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    Date submitted
  • 16-Dec-2016

Developing Novel CNS drugs

Abstract

Lead optimization of a single molecule based novel formulation for Parkinson's Disease

Background

The proposed project is based on the evidence of a well-characterized herb based single molecule formulation which is suitable for optimization in treating neurological disorders in particular to Parkinson’s disease.

This proposal is aimed at lead optimization of a single molecule based novel formulation for Parkinsons disease. Translating neuroscience research into new medicines is challenging, largely because of the complexity of the human brain. Medicinal plants are the main source of diverse chemical substances with potential therapeutic effects. Sida species is well known in Indian traditional medicine for use in prevention and management of neurological disorders, particularly in epilepsy, stress and neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. However, the active principle responsible for the neuroprotection is not identified so far. We have discovered the molecule responsible for its therapeutic activity and formulated the same.

The present proposal is aimed to study and to test the efficacy of this novel formulation for its pharmacokinetic and pharmacodynamics properties and other battery of tests to demonstrate that they are likely to be safe and effective in human studies.

Aim : Lead optimization of a single molecule based novel formulation for Parkinson’s Disease

Target identification

Molecular targets for CNS drug discovery have been identified on the basis of:

(i) Observation of the effect of known/proposed compounds on behavior;

(ii) Hypotheses derived from knowledge of pathophysiology; and

(iii) a combination of (i) and (ii).

The major imperative of the pharmaceutical industry is to effectively translate insights gained from basic research into new medicines. This task is toughest for CNS disorders. Compared with non-CNS drugs, CNS drugs take longer to get to market and their attrition rate is greater. This principally because of the complexity of the human brain (the cause of the many brain disorders remains unknown), the liability of CNS drugs to cause CNS side effects (which limit their use) and the requirement of CNS medicines to cross the blood-CNS barrier (BCNSB) (which restricts their ability to interact with their CNS target).

The successful translation of basic research results into safe and effective new medicines is the major goal of the pharmaceutical industry, which is made up of large (Big Pharma), medium (Biopharma) and small (Biotech) companies. This is particularly true for CNS medicines, which, compared to non-CNS drugs, takes longer to get to market and have a lower probability of getting there.

Disorders of the CNS represent the largest area of unmet medical need, with more than 1.5 billion people affected worldwide. It represents a massive market (worth $ 100 billion and more) and is set to grow considerably in the years ahead. This is because the incidence of many CNS disease (such as Alzheimer’s disease, Parkinson’s disease and stroke) increase exponentially after age 65 and the population of the world is getting older, with those aged 65 or more increasing in number by 1 billion between 2000 and 2050.

Although the need for new CNS medicines is large and is set to grow substantially in the years ahead, many companies are moving away from this sector. This is largely because of the high risk of failure associated with CNS medicines research and the longer the clinical phase and approval time for CNS drugs compared with other therapeutic categories.

Neurodegenerative disorders constitute a major unmet medical need in the CNS arena, so effective neuroprotective drugs are likely to have a major impact. In this scenario developing an affordable drug for treating neurological disorders becomes more relevant.

Novelty & Rationale of the Idea

This proposal is submitted based on the strong biological rationale that includes:

1) evidence that the therapeutic agent(s) has the potential to be therapeutically viable based on in vitro and in vivo study

2) Single molecule based formulation developed for human consumption.

Innovative element

a) Molecular targets for CNS drug discovery have been identified on the basis of:

(i) Observation of the effect of known/proposed compounds on behavior;

(ii) Hypotheses derived from knowledge of pathophysiology; and

(iii) a combination of (i) and (ii).

We have tested the effect of this single molecule based herbal formulation in Parkinsonian rat model and analysed the behavioural and neurochemical components. Based on the preliminary exanmination we found that the formulation is safe and efficacious (Data to be published)

Objectives

I. To conduct pharmacodynamics, pharmacokinetics, and in vivo efficacy studies to demonstrate that proposed therapeutic agent(s) have sufficient biological activity to warrant further development to treat neurological disorders (Parkinson’s Disease).

In preclinical efficacy studies, a combination of in vivo efficacy, pharmacodynamics (PD) and pharmacokinetics (PK) measures are warranted to determine the feasibility of candidate therapeutic agent(s) to serve as a starting point for further therapy development.

Pharmacodynamics studies may include but are not limited to determination of

1) target occupancy (e.g., binding) and

2) proximal target activation (i.e., signal transduction, neurotransmission, protein synthesis, and gene regulation and transcription).

In addition to the examples of proximal target activation listed above, more remote measures of target activation may also be considered, for example (but not limited to):

1) ex vivo studies of ion channel function,

Examples of activities:

• Preparation of the therapeutic agent(s) to support proposed activities.

• Characterization of therapeutic agent(s). This could include for example, confirmation of purity, stability, in vitro absorption, distribution, metabolism, and excretion, in vitro potency and selectivity, degradation products, and process impurities.

• Studies to develop dosage form(s) to support proposed PD measures and/or in vivo studies.

• Pharmacokinetics studies to determine direct or indirect therapeutic agent levels.

• Studies to confirm that therapeutic agents reach and engage the target site (directly or indirectly) at a level that exceeds pharmacological potency over the desired period.

At the end of the project Period, the results will exhibit successful completion of

1) all necessary preparation and characterization (e.g., chemical synthesis and scale up to provide material for proposed project, in vitro or in vivo potency studies, in vitro organ, tissue or cell culture systems) of proposed therapeutic agent(s),

2) pharmacokinetic studies

3) design, refinement, and validation of pharmacodynamics and/or in vivo efficacy animal studies using the appropriate positive and negative controls and demonstrating feasibility of conducting therapeutic agent testing, and

4) A detailed in vivo study design (e.g., in an animal model) that meets the guidelines and will allow for correlation of dose, therapeutic agent exposure in the target tissue, and pharmacological effect (i.e., demonstration of dose response and exposure response), thereby addressing subsequent feasibility.

Examples of activities:

• Pharmacodynamics and/or in vivo efficacy studies with chemically and biologically characterized therapeutic agent(s).

• Dose (exposure)-response activity with the intended route of administration.

• Studies correlating pharmacokinetic and pharmacodynamics measures (PK/PD)

• Validation and replication studies to confirm observed results.

• Studies to test the agent(s) along with or against positive and negative controls.

The knowledge gained from these studies will facilitate future therapeutic discovery and development for neurological disorders specific to Parkinson’s Disease.

Project Deliverables/Outcomes for each objective

Objective 1: It is expected that upon completion, investigators will have strong evidence of target engagement and/or in vivo efficacy for selected therapeutic agent(s) that meet the criteria of a novel compound for taking further as a lead molecule.

Combined measures of PK and PD greatly increase the understanding of the in vivo efficacy of the therapeutic agent(s) by exploring the relationship between the concentration of the agent(s) at the site of action and the resulting efficacy measures.

For the purpose of this proposal, in vivo efficacy measures reflect the effects of the therapeutic agent on endpoints that are closely tied to the desired clinical endpoints, but do not necessarily reflect target engagement. While PD measures may also reflect the effects of the therapeutic agent on endpoints closely tied to the desired clinical endpoint, they must reflect target engagement.

Video

Original YouTube URL: Open

Introduction Video

Additional Questions

Who is your customer?

The neurodegenerative disorders market, which covers Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, and multiple sclerosis (MS), is set to grow from $27.2 billion in 2015 to $45 billion by 2022, at a compound annual growth rate of 7.42%, according to business intelligence provider GBI Research. With a growing demand for an unmet clinical need our product aimed at patients suffering from Parkinson's disease.

What problem does this idea/product solve or what market need does it serve?

There is hardly any cure for neurodegeneration in modern medicine, whereas many drugs in Ayurveda possess neuroprotective effects; however, there is no scientific validation for these drugs. Allopathic medicine can cure a wide range of diseases, however, its high prices and side effects are causing many people to return to herbal medicines which tend to have fewer side effects. The use of alternative medicine is growing because of its moderate cause and increased faith in herbal medicine. However, despite steady market growth, various unmet needs remain and a cure is yet to be found. As with Alzheimer’s disease, a viable therapeutic target to halt or slow disease progression is currently not in scope due to the fact that underlying mechanisms that cause Parkinson’s disease are not fully understood. Most pipeline drug development programs are in their early stages, with the majority in the Preclinical stage. This means that game-changing products are far from being realized, and explains why symptom-relieving therapies will continue to dominate the market through to 2021. In order to combat the vast array of unmet needs in the Parkinson’s disease treatment space, developers are concentrating on disease modification as opposed to mere symptom relief.

What attributes will make this idea/product successful? Why do you believe that those features will create success?

Ayurveda is considered as one of the oldest of the traditional systems of medicine (TSMs) accepted worldwide. The ancient wisdom in this traditional system of medicine is still not exhaustively explored. The junction of the rich knowledge from different traditional systems of medicine can lead to new avenues in herbal drug discovery process. The lack of the understanding of the differences and similarities between the theoretical doctrines of these systems is the major hurdle towards their convergence apart from the other impediments in the discovery of plant based medicines. We have taken a bold step to reformulate the existing formula and aims to bring into limelight into the mechanism of action of the single molecule based herbal formulation and overcome the challenges towards the global acceptance such medicinal systems. Ksheerabala is an ayurvedic drug which is used to treat central nervous system disorders, arthritis, and insomnia. So far there is no proof-of-concept study to show the mechanism of action of the molecule responsible for its alleviating effect. Despite decades of research, solution for neurodegeneration still remains a challenge. Thus, there exists a significant market and clinical need for a new class of formulations that both fight degeneration and promote regeneration of neurons.

Explain how you (your team) will execute to make this idea/product successful? What gives you (your team) an advantage over others already in the market or new to this market?

Limit of current treatment options Neurodegenerative diseases refer to those conditions in which neurons in the brain, eye, and spinal cord undergo progressive degeneration and eventual death. In addition to immeasurable human suffering and caregiver burden, the economic impact of brain-related illness in the US alone has reached over $1.3 trillion of nondiscretionary healthcare spending. Since brain cells are rarely replaced by the body, sufferers of these diseases must cope with the loss of brain and body function for the rest of their lives. Neurodegenerative diseases, including Multiple Sclerosis (“MS”), Alzheimer’s disease (“AD”), Parkinson’s disease (“PD”), Amyotrophic Lateral Sclerosis (“ALS”), Huntington’s disease (“HD”), and Spinal Muscular Atrophy (“SMA”), target many distinct parts of the nervous system, but have the shared effect of slowly eliminating the ability to function and to care for oneself. The signature of many of these diseases is that their incidence increases with age. Because of this, the epidemic of neurodegenerative disease will continue to increase as life expectancy increases. Unlike many other major disease areas – infectious disease, cancer, cardiovascular disease, and psychiatric disease – the pace of drug development for neurodegenerative disease has been almost stagnant. There are very few approved drugs to treat neurodegeneration, and, in almost all of these cases, the approved treatments mitigate only the symptoms of the disease without addressing its underlying cause. The need for disease modifying therapies in neurodegeneration remains especially high, and it remains almost entirely unmet. The solution To combat the growing problem of neurodegeneration, we have developed a completely novel formulation called NeuroHerb7®. NeuroHerb7® does not rely on synthetic molecules or any other peptides. Instead, our technology uses a reliable, cost effective method of preparation to extract the single molecule based formulation which is conveniently safe for oral dosage.