Hijar Max Pharmaceuticals Business Plan Biology Essay

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Traumatic brain injury (TBI) is one of the leading causes of death and permanent disability. According to Centers for Disease Control and Prevention approximately 1.4 million people sustain a traumatic brain injury each year in the United States. The neuronal damage that is observed in patients after TBI results from a primary injury and a secondary injury that occurs over the following hours and days. Therefore, to improve patients recover it critical to protect neurons against secondary injury as soon as possible after injury. Unfortunately, there is currently no effective method for preventing neurodegeneration after TBI.

Hijar-Max Pharmaceuticals, a privately held life science company, has a broad range of experience in developing drugs targeting neurodegenerative diseases. Recently, our company focused on development of neuroprotective agents to treat patients after traumatic brain injury (TBI).

The purpose of proposed study is to determine if Talampanel (an AMPA receptor blocker) the new antiepileptic and neuroprotective agent is effective in preventing acute seizures and improve neurological recovery after TBI.

We propose to perform, randomized, double-blind II phase clinical trial to evaluate the safety and the effectiveness of Talampanel in patients after TBI. Patients with TBI will be randomly assigned to two groups. Group 1 standard care and Group 2 standard care and Talampanel 35mg for 7 days after injury. All subjects will be followed for one year. Serial EEGs and MRIs will be taken to evaluate brain function.

Endpoints of this study include:

-Decreased number of seizures

-Improvement in neurological assessments

-Improvement in neurological symptoms (headaches, etc)

-Improvement in brain MRI.

The total cost of proposed study will be approximately 555$.

We believe that Hijar-Max Pharmaceuticals has sufficiency expertise to perform proposed study. We expect to finish this study in 3years after enrollment of first patient.

2. Company description

Hijar-Max Pharmaceuticals is a privately held life science company located in St. Louis, Missouri. Our investors include pharmaceutical-focused venture capital investors, company founders and individuals.

The company is focused on the discovery and development of novel therapeutics for patients suffering from diseases associated with central nervous system (CNS).

The company is applying novel technologies that will generate first-in-class therapeutics, thereby changing the standard of care for patients suffering from epilepsy, traumatic brain injures (TBI) acute pain, and other disorders of the nervous system.

Hijar-Max Pharmaceuticals has been funded in 2005. Since this time the company has identified and patented multiple development candidates that have shown strong efficacy, safety and pharmacologic characteristics. In December 2009 our company filed Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for lead compound, NH555.

The company has also ongoing and planned clinical trials in CNS indications. Recently, Hijar-Max Pharmaceuticals has successfully finished a phase II clinical study investigating neuroprotective effect of N1226 compound in patients after ischemic stroke. Figure 1 presents detailed company`s pipeline.

The company is led by a strong management team with significant drug development experience and a strong track record of success within the field of central nervous system. In 2008 Hijar-Max Pharmaceuticals established collaboration with Washington University in St. Louis which is one of the leading medical research institutions in the United States. In addition, Hijar-Max has established collaborative relationships with pharmaceutical companies outside the U.S. In November 2008 Hijer- Max Pharmaceutical entered into a license agreement with Teva Pharmaceutical to develop and commercialize Talampanel for treatment patient after traumatic brain injury.

We believe that our partnerships will enhance the company's ability to develop and commercialize our product candidates.

Fig. 1 Hijar-Max Pharmaceuticals pipeline.

2. Agent and Study Plan

Talampanel {(R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3] benzodiazepine} (Fig.2) is noncompetitive antagonist of the AMPA receptors.

Fig.2 Molecular structure of Talampanel (4)

AMPA receptors are activated by glutamate that mediated fast excitatory neurotransmission in the central nervous system (CNS). Therefore, in normal synaptic functioning, activation of AMPA receptors is critical in many aspects of brain function. However, in pathophisiological conditions in which excess of glutamine is release over-activation of AMPA receptors leads into necrotic and apoptotic neuronal death. This process of neuronal death is called excitotoxicity and involved Ca2+ influx through AMPA receptors into the neuron (1). It has been suggested that excitotoxicity could be involved in the pathogenesis of several e neurodegenerative diseases, such as ischaemia-hypoxia, epilepsy, traumatic brain injury, Parkinson`s disease, ALS (Amyotrophic lateral sclerosis) and other motor neuron diseases, in which the activity of glutamatergic neurotransmission is elevated (2). Therefore, AMPA receptor antagonists have a potential therapeutic value in the treatment of chronic and acute neurodegenerative diseases. To date, several compounds inhibiting AMPA receptors have been developed and characterized (3). Four of those compounds are currently undergoing clinical trials for the treatment of central nervous system disorders (Table 1).

Hijer- Max, Pharmaceuticals is particularly interested in the use of AMPA receptor antagonists as neuroprotectiv agents to treat patients after traumatic brain injury (TBI). According to National Institute of Health, TBI is defined as a form of acquired brain injury, occurs when a sudden trauma causes damage to the brain. In TBI primary insult results in immediate mechanical damage (primary injury). It has been shown that the level of glutamate markedly increase early after primary injury inducing neuronal Ca2+ entry through glutamate-regulated receptors. Those biochemical and physiological events ultimately lead to neuronal death and results in a secondary injury that evolves over a period of hours to days, even months, after the primary insult. Thus, blockade of receptors activated by glutamate such as AMPA receptors may protect patients after TBI against secondary brain damage and finally improve functional outcome of TBI patients.

We believe that Talampanel a noncompetitive antagonist of the AMPA receptors may be used as a neuroprotective agent to prevent secondary brain damage in patients after TBI (5). Talampanel is orally active and well tolerated by healthy human subjects (maximum tolerated dose was 100 mg). It has also good bloodbrain penetration (7). Currently, Talampanel is being examined in patients with amyotrophic lateral sclerosis, adults with partial seizures, and patients with recurrent glioma or advanced Parkinson's disease (6).

Table 1. AMPA receptor antagonists examined for CNS diseases indication (6)

AMPA receptor

antagonist

Clinical indication

Phase of clinical trail

LY 300164

Parkinson`s disease

Phase II

Talampanel

Parkinson`s disease

Amyotrophic Lateral Sclerosis (ALS)

Epilepsy

Brain activity

Phase II

Phase II

Phase II

Phase II

Topiramate

Parkinson`s disease

Post Traumatic Stress Disorder (PTSD)

Alcohol and Comorbid Cocaine Dependence

Migraine

Epilepsy

Traumatic Brain Injury (TBI)

Bipolar Disorder

Tourette Syndrome

Phase II

Phase IV

Phase II

Phase IV

Phase IV

Phase II

Phase III

Phase III

ZK 200715

Visual system

Phase I

Talampanel was effective in reduction of seizures in patients with refractory partial seizures (7). Furthermore, it has been shown that this drug protects primary rat hipocampal neurons against gluamate-mediated excitotoxicity (8). Neuroprotective effect of Talampanel has been also demonstrated in vivo using various animal models (9). It is important to note that, Belayev et al. reported that talampanel therapy significantly reduces brain damage in rat model of TBI. In addition, preclinical studies done by our company confirmed neuroprotective effect of talampanel in various animal models of TBI (manuscript in preparation).

Based on the scientific rationale and a positive preclincal study using animas model of TBI, we hipotetized that Talampanel can 1- reduce acute seizures and prevent the development of epilepsy following TBI and 2- improve patients neurological recovery. To test this idea Hijer- Max, Pharmaceuticals proposes to preform II phase clinical trial to determine if Talampanel is effective in preventing acute seizures and improve neurological recovery in patients after TBI.

We believe that our company has sufficiency expertise and resources to preformed proposed study. SWOT analysis of the company and the proposed study is presented in Table 2.

Table 2. SWOT analysis

Strengths

- Hijar-Max Pharmaceuticals management team has a broad range of expertise in developing drugs targeting diseases associated with central nervous system.

- Hijar-Max Pharmaceuticals holds multiple patents covering Company's drug candidates.

- Company`s collaborators. Our company establishes collaboration with Washington University in St. Louis and with pharmaceutical companies outside the U.S.

- Cmpany is in a good financial situation. Recently, we received grand from NIH for study the effectiveness of Talampanel in patients after TBI. We also received 250,000 from our private investors to support this project.

Weaknesses

- Our company is exclusively focused on diseases associated with central nervous system. We may not have sufficient expertise to develop our drug candidates for different indications.

- We rely on third-party manufacturers for commercial production of our drug candidates. Third-party manufacturers may encounter difficulties in the production process that could adversely affect our ability to deliver drug candidates and could cause delays in study completion.

- Many of our drug candidates are in early stage of development.

Opportunities

- There are no approved pharmaceutical therapies for either acute or post-acute TBI, so this is an area of considerable medical need. 

- Market for drugs targeting TBI.

Children at age 0-4 are in the group of highest risk for TBI.

Military duties increase the risk of a TBI.

- Treatment of TBI is in interest of Department of Defense and Department of Veteran Affairs. We expect to receive additional funding from those departments.

Threats

- New technologies. Our company is aware of rapid development of stem cell therapeutics for treatment of neurodegenerative diseases.

- Drugs side effects.

- Cost of Company's insurance coverage may significantly increase before study completion.

-The regulatory approval processes.

- HMO`s, Medicare, Insurance. We can not predict how heath care reform affects costs of patient's standard care.

3. Market Analysis

4. Financial Analysis

5. Operations plan

Study Design - A phase II, multicenter, randomized, double-blind, placebo controlled trial to assess the safety and efficacy of Talampanel in the treatment of severe Traumatic Brain Injury (TBI)

Objective - To determine the safety and efficacy of acute administration of Talampanel on recovery from severe closed head injury

Setting - Level I Trauma Centers - subjects to be recruited in Emergency Department and/or Neuro ICU

Study Population - 18-80 year old males and females who have suffered a severe traumatic brain injury as determined by the Glasgow Coma Scales.

- A total of 30 subjects will be randomized into 2 groups, with 20 subjects in the treatment group and 10 in the placebo group at 2 sites. Training, monitoring and data management will be managed through the Center for Clinical Studies team at Washington University in St. Louis site.

Main Outcomes Measures: Improvement of brain axonal injury determined by MRI using DTI (Diffusion Tensor Imaging, Improvement in impaired brain functional connectivity, measured by using resting-state fMRI correlation analysis, and improved neurological and cognitive function using the Glasgow-Outcome Scale, and tests of attention, memory, and vigilance.

Secondary Outcomes Measures: decrease in number of seizures by EEG measurements.

Study Duration - the Talampanel in TBI trail will enroll 30 subjects at 2 sites. The total follow-up time for patients enrolled is 48 weeks. It is anticipated that the appropriate number of subjects will be enrolled within 2 years of study initiation. All subjects will be followed from the time the subject signs consent until discontinuation or completion of all study requirements. Subjects enrolled will be evaluated at baseline, hour 12, day 1, day 2, day 3, day 4, day 5, day 6, day 7, and week 2, 4, 12, 24, 36, and 48.

Randomization process - 2-1 randomization will be conducted by computer in Research Pharmacy at Barnes Jewish Hospital. Drug / placebo is initiated within 12 hours of brain injury and after baseline/screening assessments are completed. 35 mg. of IV Talampanelâ„¢ vs. placebo BID (0800 & 1200) is continued for 7 days.

Safety - Subjects will be closely monitored with vital signs, plasma drug levels to measure for toxicity, blood tests for CBC (with differential and platelets), blood chemistries to monitor liver and kidney function, neurological assessment, and physical exams as indicated.

Data Safety Monitoring Plan - There will be an independent Data Safety Monitoring Board (DSMB). They will meet regularly and will be charged with adjudicating adverse events, overseeing the study, and safeguarding the interests of study subjects. We will comply with any additional interim analysis deemed appropriate by the DSMB. Should an unexpected safety concern arise, the DSMB may recommend that the trial be stopped. A key issue in both safety and efficacy will be managing data in a timely manner and insuring quality assurance through efficient and correct data entry and site monitoring. Site visit monitoring will be done by the Washington University Center for Clinical Studies as needed based on performance (average of 1 visit per site). Sites may require more visits, depending on need.

Patent Protection -

Payments to sites - sites to be paid start-up fees up front, and then based upon accrual and reaching study milestones

Inclusion

18 - 80 years old

Males and females

Severe TBI (GCS of 8-12)

Exclusion

History of previous head injury

History of psychiatric illness

History of drug or alcohol abuse requiring treatment

History of seizure activity

Unstable cardiac disease

1. Frandsen A, Schousboe A. (2003) AMPA receptor-mediated neurotoxicity: role of Ca2+ and desensitization. Neurochem Res. Oct;28(10):1495-9.

2. Doble A. (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. Mar;81(3):163-221.

3. Gitto R, Barraca ML, De Luca L, Chimiri A. (2004) New trends in development of AMPA receptor antagonists. Expert. Opin. Ther. Patents. 14 (8): 1199-1213.

4. www.chemblink.com

5. Howes JF, Bell C. (2007) Talampane. Neurotherapeutics. Jan;4(1):126-9.

6. www.clinicaltrials.gov

7. Chappell et al (2002) A crossover, add-on trial of talampanel in patients with refractory partial seizures. Neurology (58)1680-1682

8. Belayev L et al (2001) Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats. J Neurotrauma. (10):1031-8.

9. Denes L, Szil´agyi G, G´al A, Nagy Z. (2006) Talampanel a non-competitive AMPA-antagonist attenuates caspase-3dependent apoptosis in mouse brain after transient focal cerebral ischemia. Brain Research Bulletin (70) 260-262.

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