Calliditas’ pipeline contains development programs based on a first in class, novel NOX inhibitor platform that includes lead compound setanaxib, the first NOX inhibitor to reach the clinical trial stage.1 NOX enzyme inhibitors are a set of promising novel experimental drugs in a new therapeutic class, recognised by the WHO since 2019 when it approved “naxib” as a new stem.2 Calliditas is presently launching trials with setanaxib in Primary Biliary Cholangitis (PBC) and in Squamous Cell Carcinoma of the Head & Neck (SCCHN).

If you are interested in our TRANSFORM trial in PBC, please visit our study website here: https://en-us.transform-study.com/

Nox Enzymes

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, otherwise known as NOX enzymes, are the only known enzymes that are solely dedicated to producing reactive oxygen species (ROS) as their primary and sole function.3

They are transmembrane enzymes that transfer electrons from NADPH in the cytoplasm across the cell membrane, which results in the formation of ROS.4 There are seven NOX members, each differing in composition,modes of activation and the ROS type they produce.5 NOX1, NOX2, NOX3, and NOX5 transfer electrons from NADPH to molecular oxygen, producing superoxide anion (O2·−). NOX4, DUOX1 and DUOX2, meanwhile, mainly produce hydrogen peroxide (H2O2).6

 

ROS Diagram

At appropriate concentrations, ROS have essential functions in cellular signalling processes, helping to regulate cell proliferation, differentiation and migration, as well as modulating the innate immune response, inflammation and fibrosis.7 However, disruption of redox homeostasis has been implicated in multiple disease pathways. Oxidative stress, caused by an excess of ROS, is a likely common underlying mechanism for many disorders, including cardiovascular diseases, neurodegenerative disorders, and cancer disease pathways.8 Setanaxib inhibits NOX1 and NOX4, enzymes which are implicated in inflammation and fibrosis pathways.9

Setanaxib in PBC

PBC Disease Background

PBC is a progressive and chronic autoimmune disease of the liver that causes a cycle of immune injury to biliary epithelial cells, resulting in cholestasis and fibrosis. It is an orphan disease and, based on its known prevalence rates, we estimate that there are approximately 140,000 patients in the US, where the annual incidence ranges from 0.3 to 5.8 cases per 100,000. The origin of this autoimmune response is believed to be the production of cytotoxic T-cells and B-cell derived autoantibodies directed towards the epithelial cells of the small bile ducts in the liver, resulting in inflammation and damage to the duct cells and eventually in the destruction of the bile ducts. This destruction results in the accumulation of increased bile acid in the liver, a condition known as cholestasis, to levels that are toxic to the liver cells, which in turn results in the destruction of liver cells and formation of fibrous tissue.

Early symptoms of PBC include fatigue, itchy skin, and dry eyes and mouth. As the disease progresses, symptoms range from pain in the upper right abdomen and musculoskeletal pain to oedema, jaundice, osteoporosis, elevated cholesterol and hypothyroidism. If untreated, active liver tissue is destroyed and replaced by fibrous tissue, leading to liver failure and the need for a liver transplant. Individuals with PBC are also at a greater risk than the general population of developing hepatocellular carcinoma.

Current Approved Treatments for PBC

Ursodeoxycholic acid, a generic drug also known as ursodiol or UDCA, and obeticholic acid, known as Ocaliva, are the only FDA- and EMA-approved treatments for PBC.10 These drugs are primarily anticholestatic. UDCA is a bile acid analogue which is incorporated into the bile acid pool, replacing other more toxic bile acids and reducing inflammation and cholestasis. However, while it remains the first-line therapy for patients with PBC, only 40% to 60% of patients respond adequately to UDCA.11 Ocaliva, a modified bile acid, is a farnesoid X receptor (FXR) agonist which modulates bile acid homeostasis, decreasing bile acid synthesis and increasing its clearance.12 However, despite these treatment options, there is still an unmet medical need among PBC patients, in particular when it comes to important quality of life outcomes.

Phase 2 Trial

Setanaxib previously has been investigated in a 24 week Phase 2 trial with 111 patients and has received orphan drug designation for the treatment of PBC in the United States and Europe. Although the study did not meet its primary endpoint, it met key secondary endpoints related to change in alkaline phosphatase (ALP), liver stiffness and important quality of life metrics.

nox-inhibitor-platform-2

Setanaxib 400mg BID achieved significant reduction in alkaline phosphatase (ALP) of 12.9% (p<0.002 vs placebo) over the 24-week treatment period.

Furthermore, in a pre-defined patient population with liver stiffness of ≥9.6 kPa, setanaxib had a more pronounced effect on ALP reduction and fibrosis. Patients with elevated liver stiffness are at greater risk of disease progression.13 In patients with a liver stiffness score of ≥9.6 kPa, setanaxib 400mg BID achieved a 24% reduction in ALP over the 24-week treatment period, and a 22% reduction in liver stiffness as compared to a 4% increase for placebo (p=0.038).

 

Setanaxib Page - Graphs

Furthermore, treatment with setanaxib 400mg BID resulted in a statistically significant impact on fatigue, a very common and frequently disabling symptom of PBC which is not currently addressed by existing therapies, as well as demonstrated positive effects on emotional and social aspects of the disease.

nox-inhibitor-platform-6
Mean percent changes from Baseline in Quality of Life domains included in the PBC-40 questionnaire
* = p values statistically significant
1 = Once daily, 2 = Twice daily

Setanaxib has also demonstrated a favourable safety profile in a Phase 1 clinical study in healthy subjects, which evaluated the safety and pharmacokinetics of the drug at doses up to 800 mg twice daily.

Phase 2b/3 TRANSFORM Trial

Calliditas is presently initiating a pivotal 52-week, randomized, placebo-controlled, double-blind, trial with an adaptive phase 2b/3 design. Click here to visit the TRANSFROM study website.

nox-inhibitor-platform-8

Setanaxib will be administered as an add-on therapy to approximately 318 patients with PBC and with elevated liver stiffness and intolerance or inadequate response to UDCA at up to 150 investigational centres, with the primary endpoint of ALP reduction. Key secondary endpoints include change in liver stiffness, and effect on pruritus (itching) and fatigue. Following the favourable safety data from the Phase 1 study, this trial will evaluate two dosing regimens of 1200mg/daily and 1600mg/daily. An interim analysis will be conducted once the 99th randomized patient has completed the Week 24 visit, which is expected in H1 2023, and will determine which dose of setanaxib will be used for the Phase 3 part of the study. The trial is expected to read out final data in late 2024 or early 2025. In August 2021, Calliditas received FDA Fast Track Designation for setanaxib in PBC.

Setanaxib in Head and Neck Cancer

Calliditas also intends to evaluate setanaxib in head and neck cancer. The response to immuno-oncology therapies can be affected by the tumour microenvironment, in particular by the numbers of tumour-infiltrating lymphocytes (TILs) and cancer-associated fibroblasts (CAFs) in the tumour. A relationship between cancer associated fibroblasts (CAFs) and prognosis in squamous cell carcinoma of the head & neck (SCCHN) has been established. NOX4 is highly over-expressed in CAFs and drives myofibroblastic activation within tumours, shielding them from CD8+ TILs. Targeting CAFs with setanaxib could improve patients’ responses to immunotherapies, and function as an adjunctive. There is increasing use of pembrolizumab as 1st line monotherapy in patients with relapsed or metastatic SCCHN, although response rates are low (ORR approx. 20%).

Using a CAF-rich tumour model in mice, administration of setanaxib + pembrolizumab (versus either treatment alone) resulted in:

  • Improved penetration of TILs into the centre of the tumour
  • Slowing of tumour growth
  • Improved survival

Calliditas is planning a Phase 2 proof-of-concept study in patients with SCCHN, which will investigate administration of setanaxib in conjunction with immunotherapy targeting CAFs. The study will likely involve around 60 patients and the target is to start recruiting in Q4 2021, with an interim readout in 2022 and final data readout expected in 2023.

poc-in-head-and-neck-trial-design


[1] Elbatreek MH, Mucke H, Schmidt HHHW. NOX Inhibitors: From Bench to Naxibs to Bedside. Handb Exp Pharmacol. 2021;264:145-168. doi: 10.1007/164_2020_387. PMID: 32780287
[2] Elbatreek MH, Mucke H, Schmidt HHHW. NOX Inhibitors: From Bench to Naxibs to Bedside. Handb Exp Pharmacol. 2021;264:145-168. doi: 10.1007/164_2020_387. PMID: 32780287
[3] Altenhöfer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HH. Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement. Antioxid Redox Signal. 2015 Aug 10;23(5):406-27. doi: 10.1089/ars.2013.5814. Epub 2014 Feb 26. PMID: 24383718; PMCID: PMC4543484.
[4] Elbatreek MH, Mucke H, Schmidt HHHW. NOX Inhibitors: From Bench to Naxibs to Bedside. Handb Exp Pharmacol. 2021;264:145-168. doi: 10.1007/164_2020_387. PMID: 32780287
[5] Elbatreek MH, Mucke H, Schmidt HHHW. NOX Inhibitors: From Bench to Naxibs to Bedside. Handb Exp Pharmacol. 2021;264:145-168. doi: 10.1007/164_2020_387. PMID: 32780287
[6] Elbatreek MH, Mucke H, Schmidt HHHW. NOX Inhibitors: From Bench to Naxibs to Bedside. Handb Exp Pharmacol. 2021;264:145-168. doi: 10.1007/164_2020_387. PMID: 32780287
[7] Altenhöfer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HH. Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement. Antioxid Redox Signal. 2015 Aug 10;23(5):406-27. doi: 10.1089/ars.2013.5814. Epub 2014 Feb 26. PMID: 24383718; PMCID: PMC4543484
[8] Altenhöfer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HH. Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement. Antioxid Redox Signal. 2015 Aug 10;23(5):406-27. doi: 10.1089/ars.2013.5814. Epub 2014 Feb 26. PMID: 24383718; PMCID: PMC4543484
[9] Teixeira G, Szyndralewiez C, Molango S, Carnesecchi S, Heitz F, Wiesel P, Wood JM. Therapeutic potential of NADPH oxidase 1/4 inhibitors. Br J Pharmacol. 2017 Jun;174(12):1647-1669. doi: 10.1111/bph.13532. Epub 2016 Jul 14. PMID: 27273790; PMCID: PMC5446584.
[10] Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam KK. Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches. J Clin Transl Hepatol. 2020 Mar 28;8(1):49-60. doi: 10.14218/JCTH.2019.00049. Epub 2020 Jan 29. PMID: 32274345; PMCID: PMC7132015.
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[12] Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam KK. Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches. J Clin Transl Hepatol. 2020 Mar 28;8(1):49-60. doi: 10.14218/JCTH.2019.00049. Epub 2020 Jan 29. PMID: 32274345; PMCID: PMC7132015.
[13] Mueller S, Sandrin L. Liver stiffness: a novel parameter for the diagnosis of liver disease. Hepat Med. 2010 May 25;2:49-67. doi: 10.2147/hmer.s7394. PMID: 24367208; PMCID: PMC3846375.