Fibrotic Disease

In fibrotic diseases abnormal wound healing results in a build-up of scar tissue that causes organs to become stiff and unable to function normally which can lead to organ failure. Fibrosis can affect any organ and fibrotic diseases are thought to account for at least one third of deaths worldwide.1

LOXL2 as a target in fibrotic disease

Scar tissue is made up of collagen fibres, which are produced by a type of cell called a fibroblast. Lysyl Oxidase-like protein 2 (LOXL2) is an enzyme released from fibroblasts that links collagen fibres together to stiffen scar tissue. Excessive production and linking of collagen fibres results in fibrosis. LOXL2 levels are increased in tissue from patients with fibrotic diseases, such as lung and liver fibrosis2, 3. Therefore inhibition of LOXL2 is an attractive target in treatment of fibrotic disease.

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LOXL2 Inhibitor Programme

Synairgen has collaborated with Australian pharmaceutical research company Pharmaxis to develop small molecule inhibitors of LOXL2 for the treatment of fibrotic disease. Synairgen generated data in primary human lung cell models (using cells from patients with fibrosis) and in vivo models of fibrosis showing the potential of these compounds in lung fibrosis. Pharmaxis focussed on generating data supporting liver fibrosis (including non-alcoholic steatohepatitis (NASH)), kidney and cardiac fibrosis. Lung (idiopathic pulmonary fibrosis (IPF)) and liver fibrosis (NASH) are particular areas of interest for potential large pharma partners for this programme. Two compounds from the collaboration entered clinical development in Q4 2017.

In December 2017 Pharmaxis took on full operational responsibility for the programme following revision of the terms and conditions of the collaboration. Synairgen retains an interest (circa 17%) across all fibrotic indications of all partnering proceeds and has no further obligation to finance the development of programme candidates.

With the Phase 1 results expected mid 2018 Pharmaxis has initiated a formal due diligence process and a number of pharma companies are well advanced in assessing the LOXL2 program. Pharmaxis plans to partner the LOXL2 program after the Phase 1 trials and longer‐term toxicity studies report.

Pharmaxis latest updates are here

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rare and poorly understood lung condition that causes scarring of the lungs. IPF gets worse over time and is often fatal. Symptoms include shortness of breath (even from performing day-to-day activities), which gets worse over time and persistent dry cough.

The disease appears to involve damage to the cells that line the tiny air sacs in the lungs (‘alveoli’) which causes them to die. The underlying causes of this damage is not understood (‘idiopathic’) but is likely to include both genetic and environmental factors such as cigarette smoking. The body tries to repair the damage by releasing another type of cell known as fibroblasts, but the production of the fibroblasts goes out of control and they cause scarring and hardening (fibrosis) of the delicate tissues of the lungs. As this scarring gets worse, the lungs find it more difficult to work properly, compromising the uptake of oxygen from the lungs into the blood, resulting in the symptoms of IPF.

The diagram below shows how fibrosis due to IPF affects the air sacs in your lungs:

Air Sac Illustration

 

The incidence of IPF is thought to be increasing, with evidence showing that incidence more than doubled between 1990 and 2003, even when taking into account ageing and improved diagnosis4. It is estimated that more than 5,000 patients are diagnosed with IPF every year in the UK5. In the US there are approximately 100,000 people with IPF, with 30,000 to 40,000 new cases diagnosed each year6. IPF primarily effects people over the age of 50, with six out of ten new cases being diagnosed in men. The number of people with the disease is expected to grow due to our ageing population.

The median survival time for people diagnosed with IPF is approximately 3 years (worse than many cancers, as shown in the chart below) from the point of diagnosis, however survival time varies from person to person, with approximately 20%-40% of patients surviving for more than 5 years.

5 year survival rates (%) comparing IPF to cancer7

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There is currently no cure for IPF so the aim of treatment is to try to relieve symptoms and slow its progression. Patients may be treated with supplemental oxygen or pulmonary rehabilitation (exercise classes aimed at improving the uptake and use of oxygen in the body). In terms of drug treatment two products have been licensed for the treatment of IPF:

  • Pirfenidone, whose mechanism is not fully understood, is licensed in Europe and the US.
  • Nintedanib, which targets biological pathways linked to fibrosis, is licensed in the US and Europe.

There is still a need for new therapies above and beyond pirfenidone and nintedanib because many patients still suffer a loss of lung function over time, despite the benefits of these therapies.

Non-alcoholic steatohepatitis (NASH)

Non-alcoholic fatty liver disease (NAFLD) is caused by a build-up of fat in the liver and is the most common liver disorder in Western industrialised nations. NAFLD progresses from a largely harmless build-up of fat in the liver cells (steatosis) to non-alcoholic steatohepatitis (NASH) where the liver has become inflamed resulting in liver cell damage. NASH is a major cause of liver fibrosis which leads to cirrhosis and permanent damage to the liver and an increased risk of liver cancer.

NASH represents an area of high unmet medical need. NAFLD currently affects 25% of the general adult population8 and this is set to increase with rising rates of obesity. Currently no medicines have been approved to treat NAFLD.

References

  1. Fibrosis — A Common Pathway to Organ Injury and Failure Don C. Rockey, M.D., P. Darwin Bell, Ph.D., and Joseph A. Hill, M.D., Ph.D. NEJM 2015
  2. Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment. V Barry-Hamilton, R Spangler, D Marshall, S McCauley, HM Rodriguez, M Oyasu, A Mikels, M Vaysberg, H Ghermazien, C Wai, CA Garcia, AC Velayo, B Jorgensen, D Biermann, D Tsai, J Green, S Zaffryar-Eilot, A Holzer, S Ogg, D Thai, G Neufeld, P Van Vlasselaer & V Smith. Nature Medicine 2010; 16, 9: 1009-1018
  3. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. JW Chien, TJ Richards, KF Gibson, Y Zhang, KO Lindell, L Shao, SK Lyman, JI. Adamkewicz, V Smith, N Kaminski, and T O’Riordan. Eur Respir J 2014; 43: 1430–1438
  4. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. J Gribbin, RB Hubbard, I Le Jeune, CJP Smith, J West, LJ Tata. Thorax 2006;61:980–985
  5. The rising incidence of idiopathic pulmonary fibrosis in the UK. V Navaratnam, KM Fleming, J West, CJP Smith, RG Jenkins, A Fogarty, RB Hubbard. Thorax 2011;66:462-467
  6. United States National Library of Medicine website (http://ghr.nlm.nih.gov/condition/idiopathic-pulmonary-fibrosis. Accessed 31 July 2015)
  7. Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology. C Vancheri, M Failla, N Crimi and G Raghu. Eur Respir J 2010; 35: 496-504
  8. Non-alcoholic fatty liver disease in 2015. M Ahmed. World J Hepatol. 2015