safety and toxicology studies supporting the Company’s Phase I clinical program were completed during the year. The studies were performed in Canada by a leading inhalation toxicology contract research organisation (CRO) in rats and cynomolgus monkeys. The studies were designed to satisfy international guidelines and conducted by the CRO in compliance to international regulatory standards and principles.

In all studies, inhaled PB01 was well tolerated in the two animal species tested with no adverse effects observed in either species at any of the dose levels evaluated. These results provide the Company with a high level of confidence that orally inhaled PB01 will be well tolerated and non- toxic in human subjects for the anticipated range of therapeutic doses over the intended period of drug exposure.

A first-in-human Phase I clinical study of inhaled PB01 therapeutic is planned to commence in September 2015 for completion in mid-2016. The study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orally inhaled PB01 administered to healthy, adult male subjects.

The trial will be undertaken in three stages; two in Australia and the third in the UK. All stages will be randomised, double blind, placebo-controlled studies.

Stage 1 will be a single ascending dose study evaluating four PB01 dose levels. Stage 2 will be a multiple ascending dose study evaluating up to three PB01 dose levels administered daily over 14 days. Stage 3 will be a single dose study incorporating an inhaled inflammatory challenge to induce mild lung inflammation in participants. The objective of this stage will be the evaluation of the biological effect of PB01 on biomarkers of lung inflammation and is therefore expected to provide an indication of efficacy.


SHOW MORE

PBI-4050

Company: PROMETIC

Phase 2

Comment

PBI-4050 is an orally active lead drug candidate with excellent safety and efficacy profiles confirmed in several in vivo experiments targeting fibrosis. Fibrosis is a very complex process by which continuing inflammation causes vital organs to lose their function as normal tissue is replaced by fibrotic scar tissue. The proof of concept data generated to date confirms our lead drug candidates’ anti-fibrotic activity in several key organs including the kidneys, the heart, the lungs and the liver.


Website

http://www.prometic.com


Science and clinical information

Info about the Phase 2

http://www.prometic.com/health-canada-authorizes-prometic-to-proceed-with-its-pbi-4050-clinical-trial-in-patients-with-cystic-fibrosis/


Worth reading

SHOW MORE

POL6014

Company: Polyphor

POL6014 is a inhaled elastase inhibitor

Phase 1

Comment

From Polyphors website

POL6014 is a novel, highly potent, selective and reversible inhibitor of human neutrophil elastase (hNE), a key target for the treatment of respiratory diseases like chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and alpha-1-antitrypsin deficiency (AATD).

The key elements in the assessment of POL6014 are:

  • Very potent on free and membrane bound hNE
  • Highly efficacious in animal models of respiratory diseases
  • Long and high exposure in lungs after inhalation while systemic exposure remains low
  • Excellent tolerability and safety
  • POL6014 can be formulated as an aerosol or dry powder formulation
  • Excellent IP protection
  • Significant market opportunities in orphan as well as non-orphan diseases

Cystic fibrosis (CF) is a lethal hereditary disease characterized by abnormal transport of Cl- and Na+ across the epithelium, leading to viscous secretions and neutrophil-dominated lung inflammation sustained by bacterial infections. Activated or necrotic neutrophils liberate proteases that cause damage to structural, cellular and soluble components of the pulmonary microenvironment. The progressive lung disease determines the morbidity and mortality of patients. Neutrophil elastase is the major protease released in the lung of CF patients and plays a major role in the disease process. POL6014 now offers the opportunity for a well controlled clinical study with a highly active and selective elastase inhibitor which can lead to an improved lung function.

Preclinical pharmacological studies have shown that POL6014 inhibits the aggressive, tissue degrading enzyme neutrophil elastase in a highly potent, selective and reversible manner. After local application to the lungs by inhalation POL6014 reaches high concentrations in the lung while the systemic exposure remains low, thus reducing the risk of side-effects. Exploratory toxicology studies suggest that POL6014 is well tolerated when chronically inhaled as an aerosol. POL6014 is in Phase I clinical development.


Website

http://www.polyphor.com


SHOW MORE

RPL554

Company: Verona Pharma

Inhaled dual inhibitor of PDE3 and PDE4

Phase 2

Comment

RPL554 is a dual inhibitor of the phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) enzymes. This dual inhibition enables it to combine bronchodilator and anti-inflammatory properties in one compound, differentiating it from existing drug classes used to treat COPD, including corticosteroids, beta2-agonists and anti-muscarinics.

RPL554 also activates the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which is beneficial in reducing mucous viscosity and improving mucociliary clearance, thereby potentially also making it an attractive therapy for the treatment of CF.

The three key activities of RPL554 in respiratory diseases

Previous attempts to develop PDE4 inhibitors for COPD, asthma and other indications have been limited by side effects, particularly those centered on the gastrointestinal system, such as nausea, vomiting and weight loss.  RPL554 is designed to maximize effectiveness and reduce adverse events by:

  • relying on a chemical structure that is distinct from other PDE4 inhibitors to avoid gastrointestinal and other side effects typically associated with PDE4 inhibition;
  • having high selectivity for PDE3 and PDE4 over other enzymes and receptors to minimize off-target effects;
  • enabling delivery directly to the lung by inhalation, thereby maximizing pulmonary exposure to RPL554 while minimizing systemic distribution and potential adverse events.

By acting as an inhaled, dual inhibitor of PDE3 and PDE4 and stimulating the CFTR, we believe that RPL554 has the potential to be a more effective and better tolerated treatment of COPD than existing standalone PDE4 inhibitors. We also believe these properties give RPL554 broad potential applicability in the treatment of other respiratory diseases, including CF.


Website

http://www.veronapharma.com


Science and clinical information


Mucus fix

SHOW MORE

Pulmozyme (dornase alfa)

Company: Genentech

Pulmozyme cuts apart extracellular DNA making the thick, sticky mucus that your lungs produce thin and loose.

To patients

Genotype

All


Comment

From pulmozyme.com

Consider Pulmozyme a standard part in the fight against CF

Pulmozyme is a commonly prescribed medicine that is unique in the way it works. Picture how a pair of scissors can be used to cut something into smaller pieces. Similarly, Pulmozyme cuts apart extracellular DNA by acting like an enzyme* naturally found in the lungs. By cutting this extracellular DNA, Pulmozyme helps make the thick, sticky mucus that your lungs produce thin and loose.

 


Website

http://www.pulmozyme.com


SHOW MORE

Bronchitol

Company: Pharmaxis

Bronchitol works by rehydrating the airway/lung surface and promoting a productive cough.

Phase 3

Genotype

All


Comment

Bronchitol is dry powder mannitol which is inhaled twice daily using a small handheld device. Bronchitol works by rehydrating the airway/lung surface and promoting a productive cough. Clinical trials have shown that Bronchitol helps to increase mucus clearance, and improve the lung function and the quality of life of people living with cystic fibrosis.


Website

www.pharmaxis.com.au


SHOW MORE

VX-371 (P-1037)

Company: Parion (Vertex)

The inhibition of ENaC with Parion compounds blocks the major pathway for mucus dehydration in the lungs, maintaining the viscosity (or stickiness) of mucus such that it can be cleared by the cilia.

Phase 2

Genotype

All


Comment

The drug functions as an epithelial sodium channel (ENaC) inhibitor which helps to hydrate the airways in patients better assisting the movement of mucous from the lungs.

Data from Vertex lates investor relation slides showing VX-371 results together with Orkambi

SS 2016-02-10 kl. 19.59.21


Website

http://www.parion.com


SHOW MORE

Spyryx SPX-101

Company: Spyryx Biosciences

Spyryx is advancing inhaled peptides specifically designed to degrade ENaC so that this absorption can be blocked to enable airway fluid volumes to go back to normal levels.

Phase 1

Genotype

All


Comment

Article from biocenturyBY EMILY CUKIER-MEISNER, SENIOR WRITER

Spyryx Biosciences Inc. is developing inhaled peptides for cystic brosis that inhibit the sodium channel responsible for regulating uid volume in the lungs. The peptides could o er a pan-genotypic treatment that is more e cacious than therapies targeting CFTR.

CF is caused by defects in the cystic brosis transmembrane conductance regulator (CFTR) channel that result in depletion of airway surface liquid and abnormally adherent mucus. Spyryx’s peptides target the epithelial sodium channel (ENaC), which conducts sodium and water away from the airway surface, and becomes hyperactive when CFTR is defective.

Scienti c founder Robert Tarran discovered how defects in CFTR lead to excessive ENaC activity. Namely, the inability of defective CFTR to conduct chloride and bicarbonate ions results in the airway surface uid becoming acidic. The acidity in turn causes a conformational change in SPLUNC1 (BPI fold containing family A member 1; BPIFA1; PLUNC; LUNX), a secreted protein that normally binds to and deactivates ENaC by causing its subunits to dissociate and internalize.

The conformational change in SPLUNC1 makes its ENaC binding domain inaccessible, which allows ENaC to be activated by proteases.

Spyryx is developing small peptides based on the SPLUNC1 ENaC binding domain to prevent ENaC activation.

“When you isolate the regulatory peptide from the rest of the protein, it maintains its binding a nity for ENaC, but it’s pH independent,” said CEO John Taylor.

In 2013, Tarran’s group at the University of North Carolina at Chapel Hill and researchers from the University of Lausanne reported in the American Journal of Physiology Lung Cellular and Molecular Physiology that an 18-amino-acid peptide derived from SPLUNC1 inhibited ENaC conductance in CF human bronchial epithelial cultures and produced a mean airway surface liquid depth of 7.9 μm, which is comparable to non-CF bronchial cultures. Untreated CF bronchial cultures had a mean airway surface liquid depth of 4.2 μm.

Taylor said Spyryx is optimizing versions of the peptide that contain about 12 amino acids.

Taylor said Spyryx has performed preliminary comparative testing that suggests the peptides could have greater e cacy than CFTR modulators, but also do not interfere with CFTR modulators’ activity. Thus, the peptides may complement CFTR modulators the same way CFTR and ENaC work together to regulate airway hydration in the normal lung.

Unlike mutation-speci c CFTR modulators, the peptides wouldn’t be restricted to speci c genotypes.

“Because we’re not working on the channel that’s mutated and are directly addressing airway uid regulation, our belief is that our therapy should have a universal e ect,” he said.

At least one other ENaC inhibitor is in the clinic for CF. P-1037 from Vertex Pharmaceuticals Inc. and Parion Sciences Inc. is a small molecule in Phase IIa testing to treat CF regardless of genotype. Vertex and Parion declined to provide more information.

Taylor said small molecule inhibitors of ENaC risk causing diuresis and hyperkalemia if they enter circulation and reach ENaC in the kidney, which may be less likely with Spyryx’s peptides.

“It is our belief that they are not crossing into the bloodstream in a material way, and what does is rapidly cleaved and cleared from circulation,” he said.

He said Spyryx’s peptides also may have durable e ects because they both inhibit and degrade ENaC.

Spyryx also plans to research the peptides’ ability to treat chronic obstructive pulmonary disease (COPD). Taylor said Tarran and others have shown that cigarette smoke may cause a CF-like condition by interfering with CFTR on airway epithelial cells.

Spyryx has an exclusive worldwide license to IP from UNC-Chapel Hill covering composition of matter and methods of treatment using SPLUNC1 and its derivatives. The university holds equity in Spyryx and is eligible for milestones and royalties.

In May, Spyryx raised an $18 million series A round to advance at least one candidate into the clinic. Spyryx also received an award of an undisclosed amount from Cystic Fibrosis Foundation Therapeutics Inc. in June to support development of the peptides. A timeline for entering the clinic is not disclosed.


Website

http://www.spyryxbio.com


SHOW MORE

AIR DNase™(PRX-110)

Company: Protalix BioTherapeutics

In vitro studies of AIR DNase™ demonstrated improved enzyme kinetics, less sensitivity to inhibition by actin and improved ex vivo efficacy when compared to Pulmozyme®

Phase 2

Genotype

All


Comment

From Protalix Website

AIR DNase works by cleaving extracellular DNA and thinning the thick mucus that accumulates in CF patients’ lungs. We are very optimistic about the results thus far and are excited to proceed to the clinic. We believe that AIR DNase has the potential to address some of the significant unmet medical needs of the cystic fibrosis community,

Additionally, a rheology data analysis of human sputum samples shows lower stress reduction from control for AIR DNase compared to Pulmozyme. The mean viscosity reduction as a measure of activity on patients’ sputa by AIR DNase is 70% compared to 30% for Pulmozyme.


Website

http://www.protalix.com


Science and clinical information

PRX-110 Clinical Data

We have completed a phase I trial with 18 healthy volunteers. alidornase alfa (PRX-110) was found to be safe and tolerable.

In July 2016, the first patient was dosed in Protalix’s phase IIa clinical trial of alidornase alfa (PRX-110).  In January 2017, Protalix announced positive interim results from the phase II clinical trial for the first 13 CF patients enrolled in the study. At that time, 15 patients had been enrolled in, and were expected to complete, the study. The initial primary efficacy result shows that alidornase alfa (PRX-110) improves lung function as demonstrated by a mean absolute increase in the percent predicted forced expiratory volume in one second (ppFEV1) of 4.1 points from baseline. A commercially available small molecule CFTR modulator for the treatment of CF has reported a mean absolute increase in ppFEV1 of 2.5 from baseline in its registration clinical study. This score was achieved while 74% of the patients participating in the trial of the CFTR modulator were also treated with Pulmozyme® on top of the modulator. While this marketed CFTR addresses a certain mutation applicable to less than 50% of CF patients, alidornase alfa (PRX-110) is being developed to treat all CF patients.

Sputa available DNA samples were analyzed for approximately half of the patients. A mean reduction of approximately 60% in DNA content from baseline was observed, and a mean reduction of approximately 90% from baseline was observed for sputa visco-elasticity. This data provides further supportive evidence of improved lung function after treatment with alidornase alfa (PRX-110), as demonstrated by the increase in ppFEV1.

No serious adverse events were reported, and all adverse events that occurred during the study were mild and transient in nature.

The phase II trial is a 28-day switch-over study of 15 CF patients previously treated with Pulmozyme® to evaluate the efficacy and safety of alidornase alfa (PRX-110) in CF patients. Participation in the trial is preceded by a two-week washout period from Pulmozyme® before treatment with PRX-110 via inhalation.   The main efficacy endpoint is the change of forced expiratory volume (FEV1) and forced vital capacity (FVC).  Additional endpoints include safety and tolerability, immunogenicity and pharmacokinetic data. In the trial, alidornase alfa (PRX-110) is administered through Philips Respironics’ I-neb AAD Inhaler System, for which Protalix has a supply agreement for the exclusive use of the device for the development of an inhaled product based on dornase alfa for the treatment of CF.  The I-neb AAD is a small, lightweight, virtually silent device that is fully portable and has a unique vibrating mesh technology that allows for faster administration than conventional jet or ultrasonic nebulizers.


SHOW MORE

SYGN 113

Company: Syndegen

SYGN113 works by thinning and clearing thick mucus from the lungs. It also breaks up bacteria biofilms and suppresses inflammation.

Pre-clinical

Genotype

All?


Comment

**How SYGN113 works at the lung mucosal surface

Cilia and mucus help keep bacteria and harmful substances from entering your lungs. In cystic fibrosis (CF), the mucus is thick and viscous, preventing free movement of the cilia, and allowing bacteria colonies to form biofilms and cause chronic inflammation. The modified polysaccharide drug SYGN113 interacts with the native glycoproteins in the mucus and polysaccharides in the biofilms to reduce mucus viscosity, break up biofilms, and provide an anti-inflammatory barrier to promote healing of the lung mucosal surface.

NORMAL LUNG SURFACE

CYSTIC FIBROSIS LUNG SURFACE

TREATED LUNG SURFACE

**From Synedgen.com website


Website

http://www.synedgen.com


Science and clinical information

Synedgen to Present New Treatment Options for CF complications at North American Cystic Fibrosis Conference – Synedgen

” Dr. Townsend’s work shows that a single 4-hour treatment with SYGN113 significantly reduced multiple strains of P. aeruginosa biofilms from the lung epithelial cell surface from 87-100%. Pretreatment of lung cells with SYGN113 resulted in 100 times less bacteria attached to the surface of the lung cells after 1-hour. Extending treatment over 5-hours caused an 82-98% reduction in biofilm formation on the lung epithelial cells.”


SHOW MORE

TheraduxTM

Company: OrPro

Treatment with nebulized Theradux, which relaxes abnormally stiffened mucus, is anticipated to help restore mucus transport and clearance in the majority of CF patients.

Pre-clinical

Comment

Treatment with nebulized Theradux, which relaxes abnormally stiffened mucus, is anticipated to help restore mucus transport and clearance in the majority of CF patients. Theradux is expected to work both alone and in concert with approved and in-development Cystic Fibrosis Transmembrane Regulator (CFTR) modifier therapies to further slow the progression to lung failure

 

 


Website

http://www.orprotherapeutics.c...


Administration

Inhalation


Science and clinical information

Pressrelease


RNA therapy

SHOW MORE

QR-010

Company: ProQR Therapeutics

The goal of QR-010 is to repair the underlying defect in the RNA and with that stop the progression of cystic fibrosis

Phase 1

Genotype

ΔF508


Comment

From proqr.com

QR-010 will be taken as a regularly inhaled therapy and is designed to work in a unique way. Unlike any other CF drug currently on the market it aims to repair the genetic defect in the RNA. The RNA is the “blueprint” for protein synthesis. By repairing this “blueprint” a normal healthy CFTR protein will be formed that is expected to have normal function. The goal of QR-010 is to repair the underlying defect in the RNA and with that stop the progression of cystic fibrosis.

ProQR is developing an investigational product for cystic fibrosis patients that suffer from the ΔF508 mutation, called QR-010. ΔF508 is the most common mutation in cystic fibrosis that affects more than 70% of all CF patients.

QR-010 will be taken as a regularly inhaled therapy and is designed to work in a unique way. Unlike any other CF drug currently on the market it aims to repair the genetic defect in the RNA. The RNA is the “blueprint” for protein synthesis. By repairing this “blueprint” a normal healthy CFTR protein will be formed that is expected to have normal function. The goal of QR-010 is to repair the underlying defect in the RNA and with that stop the progression of cystic fibrosis.


Website

http://www.proqr.com


Administration

Inhaled


Science and clinical information

Clinical trials

ProQR has started the first clinical trial of QR-010 in CF patients. The phase 1b clinical trial that started in June 2015 will assess the safety and tolerability of QR-010 in 64 patients that are homozygous for the ΔF508 mutation. In this study we will also look at some measures of efficacy that are commonly used to see if a medicine is beneficial in cystic fibrosis patients.

The second study is a nasal potential difference, or NPD, study in 16-32 patients that are either homozygous or compound heterozygous for the ΔF508 mutation. This study started in September 2015 and is a proof of principle study with the aim to evaluate the efficacy of QR-010, as we have successfully shown in similar pre-clinical studies.

For further details on these studies, please visit clinicaltrials.gov


Worth reading

Very nice Annual Report describing their work and ambition, worth reading!

ProQR-Annual-Report-2015+Magazine

SHOW MORE

RaNA mRNA (Shire)

Company: RaNA

Shire’s goal is to deliver mRNA that codes for a fully functional (wild type) version of the CFTR protein to the lungs of CF patients.

Pre-clinical

Comment

Messenger RNA (mRNA) is a natural material produced by living organisms to convey coded genetic information from a gene (DNA) to the ribosome, which translates the coded genetic information into protein. In many diseases, the underlying cause is the lack of sufficient levels of functional protein.

Shire is investigating therapies in its preclinical pipeline which would deliver mRNA to sites in the body where it can be used by the body’s own cellular mechanisms to produce normal working copies of the protein.

CFFT has committed to up to $15 million to support Shire’s mRNA technology platform for CF. In CF, mutations in the CFTR gene (Cystic Fibrosis Transmembrane Conductance Regulator) lead to a disruption of the normal regulation of fluids in the lung that cause the secretions to thicken, thereby restricting lung function and leading to recurrent lung infections.

Shire’s goal is to deliver mRNA that codes for a fully functional (wild type) version of the CFTR protein to the lungs of CF patients. If high enough levels of functional CFTR protein can be produced, lung function may be improved, thereby reducing the frequency and severity of infections.

Shire is also investigating other diseases that are caused by a lack of sufficient levels of a functional protein and where the Company may be able to leverage its mRNA Technology platform. Shire will highlight its mRNA platform at today’s R&D Day.


Website

http://ranarx.com


Science and clinical information


SHOW MORE

Moderna mRNA

Company: Moderna Therapeutics

Moderna’s pioneering mRNA Therapeutics™ are designed to trigger the cellular machinery to utilize their natural processes to produce functional proteins. mRNA Therapeutics may be developed to enable the delivery of correct genetic instructions into cells in the lungs, which may trigger the cells to produce functional CTFR protein. This mRNA-based approach could be applicable to any person with CF regardless of a person’s specific CFTR mutations.

Pre-clinical

Comment

mRNA is responsible for carrying genetic instructions transcribed from DNA, which cells then translate to produce proteins that, when defective or missing, can underlie certain diseases, including CF. Moderna’s pioneering mRNA Therapeutics™ are designed to trigger the cellular machinery to utilize their natural processes to produce specific functional proteins. Through this collaboration, mRNA Therapeutics may be developed to enable the delivery of correct genetic instructions into cells in the lungs, which may trigger the cells to produce functional CTFR protein. This mRNA-based approach could be applicable to any person with CF regardless of a person’s specific CFTR mutations. Moderna currently has two Phase 1 clinical studies underway of mRNA vaccines for the prevention of infectious diseases. The company has over 90 discovery programs advancing across its ecosystem of therapeutically focused ventures and external partners that span rare diseases, infectious diseases, cancer and cardiovascular disease, among others.


Website

http://www.modernatx.com


Science and clinical information


Gene therapy

SHOW MORE

GL67a/pGM169 Wave 1 Gene Therapy (liposome)

Company: The UK Cystic Fibrosis Gene Therapy Consortium

The first trial of gene therapy in humans using liposome carrier

Phase 1

Genotype

All


Comment

One hundred and thirty six patients aged 12 and above were randomly assigned to either 5ml of nebulised pGM169/GL67A (gene therapy) or saline (placebo) at monthly intervals over 1 year. Lung function was evaluated using a common clinical measure FEV1.

The clinical trial reached its primary endpoint with patients who received therapy having a significant, if modest benefit in lung function compared with those receiving a placebo. After a year of treatment, in the 62 patients who received the gene therapy, FEV1 was 3.7% greater compared to placebo.

The trial is the first ever to show that repeated doses of a gene therapy can have a meaningful effect on the disease and change the lung function of patients.


Science and clinical information

Hoppfully going into next step in the end of 2016


SHOW MORE

Wave 2 Gene Therapy (Lentivirus)

Company: The UK Cystic Fibrosis Gene Therapy Consortium

The Wave 2 product (CF gene delivered by a virus) that the Consortium has developed is now progressing rapidly

Pre-clinical

Genotype

All


Comment

The Wave 2 product (CF gene delivered by a lentivirus) that the Consortium has developed in parallel with Wave 1 over the last decade is now progressing rapidly.

“We have chosen the final form of the virus that we will take into CF patients, have learnt how to make the quantities that will be needed for the first clinical trial, and have undertaken preliminary safety studies which have not shown any unexpected problems. ”

First CF patient treated 2016/2017 according to latest video!


Website

http://www.cfgenetherapy.org.u...


SHOW MORE

CRISPR-Cas9 for CF

Company: Vertex and CRISPR Therapeutics

Cas9 is a CRISPR-associated endonuclease (an enzyme) known to act as the "molecular scissors" that cut and edit, or correct, disease-associated DNA in a cell

Pre-clinical

Genotype

All?


Comment

From : http://investors.vrtx.com/releasedetail.cfm?ReleaseID=938302

Vertex Pharmaceuticals Incorporated  and CRISPR Therapeutics today announced that the two companies have entered into a strategic research collaboration focused on the use of CRISPR’s gene editing technology, known as CRISPR-Cas9, to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. The collaboration will evaluate the use of CRISPR-Cas9 across multiple diseases where targets have been validated through human genetics. Vertex and CRISPR will focus their initial gene editing research on discovering treatments to address the mutations and genes known to cause and contribute to cystic fibrosis and sickle cell disease. Vertex and CRISPR will also evaluate a specified number of other genetic targets as part of the collaboration.

“CRISPR-Cas9 is an important scientific and technological breakthrough that holds significant promise for the future discovery of potentially transformative treatments for many genetic diseases,” said David Altshuler, M.D., Ph.D., Vertex’s Executive Vice President, Global Research and Chief Scientific Officer. “As a company founded on innovative science, we’re excited to begin this collaboration with CRISPR, as it puts us at the forefront of what we believe may be a fundamental change in the future treatment of disease — using gene editing technologies to address the underlying genetic causes of many diseases.”

“Vertex has a track record of developing innovative medicines for cystic fibrosis and other serious diseases, making them a great partner to accelerate the therapeutic promise of gene editing,” said Rodger Novak, M.D., Chief Executive Officer of CRISPR Therapeutics. “For CRISPR, this collaboration validates the potential for gene editing in human therapeutics and provides important financial support for continued investment in our platform and proprietary pipeline of programs.”

About the Collaboration

Under the terms of the collaboration, Vertex and CRISPR will jointly use the CRISPR-Cas9 technology to discover and develop potential new treatments that correct defects in specific gene targets known to cause or contribute to particular diseases. The initial focus of the collaboration will be on the use of CRISPR-Cas9 to potentially correct the mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene known to result in the defective protein that causes CF and to edit other genes that contribute to the disease. Additionally, the companies will seek to discover and develop gene-based treatments for hemoglobinopathies, including sickle cell disease. Additional discovery efforts focused on a specified number of other genetic targets will also be conducted under the collaboration. Discovery activities will be conducted primarily by CRISPR, and the related expenses will be fully funded by Vertex. Vertex has the option to an exclusive license for up to six gene-based treatments that emerge from the four-year research collaboration. Vertex will fund 100 percent of the development expenses of licensed treatments. For each of the up to six treatments in-licensed for development, Vertex will pay future development, regulatory and sales milestones of up to $420 million as well as royalty payments on future sales.

Vertex and CRISPR will collaborate on the research, development and commercialization of treatments for hemoglobinopathies that emerge from the collaboration. Specifically for hemoglobinopathies, including treatments for sickle cell disease, Vertex and CRISPR will equally share all research and development costs and sales, with CRISPR Therapeutics leading commercialization efforts in the U.S. For all other diseases, Vertex will lead all development and global commercialization activities.

Vertex will pay CRISPR $75 million in cash as part of its up-front commitment. Vertex will also provide a $30 million investment in CRISPR, which is a private company. The investment will provide Vertex with an ownership stake in CRISPR. The collaboration also provides Vertex with an observer seat on the CRISPR Board of Directors, which will be filled by Dr. Altshuler.

About Gene Editing with CRISPR-Cas9

“CRISPR” refers to Clustered Regularly Interspaced Short Palindromic Repeats that occur in the genome of certain bacteria, from which the system was discovered. Cas9 is a CRISPR-associated endonuclease (an enzyme) known to act as the “molecular scissors” that cut and edit, or correct, disease-associated DNA in a cell. A guide RNA directs the Cas9 molecular scissors to the exact site of the disease-associated mutation. Once the molecular scissors make a cut in the DNA, additional cellular mechanisms and exogenously added DNA will use the cell’s own machinery and other elements to specifically ‘repair’ the DNA. This technology may offer the ability to directly modify or correct the underlying disease-associated changes in the human genome for the potential treatment of a large number of both rare and common diseases.

 


CFTR Modulation

SHOW MORE

Kalydeco (ivacaftor VX-770)

Company: Vertex

The first revolutionary potentiator

To patients

Genotype

G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H


Comment

Helping the “gates” open more often and thereby helps the CFTR proteins at the cell surface to work better.


Website

http://www.kalydeco.com/


Administration

Oral twice daily


SHOW MORE

Orkambi (ivacaftor + lumacaftor VX-809)

Company: Vertex

First combination (Ivacaftor + Lumacaftor) to adress Df508del

To patients

Genotype

DF508del


Comment

ORKAMBI is made up of lumacaftor and ivacaftor.

Lumacaftor helps to get more F508del-CFTR proteins to the cell surface

Ivacaftor helps the CFTR proteins at the cell surface work better


Website

http://www.orkambi.com


Administration

Oral


Worth reading

www.orkambi.com

SHOW MORE

VX-661 + Ivacaftor

Company: Vertex

An alternative to orkambi

Phase 3

Genotype

one F508del mutation


Comment

Same function as Orkambi but seems to be slightly more efficient and easier to onboard for patients.

Ongoing Phase3 trials will show if it will replace Orkambi


Website

www.vrtx.com


Administration

Oral


Science and clinical information

http://www.fibrosisquistica.org/images/recursos/216.PDF

 


SHOW MORE

Kalydeco + VX 661 + (VX-440/VX-152)

Company: Vertex

Vertex triple combination (potentiator + 2 correctors)

Phase 1

Genotype

DF508del or F508del + other


Comment

Vertex is taking the game to the next level with this one.  They are adding a third corrector to their corrector / potentiator setup to increase the effect.

Look att the latest information from Vertex here:

http://files.shareholder.com/downloads/VRTX/912986151x0x854043/F5774F2E-6D10-4223-A100-7C6AE3D4AEDA/NACF_Investor_Event_Slide_Deck.PDF

And have a look at these pictures. The first from 1,5 year ago where the second corrector dubbled the chloride transport efficiency In Vitro compared to Orkambi. From 25% to 45%. (Df508del)

The second picture are from the latest investor information. Where we can see the triple  combination rising it to 75!!!. I think the In Vitro results from the kalydeco was around 50. So this looks truly amazing for Df508 but also god result for other combinations. Worth noticing is also that they seem to be leaving ivacaftor (used in Orkambi) for the new VX-661. The trials will enter Phase 2 in second half of 2016

192870_orig

test


Website

www.vrtx.com


Administration

Oral


SHOW MORE

CTP-656

Company: Concert Pharmaceuticals

A enhanced Kalydeco

Phase 1

Genotype

class III (gating) mutations (e.g. G551D)


Comment

TP-656 is a novel potentiator that may enable once-daily dosing and was developed by applying deuterium chemistry to modify ivacaftor. Concert is initially developing CTP-656 as a potential treatment for cystic fibrosis as monotherapy in class III (gating) mutations (e.g. G551D) of the gene that encodes for cystic fibrosis transmembrane conductance regulator (CFTR), a protein which regulates components of sweat, mucus clearance and digestion. In a Phase 1 cross-over comparison of CTP-656 and Kalydeco, CTP-656 demonstrated a superior pharmacokinetic profile compared to Kalydeco including a reduced rate of clearance, longer half-life, substantially increased exposure and greater plasma levels at 24 hours. The Phase 1 multiple ascending dose study was initiated in the fourth quarter of 2015.


Website

http://www.concertpharma.com


Science and clinical information

Concert Pharmaceuticals Announces CTP-656 Solid Dose Phase 1 Results Confirmed Superior Pharmacokinetic Profile to Kalydeco®


SHOW MORE

N91115

Company: Nivalis (N30)

N91115 increases and prolongs CFTR activity when added to other CFTR modulators and decrease inflammation

Phase 2

Genotype

DF508del


Comment

N91115 works through a novel mechanism of action called GSNOR inhibition that is presumed to modulate the unstable and defective CFTR protein responsible for CF. GSNOR inhibition restores GSNO levels thereby modifying the chaperones responsible for CFTR protein degradation. This stabilizing effect increases and prolongs the function of the CFTR chloride channel and leads to an increase in net chloride secretion.


Website

http://www.nivalis.com


Science and clinical information

The Company recently initiated a Phase 2, 12-week, double-blind, randomized, placebo-controlled, parallel group study to investigate the efficacy and safety of N91115 in 135 adult patients with CF who are homozygous for the F508del-CFTRmutation and being treated with Orkambi™. Results of this study are planned to be reported in the second half of 2016

Nivalis Therapeutics has completed clinical studies with N91115, including a Phase 1a dose-escalation safety study in healthy volunteers, and a Phase 1b safety study in people with CF who have two copies of the F508del mutation. In preclinical studies, N91115 has been shown to increase the function of F508del-CFTR, the mutant protein that is estimated to be present in approximately 86 percent of people with CF in the United States and Europe.

 

Nivalis Therapeutics Announces FDA Fast Track Designation for N91115 in Patients With Cystic Fibrosis


SHOW MORE

Riociguat

Company: Bayern

riociguat will hopefully result in improved CFTR channel expression

Phase 2

Genotype

unknown


Comment

Riociguat is a novel therapy that stimulates sGC, an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). Preclinical data has shown evidence that riociguat can result in improved CFTR channel expression.


Administration

Oral


Science and clinical information

The phase 2 seems to be from 2014-2017 and not on fast track

Hard to find any information about this one


SHOW MORE

GLPG1837

Company: Galapagos (AbbVie)

Potentiator similar to kalydeco for class III mutations

Phase 2

Genotype

class III


Comment

GLPG1837 has completed a Phase 1 clinical trial, with good safety and tolerability in that study. Galapagos is preparing to initiate a Phase 2 study with GLPG1837 in Class III mutation patients by year end 2015.


Website

http://www.glpg.com


Administration

Oral


SHOW MORE

GLPG1837+ GLPG2222+ GLPG2665

Company: Galapagos (AbbVie)

Triple combination with very promising in Vitro results

Phase 1

Comment

GLPG1837 has completed a Phase 1 clinical trial, with good safety and tolerability in that study. Galapagos is preparing to initiate a Phase 2 study with GLPG1837 in Class III mutation patients by year end 2015.

Our first oral corrector candidate, GLPG2222, is anticipated to start a Phase 1 trial before the end of 2015.

We nominated a second corrector candidate in October 2015, GLPG2665, the first of a number of C2 correctors to work with our C1 corrector GLPG2222 and our potentiator GLPG1837 in a potential triple combination therapy. We aim to have CLPG2665 in a Phase 1 trial by mid-2016.

We consistently achieve healthy levels of activity in HBE delF508 (Class II) homozygous cells in vitro with this triple combination of compounds, and up to a 6-fold greater restoration of CFTR than Orkambi® in vitro. These results are suggestive of a compelling therapeutic option for these patients. We believe that our CF combination therapy addresses unmet need in both homozygous and heterozygous Class II patients. Our pre-clinical data also suggest activity of our CF drugs in combination with messenger ribonucleic acid, or mRNA, translation modulation drugs in the Class I mutation, the first indication of a broader spectrum of patients to be addressed with our robust CF program.


Website

http://www.glpg.com


Science and clinical information

Galapagos Reports Initiation Of Phase 1 Study With Corrector GLPG2222

Read more:  http://www.nasdaq.com/article/galapagos-reports-initiation-of-phase-1-study-with-corrector-glpg2222-20160119-00015#ixzz3xnMMivxV


SHOW MORE

QBW251

Company: Novartis

A potentiatior like kalydeco

Phase 2

Genotype

?


Comment

QBW251 is a type of CFTR Modulator called a “potentiator”, similar to the drug ivacaftor, this drug would help to facilitate the opening of the chloride channel on the cell surface. This compound is administered through an oral pill.


Website

https://www.novartis.com


SHOW MORE

PTI-428+PTI-P271+PTI-C1811

Company: Proteostasis Therapeutics

A triple combination of amplifier, potantiator and corrector

Pre-clinical

Genotype

several CFTR mutation classes


Comment

Proteostasis Therapeutics, Inc. (PTI) include the addition of a novel triple combination therapy of PTI’s own CFTR amplifiers, correctors and potentiators. PTI’s testing has shown that a triple combination comprising a proprietary corrector and potentiator, currently in late lead optimization stage, and one of PTI’s CFTR amplifiers, can restore the activity of mutant F508del CFTR protein to 80% of normal activity in Ussing chamber assays.

The components of the triple combination were developed internally using the Company’s proprietary Disease-Relevant Translation, or DRT™, platform. The screening assay was optimized to identify novel CFTR modulators that show functional synergy with the Company’s lead drug candidate, PTI-428, which belongs to a novel class of CFTR modulators the Company refers to as “amplifiers”, while restoring chloride currents above levels achieved by existing commercially available products. In Ussing chamber assays, one PTI potentiator, PTI-P271, has shown comparable efficacy with Vertex Pharmaceuticals’ (Vertex) potentiator, ivacaftor, and did not cause F508del CFTR protein destabilization under chronic administration conditions when combined with a PTI corrector. Also in Ussing chamber assays, one PTI corrector, PTI-C1811, has been shown to restore at least 140% of CFTR functional levels relative to Vertex’s corrector lumacaftor, which is currently marketed together with ivacaftor as Orkambi™.

Based on the data generated in the human bronchial epithelial (hBE) cells homozygous for the F508del mutation, the Company believes that the combined use of the three molecules has the potential to restore mutant CFTR function in CF patients homozygous for the F508del mutation to approximately 80% of normal activity. Further, PTI-C1811 and PTI-P271 combined have demonstrated higher levels of CFTR function in vitro than Orkambi™.

“The unique screening set-up allowed us to identify novel chemical moieties with corrector and potentiator properties that act synergistically with our CFTR amplifiers across several CFTR mutation classes,” said Meenu Chhabra, President and Chief Executive Officer of PTI. “We are very pleased with the rapid advancement of all of our CF programs, and are confident that we will continue to build on our promising amplifier program to expand the range of treatment options for most CF patients.”

PTI is advancing its CFTR amplifier PTI-428 as its lead clinical development candidate for the treatment of CF and expects to file an IND with the FDA by the end of 2015. The PTI correctors and potentiators are expected to enter clinical development by the middle of 2017.

 

PTI-428 Amplifier
PTI-C1811 corrector (lumacaftor)
PTI-P271 potentiator (ivacaftor – kalydeco)


Website

http://www.proteostasis.com


Science and clinical information

Proteostasis Therapeutics presented the following two posters at the European Cystic Fibrosis Society (ECFS) Basic Science Conference – April 2016
Looks like their Amplifier can give a real boost to current and coming modulators

NACFC_poster_correctors_FINAL

NACFC_poster_amplifiers_FINAL

SS 2016-04-02 kl. 20.30.57

 

 


SHOW MORE

Genzyme CFX*

Company: Genzyme

F508del

Pre-clinical

Comment


The CFF and Genzyme have been working together since 2011, when the two entities established a collaborative research program, which has already resulted in the study of numerous chemical compounds able to address abnormalities in the CFTR protein with the F508del mutation, as well as assist in the relocation of the defective protein for it to move into the cell’s surface.


Science and clinical information

CFF founding

2011 press release

 


SHOW MORE

Vanda X

Company: VANDA Pharmaceuticals

Pre-clinical

Comment

In 2017, Vanda intends to complete the technology transfer activities from UCSF and initiate IND enabling studies for several CFTR indications.

New License for CFTR Activators and Inhibitors


Website

http://www.vandapharma.com


SHOW MORE

FDL169: F508del-CFTR Corrector + FDL176: CFTR Potentiator

Company: Flatley Discovery Lab

Phase 1

Comment

FDL has a robust pipeline of CFTR “correctors,” “potentiators,” and “2nd generation modulators” as well as backup compounds for each of these approaches.  FDL169 has been in multiple Phase I clinical trials in both healthy volunteers and patients with CF.  FDL176 is also in clinical development.  We continue to optimize our “second generation correctors”.


Website

http://www.flatleydiscoverylab...