Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common disorders affecting 24% and 1.5 to 6.5% of the adult US population respectively (https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts).
NAFLD/NASH are also increasing rapidly in India and China as well as the more affluent nations.
The global non-alcoholic steatohepatitis (NASH) market was valued at USD 4.57 Billion in 2020 and is projected to reach USD 180.09 Billion by 2028, growing at a CAGR of 58.64%from 2020 to 2028 (https://www.reportsanddata.com/report-detail/non-alcoholic-steatohepatitis-nash-market).
There is currently no approved medication to treat NASH but there a number of medications in development for this large affected population.
Lipid peroxidation and oxidative stress play a pivotal role in the pathogenesis and progression of NAFLD/NASH.
The inflammatory cascade that drives the progression of the disease from fat accumulating in the liver setting off the inflammatory process to NASH to cirrhosis to hepatocellular carcinoma is shown in the following diagram.
Ref: Hanza El Hadi et al. Antioxidants (Basel) 2018 Jan: 7(1):12.
Magosso,E et al. Nutrition J. 2013.12:166)
Tocotrienols inhibit progression throughout the cascade.
A 247 patient study reported in the NEJM in 2010 showed that 800iu daily of vitamin E (alpha tocopherol) for 96 weeks significantly improved the histology of NASH (43% vs 19% for placebo, p=0.001).(Sanyal A et al. N Engl J Med. 2010;362(18): 1675-85).
Tocotrienols are preferentially distributed to the liver (Patel V et al. J Nutrition. 2012;142(3):513-9.) and are more powerful anti-oxidants than alpha tocopherol. This suggested further investigation of tocotrienols.
Patel in the reference above demonstrated that tocotrienol supplementation in patients on the liver transplant list could reduce the level of disease severity in 50% of patients, whereas the same improvement was only obtained in 20% of patients in the tocopherol supplemented group.
A 2013 one year treatment, double-blind, placebo-controlled study of tocotrienol supplementation in NAFLD patients in Malaysia with ultrasound measurement showed normalisation of the hepatic echogenic response was obtained in 15 out of 43 patients in the tocotrienol group versus 8 out of 44 in the placebo group (p=0.039). No adverse events were noted. (Magasso E. Nutrition J. 2013;12(1):166.
Thendiono and Anguillas investigated the effect of lifestyle changes (nutritional counselling and exercise) with or without 100mg/day of a mixed tocotrienol product for 3 months on liver fibrosis assessed by Fibroscan in patients with NAFLD. After 3 months 57% of patients showed a decrease in their liver stiffness. 79% of those who improved were in the tocotrienol group and 21% in the lifestyle only group. (Thendiono E, Anguillas M. Poster presented at APASL Liver Week 2013)
Pervez conducted a randomised, double-blind, placebo-controlled study in patients having ultrasound confirmed fatty liver disease with a fatty liver index (FLI) of >60 and persistent ALT elevation. 71 patients were randomised to delta tocotrienol 300mg twice daily or placebo for 12 weeks. Delta tocotrienol showed greater efficacy than placebo in decreasing ALT, hs-CRP, malonaldehyde and FLI score (p<0.001). No adverse events were seen in this study.(Pervez M et al. Turkish J Gastroenterology. 2018; 29:170-172)
In 2022 Pervez published an additional study of delta tocotrienol in NAFLD. This was a double-blind, randomised study comparing Delta Gold to alpha tocopherol in NAFLD patients. 100 patients with ultrasound diagnosed NAFLD were randomised to either delta tocotrienol 300mg twice daily or alpha tocopherol 286mg twice daily for 48 weeks. The primary endpoints were change from baseline in fatty liver index (FLI), liver to spleen attenuation ratio (L/S ratio), and HOMA-IR for 48 weeks. Secondary endpoints were changes in markers of inflammation, oxidative stress and hepatocyte apoptosis. Clinical assessment, biochemical analysis and CT of liver were performed at baseline, 24 and 48 weeks.
Compared to baseline there was significant improvement (p<0.01) in FLI, L/S ratio, HOMA-IR and serum malonaldehyde in both groups at 48 weeks. There was significantly greater decrease in body weight, serum IL6, TNF-alpha, leptin, cytokeratin-18, and increase in adiponectin in the delta tocotrienol group. (Pervez M et al. Complement Ther Med. 2022 Nov; 70:102866.
In view of the very considerable evidence of the efficacy and lack of adverse events of oral tocotrienols in NAFLD/NASH, Invictus decided to perform a phase 2 proof of concept study of transmucosally delivered tocotrienols in NASH using MRI-PDFF measured hepatic fat levels in addition to ultrasound and numerous biochemical measurements as well as weight.
The phase 2 study has commenced and is recruiting patients.
Study Description:
A randomised, double-blind, placebo-controlled phase 2 study to evaluate the efficacy and safety of sublingual IVB-001 in the treatment of NASH.
Patients with NASH including a hepatic fat level of greater than 8% by MRI-PDFF are randomised to IVB-001 or placebo for 24 weeks.
The primary endpoint is change from baseline in hepatic fat level using MRI-PDFF.
Secondary endpoints are changes from baseline in liver elasticity measured by Fibroscan at weeks 12 and 24 and
Changes from baseline in FIB4, HOMA-IR, LFTs, hs-CRP, body weight and waist circumference.
"Tocotrienols address multiple steps in the NAFLD/NASH cascade including the abnormal retention of fat in liver cells (steatosis), the inflammation caused by the steatosis and the generation of scar tissue (fibrosis/cirrhosis) that results from inflammation.
Several clinical studies of orally administered tocotrienols have demonstrated efficacy and safety in NAFLD/NASH.
By delivering pure tocotrienols (no tocopherol) using the Invictus transmucosal delivery platform we bypass the first pass metabolism associated with the oral route and deliver more unmetabolised tocotrienols for distribution within the liver.
This should improve the efficacy and provide an enhanced efficacy product that is very well tolerated.The non-invasive delivery method maximises patient compliance which is really important for a chronic disease like NAFLD/NASH."
"I am excited to join Invictus’ Scientific Advisory Board and take a more integral role in managing its Phase II clinical study in NAFLD/ NASH.
Having a naturally derived drug candidate with a good safety profile like IVB001 delivered directly and non-invasively presents great potential to develop a much-needed treatment for NAFLD/ NASH."
ABN 16 657 241 533