Cancer

Lysyl oxidase inhibitors for haematoligical malignancies and solid tumours

Lysyl oxidases are a family of five enzymes (LOXL and LOXL1-4) responsible for catalysing the formation of cross-links in collagen and elastin. In diseases states, excessive cross-link formation overwhelms endogenous degradation processes, shifting the balance towards hardened fibrotic tissue. This can occur in organs as well as the microenvironment surrounding tumours. The anti-fibrotic effects of lysyl oxidase inhibitors have been described in many diseases.

In addition to mediating collagen cross-link formation, lysyl oxidases also regulate growth factors. Inhibition of lysyl oxidases reduces the activation of platelet-derived growth factor receptors, further slowing fibrosis.

Besides these extra-nuclear effector functions, intra-cellular and intra-nuclear effects are also mediated by LOX, including gene regulation via the STAT pathway and histone modification. These effects, namely changing gene expression and promoting clonal selection, are implicated in haematological malignancies and solid tumours.

What diseases are we studying?

Primary Myelofibrosis

Primary Myelofibrosis is a cancer affecting the bone marrow that occurs in 1 in 500,000 people worldwide. Once diagnosed the life expectancy of patients is 5 years. Myelofibrosis is caused by a buildup of scar tissue (fibrosis) in bone marrow reducing the production of blood cells.

Reduced red blood cells can cause extreme tiredness (fatigue) or shortness of breath
Reduced white blood cells can lead to an increased number of infections
Reduced platelets can promote bleeding and/or bruising
Spleen increases blood cell production and becomes enlarged
Other common symptoms include fever, night sweats, and bone pain

The current Standard of Care are a group of drugs called JAK inhibitors. They work by suppressing the growth of aberrant cells and thereby provide symptomatic relief plus some limited survival improvement. The majority of patients will discontinue treatment with these drugs within 5 years due to poor tolerability which often leads to reduced blood cell counts.

How does SNT-5505 work in myelofibrosis?

SNT-5505 has a unique mechanism of action that is different from all other drugs approved for myelofibrosis and under development. Inhibition of lysyl oxidase enzymatic activity prevents collagen cross-linking in the bone marrow and that has already been demonstrated in phase 2 clinical trials to lead to reductions in bone marrow fibrosis [link to press release]

Figure: How does SNT-5505 work in myelofibrosis

Myelodysplastic Syndrome (MDS)

Myelodysplastic syndrome (MDS) is a blood cancer

Diverse bone marrow disorders characterized by inadequate production of healthy blood cells1

Key Facts: 12–20k new cases are reported every year in the US (87k p.a. worldwide)

Prognosis and overall survival depend upon multiple factors including the severity of cytopenias (low blood counts)
Low-risk MDS therapy is aimed at improving cytopenia(s) to prevent complications
25–30% have high-risk MDS with average survival of ~ 1 year
1 out of 3 MDS patients progress to acute myeloid leukemia (AML)

The potential use of SNT-5505 in myelodysplastic syndrome was the subject of a poster presentation at the 2022 American Society of Hematology conference (ASH) in in December 2022. The poster reported on ground breaking work done in collaboration with Professor Wolf‐Karsten Hofmann and Professor Daniel Nowak at Heidelberg University, Germany. The preclinical models combined SNT-5505 and the standard of care (5-azacytidine) and were reported in Nature Communications in March 2023. The paper concludes that the work makes a strong case for trialling the combination in MDS patients, especially those who are anaemic. Read more here.

1.Platzbecker U, 2021, Leukemia 2021
2.Total global MDS market US$3.2b, with prevalence of high-risk MDS 25–30%

Solid Tumours

In addition to the potential treatment of blood cancers like myelofibrosis and myelodysplastic syndrome, SNT-5505 has also been shown to increase the efficacy of existing chemotherapy in treating solid tumours like liver and pancreatic cancer.

How does SNT-5505 work in solid tumours?

SNT-5505 is thought to reduce the fibrotic tissue associated with solid tumours, allowing increased penetration of existing chemotherapy agents and the body’s own cancer fighting T cells into the tumour. In pre clinical animal models of these solid tumours the investigators have observed reduced tumour growth and increased survival. Other pre clinical studies have also shown that by reducing the fibrotic microenvironment outside of the tumour that SNT-5505 may be able to reduce metastases.

Liver Cancer

The combination of SNT-5505 and standard of care in preclinical models demonstrates a novel therapeutic strategy for liver cancer. Data presented from a collaboration between Syntara and the University of Rochester Medical Center at US Scientific Meeting. Read more here.

A planned investigator-initiated clinical trial by the University of Rochester in hepatocellular carcinoma (HCC) patients will not progressed at this point as Syntara focuses its resources on haematological malignancies such as MF and MDS.

Syntara’s collaboration with the research team at University of Rochester continues, with further pre-clinical evaluation of Syntara’s pipeline assets.

Pancreatic Cancer

A collaboration between Syntara and the Garvan Institute of Medical Research resulted in a publication in the prestigious journal Nature Cancer of preclinical results showing pan-Lysyl Oxidase (pan-LOX) inhibitor SNT-5505 increases survival by 35 per cent compared to chemotherapy treatment alone in the treatment of pancreatic ductal adenocarcinomas. Research in mouse models also showed SNT-5505 combined with chemotherapy reduced the spread of the cancer to other organs such as the liver by 45 per cent. Pancreatic ductal adenocarcinoma is one of the most aggressive forms of pancreatic cancer with a five-year survival rate of less than 10%. Many pancreatic cancers develop chemotherapy resistance soon after treatment starts, which contributes to the poor survival of patients. Part of this resistance is driven by tumour fibrosis – the formation of a mesh of scar tissue-like collagen – within and around pancreatic tumours that in turn reduces the effectiveness of chemotherapy drugs. SNT-5505 returns the tumour microenvironment to a more ‘normal’ state by reducing fibrosis and decreasing tumour stiffness allowing chemotherapy drugs to penetrate the tumours more easily, work more effectively, and destroy more cancer cells.