PowerPoint Presentation

[Virtual Presenter] Good morning everyone. I'm here to present to you a revolutionary and ground-breaking concept that will revolutionize the way we combat Parkinson’s Disease. I look forward to sharing with you how Maavrx Ltd can provide game-changing solutions that will improve the lives of countless people. I appreciate your time and attention..

[Audio] Maavrx Ltd understands the importance of having appropriate resources both inside and outside of the organization. From therapeutic models to vector designs and development plans, everything is handled internally. For laboratory tests, production, assessments and quality control, we collaborate with the top contract research and manufacturing organizations, that provide the indispensable expertise and knowledge for the job. Moreover, our founder has considerable experience in managing outsourced studies and a good understanding of regulatory guidelines. All these factors make Maavrx Ltd a great choice for your research or development objectives..

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[Audio] Parkinson's disease is a debilitating and complex neurodegenerative disorder, which affects over 10 million people worldwide. Characterized by tremors, bradykinesia, postural instability, and rigidity, this condition can lead to substantial disability in those affected. With the prevalence of Parkinson's disease increasing largely with age and approximately 60000 new cases diagnosed each year in the United States alone, it is a growing concern and serious health issue across the globe. GlobalData's PharmaPoint report found that the US market for Parkinson's disease drugs is forecasted to reach over USD 1.4 billion by 2022..

[Audio] The economic burden of Parkinson's disease in the United States is estimated to be nearly $52 billion a year, consisting of $25.4 billion for medical costs and $26.5 billion for non-medical costs, such as lost wages, early retirement and the time spent by family caregivers. It is projected that the PD technology and pharmaceuticals market will reach $5.3 billion by 2022, reflecting the importance of continuing to invest in research and development..

Parkinson’s disease. Parkinson’s disease follows gradual loss of dopamine producing cells in the substantia nigra of brain. These cells project into the striatum providing dopamine. Asymptomatic until dopamine level in the striatum falls to <30% of normal..

[Audio] The current treatment for Parkinson's Disease is L-DOPA, which is administered orally and works by passing the blood brain barrier and being converted to dopamine in the striatum. This remains the most effective treatment available, with nearly all Parkinson's Disease patients eventually taking it. A potential side effect of this treatment is the developing of L-DOPA induced dyskinesia and on/off variation, which affects around 10% of patients per year..

[Audio] Presentation will explore the problem posed by oral L-DOPA, a medication used to treat Parkinson's disease. Absorption across the gut wall is variable and its half-life is relatively short, resulting in chaotic plasma and brain levels with marked peak and trough variations. This can lead to dyskinesia, an involuntary and uncontrolled movement of the body. Intravenous infusions of L-DOPA can smooth out these symptoms, however prolonged periods are not tolerated due to phlebitis. We will look at how 100/25 mg standard-release tablets can help manage this problem..

[Audio] Examining current treatment options for Parkinson's Disease, sustained release L-DOPA has seen limited success due to its short half life, and competition from dietary amino acids in active transport across the gut and the blood-brain barrier. Deep brain stimulation may provide some benefits, but carries the risk of dysarthria and requires ongoing oral L-DOPA, with the added risk of "foreign body" wires being inserted through the skull. Duodopa, a continuous IV or subcutaneous infusion of either L-DOPA or agonists, is not well tolerated..

[Audio] Analysis has revealed that providing l-dopa in a continuous infusion decreases dyskinesia and helps regulate motor fluctuations with more accuracy. Nevertheless, this method is difficult to control and is not well-tolerated over long periods of time, as it requires patients to have nimble digits. Moreover, it necessitates the insertion of a tube through the abdominal wall, which can lead to infection, displacement, kinking, and clogging. Additionally, it is very expensive, ranging from £30000 to £55000 for each patient annually. This sum of money adds up to over $500 million each year for Sinemet and Duodopa..

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[Audio] Our research and development department have been working diligently to develop a single injection of AAV-based gene therapy transducing TH and GCH1 enzymes, which will allow the brain to produce L-DOPA. This injection could provide a long-term, sustained level of L-DOPA in the brain, potentially eliminating or reducing the need for oral medication. This could theoretically lead to improved efficacy, and fewer incidents of dyskinesia and off periods. We believe our proposed product could be just as effective, if not more so, than the existing Duodopa treatment, without the requirement of a pump or tube being passed through the abdominal wall..

[Audio] One in four adults in the United States is living with a chronic disease like Parkinson's. Maavrx PD is on the forefront of a movement to understand and treat such conditions. We focus on finding the most effective treatments for people suffering from Parkinson's and enhancing the lives of those living with the disease. Through advanced research, cutting-edge technology and high-quality care, Maavrx PD has taken a leading role in building a better future for those with Parkinson’s..

[Audio] Dopamine production in the striatum is the topic of discussion today. Parkinson's disease is caused by a reduction of dopamine producing neurons in the striatum, which results in a lack of the necessary enzymes for dopamine production. There are three enzymes necessary for the production of dopamine from tyrosine: tyrosine hydroxylase, GTP cyclohydrolase 1, and amino acid decarboxylase. To increase dopamine production in the surviving cells of the striatum, gene therapy strategies have been developed to enhance the expression of amino acid decarboxylase. Examples of these therapies are AAV-AADC, Prosavin, and triple monocistronic AAV therapy..

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[Audio] Gene therapy has presented the possibility of treating Parkinson's disease with one injection. Studies have revealed that several gene therapy vectors, delivered into the striatum, can give key proteins that reset dopamine levels and cause notable augmentations in motor malfunction as well as movement for both rats and non-human primates. Research has shown that the effects of a single injection can last up to fifteen years! With incredible efficacy that has been observed and its wide safety margin, gene therapy holds the prospect of normalizing dopamine levels to between 30 to 100%. This has the capability to completely reverse symptoms of Parkinson's disease..

[Audio] This presentation will examine the impact of AAV-GCH1-TH gene therapy for treating Parkinson's Disease. On a cross section of a healthy rat's striatum, tyrosine hydroxylase is clearly expressed in row A. After treatment with 6-OHDA that causes Parkinson's Disease, expression of TH is diminished in row B. In contrast, after AAV-GCH1-TH gene therapy, expression of TH is restored in row C. Further, this gene therapy has been linked with reversal of motor deficits in rats with 6-OHDA-induced Parkinson's Disease..

AAV-GCH1-TH |MPTP NHPs. A picture containing graphical user interface Description automatically generated.

[Audio] We are introducing an innovative product to the market: the Bicistronic AAV-GCH1-TH. This new technology is designed to increase accuracy and efficiency in MPTP studies in non-human primates. This is another step in our pursuit to continue pushing the boundaries of what we can achieve..

Genepod Bicistronic AAV-GCH1-TH |MPTP NHPs. 07/04/2022.

[Audio] A study was conducted on a Non-Human Primate to evaluate the potency of a new gene therapy utilizing Adenovirus Vector AAV2/5. GCH1-TH.002. Its results revealed that treating the subject with the maximum titre of the virus did not have any impact on the TH expression. Nevertheless, a noteworthy increase in the GCH-1 expression in the striatal region was observed, which may have potential extensive implications for future gene therapy experiments..

[Audio] A subset of neurons in the putamen show distinct patterns of immunostaining. Whilst the coverage of immunopositive neurons was comparable, only a subset of GCH1-positive neurons displayed clear TH+ immunostaining and the overall staining level was significantly reduced in comparison to expectations. This is alarming, considering that endogenous TH was effectively stained in the hosting dopamine neurons and terminals. Notably, the TH immunostaining pattern in the transduced putamen was similar to that acquired from a tricistronic lentiviral vector, suggesting potential for further optimization of the vector construct to enhance efficacy in the primate striatum..

[Audio] All the indicators point to the success of our approach, however, there are still many unknowns that could potentially lead to a different outcome. Therefore, it is essential that we continue to put in effort and make sure that our team is informed and alert to any changes. With due diligence and the right proactive steps, we can guarantee the accomplishment of our aims..

[Audio] When it comes to finding success, a stronger mental construct is required. The story of Cinderella has been passed down through generations, reminding us that no matter how hard things seem, we all possess the capability to change our paths and societal standing, and rewrite our own endings. Let us further examine the ageless tale of Cinderella..

[Audio] Our data indicate that Maavrx vectors are better performing in vitro than AAV-GCH1-TH. Specifically, Construct “Test 1” was observed to be 10 times more effective than the reference, and 4 times more potent than when co-administered with “Test 4”. In 2017, a patent application of our research in this area was submitted..

[Audio] The potential of Maavrx vectors, specifically MRX002, is greater than the potential of AAV-GCH1-TH, also known as GPT002. To verify this hypothesis, an amphetamine challenge was administered to a group of 6-OHDA rats who were given the same titre of each vector. The results showed an increased dopaminergic activity in the case of MRX002 with a statistical significance of less than 0.0001 determined by Kolmogorov-Smirnov test..

[Audio] In our search for the best vector construct, we conducted a comparison of various AAV constructs in vitro and observed a clear superiority demonstrated by the combination of self-complementary AAV-TH and self-complementary AAV-GCH1 in neuronal cells. This superior construct was further confirmed in two independent commercial laboratories, leading to an increase in expression of more than ten-fold versus our previous constructs. After thorough examination, our board has agreed to advance this preferred combination of constructs to proof of concept studies..

[Audio] Today's slide focuses on the results of a pilot study involving a novel vector construct that we designed. Our study showed that this construct had superior expression of the TH protein when compared to previously published bicistronic constructs. These findings are an encouraging step forward for our broader research goals..

[Audio] We will examine our proof of concept examinations on the scAAV5-TH and scAAV5-GCH1 6-OHDA rat model of Parkinson's illness, as found in the picture. Performing thorough cylinder tests to assess the outcomes, the outcomes are rather encouraging. This could be a noteworthy development in our research into developing treatments for Parkinson's illness..

[Audio] Today, I'm going to talk about the MPTP NHP Model of PD. This model has been designed to provide an accurate and comprehensive assessment of movement capabilities. It can help identify potential issues with mobility, as well as identify physical or functional areas that may be affected by movement. The Movement Assessment Panel contains a series of tests which are designed to measure a wide range of movement abilities. The results of these assessments can then be used to inform treatment and rehabilitation..

[Audio] The presentation is focused on understanding the results of the mMAP changes as a percentage of pre-treatment results. The actual result shows a change of % while the hypothetical test we conducted indicates a % change, suggesting there is significance not due to increases on Rt. The following slides will provide further insight into the results..

[Audio] Today we will be taking a look at the findings from an ongoing study on the Maavrx TH staining in MPTP lesioned Non-Human Primates. Our preliminary results from n=1 pilot study data have been very encouraging but at this point we are awaiting definitive results which have been anticipated for the 10th of September 2021..

Thank you.