Preclinical Success with Targeted Combination Therapies

ASX Announcement Neurotech International Ltd Suite 5 CPC, 145 Stirling Highway Nedlands, Western Australia 6009 T: +61 (8) 9389 3130 E: [email protected] W: neurotechinternational.com ABN: 73 610 205 402 ASX: NTI 1 of 5 1 December 2021 Preclinical Success with Targeted Combination Therapies: Prednisone + NTI164 • NTI continues to expand and validate its preclinical progra m using lead NTI164. NTI164 is a novel cannabis strain developed by Dolce Cann Global that contains f ull spectrum plant composition with high levels of minor cannabinoids and less than 0.3% THC. • Prednisone belongs to a $5B annual sales class of drugs kno wn as Corticosteroids. Prednisone medication is used to treat a large variety of conditions: autoimmun e disorders, neurological disorders, rheumatoid arthritis, and multip le sclerosi s. Whilst extremely effective, there are many adverse side effec ts that limit the use of corticosteroids, particularly long-term use. • Preclinical studies conducted in human ne uronal cells have demonstrated that NTI164, when combined with prednisone, is able to significantly reduce and normalise the levels of key inflammatory markers such as Tumour Necrosis Factor (TNF) -alpha, COX -2 expression, Interleukin -6 (IL-6), Interleukin – 1A (IL-1a), granulocyte-macrophage colony- stimulating factor (GM -CSF) levels. Prednisone alone had a limited ef fect on these markers. • When combined with N TI164, prednisone efficacy was significantly increased, showing a 33% in the reduction of TNF-alpha and 87% reduction in the suppression of IL-6. • These key bio markers/cytokines all play vital roles in the onset, d evelopment and progression of multiple neuro-inflammatory disorders such as Multiple Sclerosis, Alzheimer’s Disease and Rheumatoid Arthritis. • Reducing th e prednisone dose whilst achieving increased e fficacy (with NTI164 compared to prednisone alone) could overcome many of the adverse side effects that are directly related to the dosage of prednis one. The results provide NT I with an ideal platform to progress strategic partnerships and further expand its clinical trial portfolio. Neurotech International Limite d (ASX: NTI) ( “Neurotech” or “the Company”) is pleased to advise that preclinical studies demonstrate that NTI164 can improve the efficacy of prednisone at low doses (i .e. 5uM and 25uM). Significant anti -inflammatory synergistic activ ity was observed when NTI164 was combined with prednisone (at the low doses). These findings may have significant applications with regards to the use of prednisone across a variety of indications. Important ly, the combination treatment and formulation fall under NTI’s recently lodged patent applications (refer ASX announcement 14 October 2021). As mentioned above, r educing th e prednisone dose whilst achiev ing increased effic acy (with NTI164 compared to prednisone alone) could overcome many of the adverse side effects that are direc tly related to the dosage of prednis one1. The results provide NTI with an ideal pl atform to progress strategic 1https://www.medicalnewstoday.com/articles/prednisone-oral-tablet Neurotech International Ltd Suite 5 CPC, 145 Stirling Highway Nedlands, Western Australia 6009 T: +61 (8) 9389 3130 E: [email protected] W: neurotechinternational.com ABN: 73 610 205 402 ASX: NTI partnerships and further expand it s clinical trial portfolio. The prednisone / NTI164 study further expands NTI’s preclinical portfolio allowing t he Company to develop a solid pip eline of combination products using major off patent generic actives with proven efficacy without side effects. The Company will look to fast-track commercial negotiations with strategic partners to further develop and commercialise the most co mmon world wide off patent actives used in combination wit h NTI164 a cross multiple indications. Brian Leedman, Chairman of Neurotech International commented: “From a Company development perspective, we can’t understate the clinical significance of the se results. We have prednisone, one of the world ’s mos t c ommonly used off patent pharmaceutical drug s for neuroinflammatory dis orders (including Rheumatoid Arthri tis, Alzheimer’s and MS )1, demonstrating significant improvement in efficacy using anywhere from 70% to 90% less active dosage when used in combination with NTI164. Given the very well document ed adverse side effects of prednisone usage, the potential to create a combination treatment with NTI164 and prednisone which increases e fficacy and significantly reduces side effects is now a major dr iver for the Company. We are now pursuing other synergistic opportunities with blockbuster generics and other unique combination therapies. An all-natural, no THC comb ination treatment option will put N TI at the forefront of full spectrum can nabis strain development and comme rcialisation and we look forward to updating stakeholders with progress on an ongoing basis.” Neurotech International Non-Executive Director, Prof. Emeritus Allan Cripps said: “The synergistic suppression of the inflammatory response with combined prednisone and NTI 164 treatment in the preclinical in-vitro studies is a very exciting finding. Clearly, we are seeing the applications of the “entourage effect” of our full spectrum can nabis strains. If this can be transla ted to human studies; better clinical outcomes with less side effects would be expected for the treatment of diseases associated immune inflammation. The Company is looking forward to seeing the results of the recently commissioned combination preclinical studies utilising other majo r off-patent anti-inflammatory drugs such as Diclofenac and Celebrex which also have significant adverse side effects.” Table: A Summary of Results Biomarker Analysis Control PBS buffer Inflammation only: Interleukin & Interferon activation PDN 5uM concentration PDN (5uM)+ NTI164 (7.5ug/ml) Significance PDN vs PDN+NTI164 % Reduction in inflammation using combination therapy versus PDN alone COX-2 Protein 0.799 1 0.888 0.586 P=0.0210 Significant 34% +/- SEM 0.075 0 0.057 0.200 TNF-a 20.33 45 30.17 20.33 P=0.0105 Significant 33% +/- SEM 5.01 8.35 1.53 2.02 IL-6 9.50 366.33 228.50 30.33 P=0.0002 Highly Significant 87% +/- SEM 2.77 60.41 11.53 25.27 IL-1a 77.5 154.83 144.5 69.00 P= 0.0213 Significant 53% +/- SEM 38.66 33.11 27.54 22.52 GM-CSF 168.80 768.13 611.97 278.97 P=0.0398 Significant 54% +/- SEM 83.29 294.36 375.14 138.58 Neurotech International Ltd Suite 5 CPC, 145 Stirling Highway Nedlands, Western Australia 6009 T: +61 (8) 9389 3130 E: [email protected] W: neurotechinternational.com ABN: 73 610 205 402 ASX: NTI Results are expressed as: Average +/- SEM (standard error of mean) Treatment groups include: Control: PBS Buffer Positive control: Inflammatory stimulation by Interferon gamma and Interleukin – 1B activation Prednisone (PDN) concentration 5uM Combination therapy: Prednisone (PDN) 5uM + NTI164 concentration 7.5ug/ml Result Analysis: Calculated as % reduction in inflammation, PDN versus Combination therapy (prednisone 5uM + NTI164 concentration 7.5ug/ml). Student’s t-test was used for statistical analysis. Background Information Prednisone belongs to a class of drugs known as Corticosteroids. Corticosteroids are drugs used in the management and treatment of almost all areas of medicine. Prednisone medication is used to treat a large variety o f immune inflammatory conditions such as ; autoimmune disorders, neurological disorders, rheumatoid arthritis and multiple sclerosis. The corticosteroids market is expected to witne ss a CAGR of 4.3%, during the forecast period (2 020-2025). Current market s ize is estimated at $5Billion USD. The m ajor factors accounting for the growth of the corticosteroid market are i ncreasing the incidence of chronic disea ses, growing geriatric popul ation an d surging inv estment in research and dev elopment. The United Nation s forecast human population is expected to increase from 7.2 billion today to 8. 2 billion by 2025. This will increase the burden of chronic diseases to 57% worldwide according to WHO by the end of 2020 and is expected to increase further during the forecas t period. Hence, this uninterrupted inci dence and prevalence of chronic di seases lead to the growth of the Corticosteroids market during the forecast period2. Prednisone Use and Side Effects Despite its significant efficacy, the many adverse effects limit th e utility of prednisone and corticosteroids. Adverse effects appear to be related to both their average dose and cumulative duration. High dose use is commonly associated with2: • Elevated pressure in the eyes (glaucoma). • Clouding of the lens in one or both eyes (cataracts). • High blood sugar, which can trigger or worsen diabetes. • Increased risk of infections, especially with common bacterial, viral and fungal microorganisms. • Thinning bones (osteoporosis) and fractures. • Suppressed adrenal gland hormone production that may result in a variety of signs and symptoms, including severe fatigue, loss of appetite, nausea and muscle weakness. • Thin skin, bruising and slower wound healing. • Significant weight gain. Therefore, being able to red uce the dose whilst providing high level efficacy can be a breakthrough in the use of prednisone and related corticosteroids. 2https://www.mordorintelligence.com/industry-reports/corticosteroids Neurotech International Ltd Suite 5 CPC, 145 Stirling Highway Nedlands, Western Australia 6009 T: +61 (8) 9389 3130 E: [email protected] W: neurotechinternational.com ABN: 73 610 205 402 ASX: NTI Preclinical studies conducted in human neuronal cells have demonstrated that prednisone formulated with NTI164: • Lower doses of prednisone are required to achieve maximum efficacy. • Studies were focused on key inflammato ry biomarkers as well as cytokines that are directly involved in the progression of inflammation and various chronic neuro-inflammatory disorders. • TNF-alpha, COX-2 a nd cell mitochondria output were assessed using prednisone alone, NTI164 alone and prednisone + NTI164 across a number of doses. Results • Across all the preclinical studies prednisone had a mo dest effect in suppressing / reducing these key biomarkers and cytokines. • When combined with NTI164, prednisone + NTI164 proprietary combination formulation were able to reduce and normalise the levels of TNF-alpha, COX-2, IL-6, IL-1A and GSCMF. • These res ults demonstrate a significa nt combin ation | synergist ic output between NTI164 and prednisone. NTI164 can improve the efficacy of prednisone whilst being able to use minimum dosage . These findings may have significant applications with regards to the use of prednisone across a variety of indications. Reducing the prednisone dose whilst achieving increased efficac y (with NTI164 comp ared to prednisone alone) could overcome many of the unwanted and dangerous side effects that are directly related to the dosage of prednisone. These results reconfirm the potent anti-inflammatory, neuro-regulatory effects of NTI164. Combination therapy development and applications have been increasing over the past 5 years 3, 4 . The rationale for combination therapy is to use drugs that work by different mechanisms, thereby decreasing the likelihood that resistant cells will develop. When drugs with different effects are combined, each drug can be used at its optimal dose, without intolerable side effects , thereby providing the best outcomes for patients. For example, TNF-alpha inhibitors (eg. Infliximab) combined with anti-seizure meds (eg. Lamotrigine) have proven to be very effective in managing seizures and related inflammatory conditions*. In the case of prednisone + NTI 164 combination, prednisone mimics the effects of hormon es your body naturally produces in your adrenal gland . When prescribed in doses h igher than your body's usual levels, prednisone dampens inflammation. Preclinical studies have shown that NTI164 is able to regulate multiple pathways i e., Arginase-1, B eta-tubulin and iNOS pathwa ys. As p reviously announced to the ASX (date: November 2020) results have demonstrated that the NTI strains may regulate and su ppress inflammation by acting on these pathways which are directly involved in complex anti-inflammatory processes relating to immunity and natural defence mechanisms. 3: Treatment approaches to patients with multiple sclerosis and coexisting autoimmune disorders https://doi.org/10.1177/17562864211035542 4It’s Time For Combination Therapies: in Multiple Sclerosis Innov Clin Neurosci. 2017 May-Jun; 14(5-6): 28–30. Published online 2017 Jun 1. Neurotech International Ltd Suite 5 CPC, 145 Stirling Highway Nedlands, Western Australia 6009 T: +61 (8) 9389 3130 E: [email protected] W: neurotechinternational.com ABN: 73 610 205 402 ASX: NTI Authority This announcement has been authorised for release by the Board of Neurotech International Limited. Further Information Brian Leedman Chairman [email protected] +61 (0)41 228 1780 Winton Willesee Non-Executive Director [email protected] +61 (0)41 066 7844 Media: Juliana Roadley IR Department [email protected] +61 (0)41 488 9863 About Neurotech Neurotech International Limited is a me dical device and solution s company conducting clinical studies to assess the neuro -protective, anti -inflammatory and neuro -modulatory acti vities of our pro prietary NTI/Dolce cannabis strains. Ne urotech is also commercialis ing Mente, the world’s first home therapy that is clinically proven to increase engagement and improve relaxation in autistic children with elevated Delta band brain activ ity. For more inf ormation a bout Neurotech and Mente Autis m please visit http://www.neurotechinternational.com

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