CED Tight Space Innovation Market Entry- final report

Company X Pump for Convection Enhanced Delivery (CED) Market Entry/Validation – Final Report (Primary KOL Qualitative Research) 5/4/11

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Company X Pump for Convection Enhanced Delivery (CED) Market Entry/Validation – Final Report

Table of Contents Pages

n  I. Profile of KOL Respondents, Research Objectives and Methodology 3-4

n  II. Executive Summary - Key Research Findings q  Overview of existing CED and Alternative Approaches (Pros/Cons/Unmet Needs) 6-16

q  CED Delivery of Active Agents for In-Brain Drug Delivery – Pros and Cons q  Pros and Cons to CED (Pump and Catheter System) q  Barriers to Market Adoption of CED q  Alternative Approaches (Insights)

q  Key Disease Target Populations and Opportunities 17-19 q  Ranked diseases with highest potential to use CED 20

q  Key Customers & Decision Makers 21 q  Key Features of Pumps/Catheters 22-26 q  The CED System – Purchasing/Packaging Preferences 27-28 q  Intracranial Infusion – Technique of Choice? 29-30

q  Alternatives to Intracranial Infusions q  Potential of a CED system to be used as a Post-Op Immunotherapy Treatment 31 q  The Potential of Selective Gene Therapy on CED 32 q  Stem Cells Potential Impact on the Treatment of Cancer 33 q  Stem Cells Potential Impact on the Treatment of Cancer 34 q  Safety of a CED System 35 q  Potential for a CED Treatment to be Inpatient and/or Outpatient 36 q  Potential for the adoption of the CED system (pump and catheter) for Research Purposes 37 q  Acceleration of the Development of Drugs for CED (for in-brain and intra-organ delivery) 38 q  Competitive Landscape (Outlook) 39-40 q  Economic/Business Factors – Pricing / Reimbursement Potential 41 q  Easiest regulatory/clinical trial pathway for a CED System 42-45 q  Getting Buy-in from Neuro Surgeons, Neuro-Oncologists 46 and Other Types of Medical Research Professionals

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Table of Contents – cont’d.

Pages n  III. Emerging Market Entry Insights (Drivers, Barriers) 48-54

q  Ongoing Clinical Trials (Insights/Profiles)

n  IV. Competitive Landscape 56-63 q  Companies and Technologies on Market and in Development (Profiles)

n  V. Recommendations 65-71

n  VI. APPENDIX 73-75 q  List of KOL Study Participants

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n  I. Profile of KOL Respondents

Number of KOLs Interviewed:

Geographic Scope: Represented Countries:

-- 26 -- Includes: US, Canada, Switzerland, Netherlands, Israel

Professional

Categories of KOLs Interviewed:

--Researchers/clinicians in neurosurgery, neuro-oncology, neurology, bio-medical engineering; Professors of Surgery, Oncology and Cancer Biology; Chemical and Biomedical Engineering, Directors of Neurosurgical Oncology and Neuro-Oncology research.

KOL Specialties & Research Area Focus:

--Medical Neuro-Oncology --Neurosurgery --Oncology and Cancer Biology --Neurology --Chemical and Bio-Medical Engineering --Nanoparticles (How they are transported in the brain) --Immunology --Novel Delivery Vehicles --Fluid Dynamics and Biological Systems --In vivo and in vitro research --Pharmacology --In-brain and intra-organ CED delivery method research (clinical trials) --Principal investigators in CED/Parkinson’s and other neuro-degenerative diseases clinical trials --Chiefs of Neurosurgery and Brain Tumor clinics at various academic institutions

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Company X Pump for Convection Enhanced Delivery (CED) Market Entry/Validation – Final Report n  I. Research Objectives and Methodology

q  Research Objectives and Methodology:

§  Provide primary and secondary market research/analysis, while assisting in the identification of market adoption and validation factors (economic/business; regulatory/reimbursement environment; medical/surgical; similar device technology; key customers; and competitive factors, along with insights into potential target customer/ disease population segments and extended product development opportunities.

Primary Qualitative Research Methodology: Harrison Hayes utilized a primary, qualitative Key Opinion Leader (KOL) research module – customized specifically for the needs of research initiative along with supplementary secondary research.

§  KOLs based in the US, Canada, Netherlands, and Switzerland - and were interviewed by

phone. The KOL's were pre-screened to assure they could provide insightful observations and innovative approaches.

§  All interviews are conducted by Harrison Hayes’s Principals and Market Research Team who had the autonomy to probe deeper and maneuver through unique issues that arose during discussions with the KOLs – what is referred to as improvisational interviewing.

§  Secondary Research Methodology: Harrison Hayes also utilized a variety of database

resources to recruit a world class group of KOLs. Harrison Hayes identified a number of valuable individuals to interview and created a project-specific database with all pertinent KOL contact information for the project.

§  The overall content of this study reflects (1) the combined/integrated feedback and in some

cases, consensus, of the KOLs who participated in this study, and (2) Harrison Hayes data and qualitative primary and secondary research analysis .

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n  II. Executive Summary - Key Research Findings

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Company X Pump for Convection Enhanced Delivery (CED) Market Entry/Validation – Final Report n  II. Executive Summary – Key Research Findings

n  Overview of existing CED* and alternative approaches (Pros/Cons/Unmet Needs)

ü  CED has yet to matched in terms of infusion depth, rate and coverage area; spatial penetration is more limited without CED. Existing, alternative approaches are not achieving adequate penetration in an adequate amount of time. (Note: Once you infuse a drug through a needle, you have very little degree of freedom in which to control the way it moves through the tissue. It is proven to be one of the major problems with CED. However, once a preferred CED strategy is developed, it is anticipated that adopting it to whatever molecules are on hand will take place.)

ü  The KOLs indicated that the CED technique for active agents delivery to brain tumors is now being tested in various clinical trials on both animals and humans. The KOL consensus indicates the CED technique is still an attractive type of active agent delivery strategy for infusing drugs, including nano particles, antibodies, viruses, and/or whatever appropriate active agent into the brain.

ü  Although CED is a useful technique, according to some KOLs, it may not have used the right therapeutic molecules. They believe it is not the technique that has failed. They need to do better with selecting the molecules that are delivered to the tumors; and the same with Parkinson’s and Huntington diseases, where it is uncertain what the proper molecules to be delivered would be. They would use the CED approach, however.

ü  KOLs also noted there has been an effort to test CED for other types of neurodegenerative diseases (including Parkinson’s disease and other rare congenital diseases), with enzyme replacement therapies, including a trial where they are investigating the use of the CED delivery approach. Preliminary indications are that the CED approach is safe to do, however, whether it is efficacious to do, results will follow.

§  *CED- is a promising method of drug delivery to the brain for the treatment of several disorders, including glioblastoma multiforme, a high-grade glioma

that presents an especially poor prognosis for patients. CED bypasses the blood-brain barrier by infusing compounds through a needle or microcatheter directly into brain parenchyma or brain tumor. The infusion establishes a pressure gradient in the tissue that drives a flow of infusate away from the needle. CED has been tested extensively in animals and somewhat in humans to deliver a variety of agents including small molecules, proteins, chemotherapeutics, and viral vectors.

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Company X Pump for Convection Enhanced Delivery (CED) Market Validation – Final Report

n  II. Executive Summary – Key Research Findings

n  Overview of existing CED and alternative approaches (Pros/Cons/Unmet Needs) –cont’d.

ü  Being able to control the infusion is absolutely critical. This has been an ongoing problem with many CED clinical trials.

ü  Real-time monitoring of an infusion during and after a CED procedure is anticipated by the KOLs to be an up and coming trend. If there is a protocol that has been developed and works, it will also mandate that a CED system be MRI compatible. KOLs also stated that during a CED infusion procedure , there is a need for MRI for targeting. The MRI will give an image of what happens, in real-time and after the infusion has taken place.

ü  Several KOLs stated that having an entire CED system set-up which is compatible with MRI, would have advantages over systems that didn’t have this type of capability

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n  CED Delivery of Active Agents for In-Brain Drug Delivery – Pros and Cons

ü  One of the biggest challenges (with in-brain drug delivery, in particular) is getting a drug that works (according to a number of KOL respondents).

ü  Problems with CED approaches being used today: Problems are difficult to determine. The groups performing CED approaches don't necessary report the toxicities associated with these, such as cerebral edema is concerned, along with local, immediate or delayed toxicity. According to the KOLs, it is a very tough issue to identify exactly what problems they are having. On the surface, cerebral edema and the white matter changes that are delineated on magnetic scans as flair or diffusion alternations and the risk of clinical worsening of the patient, would all be viewed as potential complication. It is tough to read those in the current, ongoing trials.

ü  KOLs indicated that at UCSF (University of California at San Francisco), researchers are in the process of designing better infusion parameters and placement of catheters, along with 3D imaging software tools that are trying to optimize all these parameters that impact the volume of distribution of active agents.

ü  KOLs expressed potential toxicity issues with a CED approach, such as: Worsening of neurological deficits, including seizures; infections and having to see patients in the hospital for the duration of treatment (more expense involved).

ü  KOL-related CED results from a toxin trial: Found that catheter placement accuracy (getting into the tumor, and not picking the ideal target with the right precision) - especially when placing multiple catheters. The recommendation going forward was to have more centralization and some standardized training in terms of catheter placement. There were no safety concerns; no infections; however, strange signals appeared in six months after via an MRI. They found out it was caused by some reactions to the catheter.

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n  Overview of existing CED and alternative approaches (Pros/Cons/Unmet Needs)

n  CED Delivery of Active Agents for In-Brain Drug Delivery – Pros and Cons – cont’d. ü  Potential side effects from an in-brain CED procedure could occur, such as: brain edema; infection;

malfunction and delivery failure and/or seizures.

ü  CED (Standardized) Training Lacking: KOLs recommend that going forward with CED would require more centralization and/or standardization of the CED (in-brain catheter placement) technique, particularly for surgeons/investigators conducting clinical trials that utilize the CED. Therefore, standardized training in catheter placement, is recommended.

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Company X Pump for Convection Enhanced Delivery (CED) Market Validation – Final Report n  II. Executive Summary – Key Research Findings


n  Pros and Cons to CED (Pump and Catheter System)

ü  A pump and catheter (CED) approach is a little more sophisticated because if provides slow release well below the threshold of producing cerebral edema. It is also quantifiable, therefore there is no alternations in the expected administration that would be profoundly better for the patient - who might tolerate it over 36 hours and for the physician who would not want to stay by the bedside of the patient to oversee the drugs.

ü  In several CED clinical trials, patients didn't respond. Investigators were not sure if this was due to the type of drugs or the method of delivery, which may not be getting into the tumors successfully.

ü  Results from clinical trial CED of active agents for in-brain drug delivery investigations indicated that approximately 80% of the catheters weren't getting the volume of infusion needed. And the infusions were not going where they wanted the agents to go. Instead there was pooling of fluids within the tumors. Based on those observations, the investigators have gone back to the drawing board.

ü  Cather placement accuracy is a concern with (KOL respondent) CED clinical trial investigators, especially when placing multiple catheters.

ü  Other types of in-brain delivery of drug approaches include refinements to the catheters, themselves; still working within the CED model, but increasing the precision, materials and diameters of the catheters to improve the flux into the target.

ü  Will require having a skilled surgeon that knows how to operate/surgically apply a CED system.

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n  Barriers to Market Adoption of CED

q  Costs, technical issues, drug agents that are not going where they thought they would go, potential toxicities

q  Lack of efficacy

q  Choice of wrong active agents

q  No one has shown it has a consistent benefit of treatment. The failure of prior attempts of clinical trials that were done revealed the investigators had no idea where the agent was going. In a clinical setting it didn't work.

q  Other KOLs stated they didn’t think it was because that the drugs didn't work. The barriers to distribution weren't well thought out. And the delivery of agents to where you wanted them to go , wasn't worked out.

q  Could probably sell to a neurosurgeon, however, would have a huge degree of push back from medical neuro -oncologists and radiation therapists. There would be insufficient rationale to go out and support a neurosurgical approach.

q  Need clinical evidence and need champions, such as leading academicians, that will test it and teach other people how to use the system/technique.

q  KOLs stated that it would be very tough for a company to get sufficient data to support a phase 3 trial to identify the efficacy. Probably would need 40-50 patients in each trials and patients with localized, lesions that could not be excised that would be treated with CED. Estimated costs of trials, would be $40K to $50K per patient.

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n  Barriers to Market Adoption of CED- cont’d.

q  At the moment, technical issues related to efficacy, accuracy, and dosing, penetration, and the movement to improve catheter design

q  Would need to have a buy-in, if proven efficacious, in a randomized trial. It would have to be appealing, conceptually.

q  Improvements are needed in the catheter’s capability to limit the reflux and improving their inflow rates would make it more appealing

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n  Alternative Approaches (Insights)

ü  Other approaches have yet to match CED in terms of infusion depth, rate and coverage area; spacial penetration is much more limited without CED. The CED technique has proven it will effectively deliver, for example, a virus or toxin or tracer drug and will take it to the target destination.

ü  There are a number of active agents against brain tumors, but they do not have a good way of delivering them.

ü  None of the alternative approaches to CED have figured out the problem of distribution that is inherent with a liquid medium (Note: Several problems include backflows along the catheter, where you can't get a fluid wave to distribute to the brain, thus, it doesn’t get absorbed.)

ü  It is not clear that the average clinician as a neuro oncologist, would have much of an investment in CED, which is predominately a neurosurgical enterprise. As a consequence, it can put neurosurgeons somewhat at odds with neuro-oncological clinicians who would be interested in phase 1 or 2 agents with either oral or intravenous administrations, but would not be very interested in phase 1 or 2 agents that would require a full-time neurosurgical commitment to their infusion.

ü  Current CED procedures are not achieving adequate penetration in adequate amount of time.

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n  Overview of existing CED and alternative approaches (Pros/Cons/Unmet Needs) – cont’d.

n  Alternative Approaches (Insights) – cont’d.

ü  For brain tumors in adults & children, a combination of surgery, radiation and chemotherapy (chemo has a role to play, but it is modest). NOTE: Radiation therapy has been used for brain tumors for adults.. for most malignant tumors and secondary tumors. Its efficacy is short lived. Patients will relapse and die. Radiation therapy is used for children over the age of six. Under age of three, radiation is not possible to use. Must rely exclusively on chemotherapy for this age group.

ü  Only recently chemotherapy has a role to play in adult malignant brain tumors. For children, chemotherapy

has been shown for a number of years quite successful. However, there are two major problems with chemotherapy. Many chemos will not cross the BCompany X, however, there are ways to get around it. By and large, there is intrinsic brain tumor resistance (e.g. BBB) to the chemotherapy that is being administered.

ü  As for the BBB, there are efforts to obviate its presence and to get around it, and to break it down in a number of fashions. One is to open up the BBB using pre-administered agents (e.g. osmotic diuretics) and then administer the agents intra-arterially. This technique has had limited and modest success with two decades of investments.

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ü  Feedback from the KOLs indicate that we do not have any measure of the concentrations of orally, intravenously or CED administered drugs as they relate to the brain tumor in situ*. Therefore, the advantages of CED could be demonstrated by knowing the concentrations that are associated with CED approaches as distinct from intravenous or oral approaches.

ü  The study also revealed from the KOLs that the field of neuro-oncology has moved ahead to the point that there are boutique treatments for each form of glioblastoma (multiforme) brain tumors. The molecular mutations associated with glioblastoma patients formerly thought to have a homogeneous tumor, may now have not only one, but perhaps as many as 7 or 8 sub-types of glioblastoma. Each one of which will ultimately require a specific targeted molecular therapy. So that the provision of CED to glioblastoma or other types of local delivery systems with a single drug, may not actually deal with the type of targeting that would be required for a particular molecule end-point.

* In oncology: for a carcinoma, in situ means that malignant cells are present as a tumor but has not metastasized, or invaded, beyond the original site where the tumor was discovered.

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ü  Other treatments for brain tumors include modifications on previous types of strategies such as, the human vaccine approach, where a patient with a brain tumor is being vaccinated against specific antigens within that brain tumor. Current clinical trials are being done out of Duke (via Dr. John Sampson. Note: He will be a future KOL). This is appealing for a sub-set of patients with brain tumors, and which only applies to approximately30% of patients with brain tumors.

ü  There are also some modifications of radiation therapy, including raidosurgery, linear accelerators, XKnife Stereotactic Raidosurgery and Cyber knife radiation delivery strategies that will target the brain tumor. There are problem in their invasiveness and that they can't get to all the cancer cells unless you used a huge volume of radiation which the brain cannot stand.

ü  For Parkinson’s disease, there are many drug and deep brain stimulation treatment, which is an invasive approach, but becoming more popular. Deep brain stimulation does not cure the disease, however.

ü  A gene therapy developed by Neurologix Inc. (NRGX) has been able to shoot a gene deep into the brains of people with Parkinson’s disease, easing their jerking motions and tendency to freeze, according to a study sponsored by the company. This type of treatment is aimed at ameliorating the immediate symptoms of Parkinson’s, not reversing its course. NOTE: No gene therapy has yet been approved by the U.S. Food and Drug Administration. (Neurologix Company link: http://www.bloomberg.com/news/2011-03-16/neurologix-gene-therapy-helps-parkinson-s-patients-walk-move-in-study.html)

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n  Key Disease Target Populations and Opportunities

q  Glioblastoma patients

q  The study KOLs see a strong potential use of a CED treatment in Parkinson’s disease, as a means of pumping up localized, dopamine levels. Although there are multiple treatments for Parkinson’s, to some extent they help in reducing the symptoms and enhance the quality of life, they are not curative. None of the treatments stop the brain degeneration that is occurring. Ultimately, the patients succumb to the disease at the end stage. There is still is a need to slow the progression of the disease. §  NOTE: This disease has a much larger patient population, than Glioblastoma, particularly in the US.

Approximately, 1.5 Million people in the US have Parkinson’s disease, according to the Parkinson’s Disease Foundation.

q  Other diseases to apply CED include many of the neuro-degenerative types of diseases, including getting trophins to penetrate the brain. Additional focus on CNS (central nervous system) diseases such as Alzheimer’s, Huntington Chorea, Epilepsy, and Multiple Sclerosis has potential according to the KOLs.

q  Many of the neurodegenerative are genetic. A CED replacement of enzymes that is deficient has great potential. If you could get the CED to diffuse the agent throughout the hemisphere and deliver the enzyme to the target site without degradation, making its connection and having it absorbed, it would greatly increase its therapeutic potential.

q  Epilepsy should also be considered. Currently, there are 25 drugs to treat this disease, that are marketed worldwide. Most are generic. This disease affects about 1% of the population or 3 M people in the US. However, 30% of those patients are not adequately controlled with orally available drugs. Some of these patients become candidates for surgery, where a high percentage of those patients do much better after surgery. However, there is not enough capacity in the US for all of these patients to have this type of surgery. A CED approach could possibly benefit these patients.

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n  Key Disease Target Populations and Opportunities (cont’d.)

q  Diseases like stroke may also benefit from CED. There has been some work that is showing that the post-synaptic membrane is very important in the context of stroke. NOTE: CED could be used when a clot is taken out by delivering neuro protectant compounds to protect the tissues after a clot is resolved. However, a KOL stated that there is a very short time window to treat this situation. Not sure if the CED procedure would be fast enough

q  Uniformly fatal and hard to treat intra-organ diseases such as, cancer, colon, pancreas, liver and solid organ structures would be reasonable to approach with CED.

q  The Company X CED system could also be used in both in-patient and out-patient scenarios, which would be dependent on the type of CED procedure (in-brain versus intra-organ) initiated. This was supported by a consensus of the KOL study respondents.

q  There is potential for CED in uniformly fatal, and hard to treat diseases such as liver and pancreas cancers (This type of cancer could support a pancreatic infusion, but it is complicated).

q  A segmental infusion strategy for the liver is hugely acceptable and highly effective. This would be driven by the arterial circulation in the liver. Criteria for regional infusion of the liver are well worked out.

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n  Key Disease Target Populations and Opportunities (cont’d.)

q  Any sort of congenital deficiency, where a child or young adult is missing an enzyme in the brain. You could attempt to replace the enzyme through CED delivery using either stem cells that carry the enzyme. Or viruses carrying the enzyme. In general, you could kill something that shouldn't be there (tumor) or you can use it to replace it with something missing for Parkinson's or some congenital disease

q  There is significant, non-tumor utility potential for CED to treat a variety of illnesses not treated now such as, Prion disease, active viral infections and diseases that have a profound degree of unresponsiveness. §  Suggestion: To explore uniformly fatal, untreatable diseases that have affectively no therapy, but could

be altered.

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n  Ranked disease states with highest potential to use CED (according to the KOL study respondents)

q  1- Malignant Brain tumors (Glioblastoma) q  2- Parkinson's (there are approved drugs that are known to work for Parkinson’s disease) q  3-4 Epilepsy (certain localized/focal types; and where the site of the lesion is known) q  4- Solid intra-organ (focal) tumors (including liver and pancreas) – (has a lot less certainty about where to

target the infusion) q  5-Alzheimer’s (no known drug cures; disease encompasses entire brain; not localized/focal) q  6- Additional disease types: ALS (Lou Gehrig's Disease), Multiple Sclerosis q  7-Stroke

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n  Key Customers & Key Decision Makers

q  Neuro-Surgeons

q  Neuro-Oncologists

q  Team approach: Consisting of both neuro-oncologists and neuro-surgeons

q  Hospital Tumor Boards (consisting of both neuro-oncologists and neurosurgeons – primarily in larger hospitals in the US). Smaller hospitals (in the US) do not necessarily have neuro-oncologists present. Therefore, the key decision maker would be a neuro-surgeon.

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n  Key features that a CED Pump and Catheter Must Have

q  Key features of a CED pump:

§  A clear, ambulatory approach--so that a small cassette availability could be used to pump into a patient who is ambulatory would be of great value.

§  There was an overall consensus from the KOLs that having the ability to monitor how the infusion is proceeding (including the presence of a restriction/occlusion in the flow path, overpressure, under pressure) was a key advantage. The more controllable the technology, the better.

§  Having the ability to continuously monitor the pressure gradients and maintain within a well-defined range for a given patient, is a critical feature.

§  The smaller the pump, the better.

§  An implantable pump was very popular with the KOLs. A pump that can be accessed with a needle through the skin, so that once a pump is implanted, it can be reloaded when necessary, with a low profile, and ease of insertion would also be beneficial.

§  Having the ability to monitor the infusion and how it is proceeding would be a key advantage. This would help to avoid pump failure and pump fatigue.

§  Having the choice of the solution that is to be infused would be an important add on. The KOLs would also like to see a tracer to be able to see where the infusion is going as the CED procedure is being performed.

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n  Key features that a CED Pump and Catheter must have

q  Key features of a CED pump – cont’d.

§  KOLs stated it would be nice to have a small size, reliable, easy to use and manipulate.

§  KOLs would like pumps that could be programmed readily. They would very fewer technical errors associated with the tubing that attaches to the catheter system should be straight forward to reduce infections.

§  The pumps would need to have a well-defined pressure limit and stop mechanism on it in order to avoid fatal errors of injecting too high of a volume of the active agents into the brain. This mechanism would also help to avoid an overdose and have an absolute stop mechanism of fluid.

§  Pumps that would have the ability to continuously self -adjust and monitor would be very important.

q  Ability to Monitor Infusion As a Key Advantage – KOL Feedback

§  A majority of the KOLs stated they believed that having the ability to monitor how the infusion is proceeding (including the presence of a restriction/occlusion in the flow path, overpressure, under pressure), as key advantages. However, with MRI real-time imaging during the infusion, some these capabilities could possibly be provided by the MRI.

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n  Key features of a CED catheter:

q  KOLs suggested that the catheter should be implantable to accommodate not just a one -time infusion, and to be used for potential out-patient treatments.

ü  NOTE: A problem with multiple infusions is that if the catheter is removed and then goes back in, the presence of

the first catheter leaves a defect in the tissue. When the second catheter comes in and starts a flow, the fluid would move along the original catheter pathway, rather than where you want it to go. Therefore, implantable devices have potential to prevent this type of problem.

q  Previously, CED catheters created backflows, which has been a major inhibition in using CED. The KOLs are not sure if you can eliminate this problem. A suggested step down method used in trying to accommodate this problem to minimize backflow, however, gets into product design issues.

q  A catheter technology that allows for administration, yet also allows for scans to be done so you know the extent of the crisis, at the catheter tip and distances from the catheter tip. This would allow the doctor to scan the patient and be able to cover the tumor based on the magnetic scanning.

q  Any marriage between the CED technology and actual measurements of in situ drug levels, would be hugely valuable. It would help to reduce the risk of the physician getting sued for drug related toxicities or the amount of drugs are being put into the patient. Therefore, measuring how much drugs that are being put in the catheter tip would be good.

q  Some catheters get clogged and some have blockages. Being able to minimize the blockage factors that would prevent the infusion being conducted with the catheter would be advantageous.

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n  Key features of a CED catheter – cont’d.

q  The ends of catheters should be made of materials infused to optimally achieve volumes of distribution.

q  Monitoring the pressure could indicate whether the fluid is behaving the way the surgeon hopes it should. You could put pressure sensors at the tip of the catheter. Just by knowing the pressure at the tip of the catheter, would give you information about the flow line and about the fluid that moves around the tissue.

q  A very flexible (micro-fabricated) catheter that is a wiggly, soft tube that might be implantable for a longer timeframe. (Note: A major drug company is currently testing this type of catheter for its drug in a pre-clinical trial- name of drug company, was not provided.)

q  The catheter needs to be relatively small, so it creates minimal damage of insertion.

q  Can't be too thick with a diameter of IV tubing or pencil that can be manipulated easily.

q  The connections need to be seamless to the pump, going to the pump to the tip of the catheter.

q  The type of surface of the catheter would be important, so as not to create an immune reaction.

q  The catheter needs to be implanted and that the system of communication between the pump and catheter is well placed.

q  Would like to see catheters have antibiotic impregnation, radio opaqueness and opportunity that after surgery you can track where the catheter is placed via x-ray.

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n  Key features of a CED catheter: - cont’d.

q  COMPETITION & ADVANCED NEW FEATURES FOR CED CATHETERS – There have been advancements made to the catheters which are still working within the CED model, including the following examples:

§  Increasing the precision and diameters and materials of the catheters to improve the flux into the target (e.g. companies working on advanced catheters include: Medtronic, Codman and Integra all have some level of interest and efforts going on in this area with new advancements).

§  Step-Down Catheter: A reflux resistant cannula that allows for more even spherical distribution by putting a tapered step at the tip that blocks backflow after the injections is one of the catheter advancements developed by Dr. K. Bankiewicz’ laboratory at the University of California – San Francisco) NOTE: Dr. K. Bankiewicz is also a participating KOL in this study.

§  Multiple Channel Catheter (in prototype development at Cornell University): One of their catheters (being tested) has multiple channels, which can handle 1-3 fluids in sequence in a single device. Various types of active agents can be put into them. The channels are totally independent, with no cross over between the channels. This catheter is also interchangeable with any type of pump. NOTE: Different types of active agents could attack various types of glioblastoma.

ü  It should be noted that this type of catheter is currently being tested in Dr. William

Olbricht’s lab, at Cornell University, in New York. Dr. William Olbricht is also a participating KOL in this study.

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n  The CED System – Purchasing/Packaging Preferences

q  KOLs stated that it would be valuable to purchase the pump and catheters, together. Most people would prefer the whole system be self -contained in one package, particularly for places that will have a significant learning curve. The system will have to be laid out to make it as easy as possible.

q  KOLs also indicated that an integrated pump and catheter CED system would also be a preferable

option. The pump, which could either be attached or implanted into the skull, could be activated, remotely when a doctor reads an MRI from the patient. The MRI could indicate active agent flows, problems, etc. The remote system could then be activated by the physician, based on need, new prescription treatments, etc.

q  There could also be a separate system for purchasing each device separately. Some KOLs thought it may be best to unbundle the system so that you could use multiple catheters for any type of pump system.

q  It was also suggested that if there was a bundled option, at a discount, that would be appealing to purchasers.

q  If the CED system could be used for multiple patients, it would be lesser of a cost/reimbursement issue. If it only could be used for one patient, then it could create a bigger cost/reimbursement issues.

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n  The CED System – Purchasing/Packaging Preferences – cont’d.

q  CED System Packaging with or without Drug Preferences

§  Purchasing a CED system which is already loaded with an active agent (drug) is preferred by some of the KOLs. This way, the volume that is pre-loaded into the catheter would be the volume required for the total treatment. If, however, you need to administer the drug every month the patient is alive, you may need to have the capability to load the catheter with different dosages, based on the regime prescribed. For example, you can have the first five doses loaded and have a way to reload the device.

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n  Intracranial Infusion - Treatment of choice?

q  It will always be a viable and valuable option. However, KOLs state that ultimately malignant brain tumors are heading toward more personalized treatments, rather than uniform types of treatments. Personalized treatments may be based on individual tumors which can be based on mutations or based on their spatial presentation which might be better suited for CED (e.g. focal tumors would be treated with CED). Other types of tumors might be better treated with systemic drugs.

§  A personalized approach: Every tumor at the time of diagnosis has a distinct MRI and a pattern of mutations; mutations would influence the type of drugs you would give, and spatial presentation in terms of what sort of spread and active agent loads are involved.

q  According to some KOLs, the therapeutics in this approach are exquisitely potent and tumor specific . And the lack of systemic toxicity is a great advantage for the patient. Therefore, KOLs believe there still will be a lot of enthusiasm that can be resurrected for this type of approach. However, a lot of people have backed off from this approach due to lack of efficacy, particularly in Glioblastoma clinical CED trials, along with potential expense, its uncertainty in value and potential toxicity issues.

q  Some of the KOLs believe CED will be a complimentary treatment strategy and will not be a sole solution. However, it has tremendous potential for a complimentary approach to what is currently being done, which may push the envelope for a patient's survival if CED shows efficacy. The biggest problem is reaching the target effectively.

q  Because of the nature of the disease (Glioblastoma), it could be the method of choice, provided the hardware that is used for the infusion is user friendly. This is not the case, right now. This approach will not be the sole treatment, however, but its potential may increase over the next 5 -10 years, based on efficacy.

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n  Alternatives to Intracranial Infusions

q  Nano-encaptualization of active agents to pass the BBB or usage of nanomedicine.

q  Use of MR magnetic resonance guided focused ultrasound that will focally break down the BBB where it is administered and where it is focally broken down.

q  Can they segregate tumors and do these alternatives have side affects? Yes, they do. Side affects could include kidney failure, liver problems, or bone marrow suppression where the immune system is eradicated. This could happen when there are more drugs infused.

q  Targeted agents will occupy most of the activities for the next 10 years. Standard surgery will be hard to be replaced, and progressive and alternative schemes for radiation therapy and genetic therapies will be coming on line, along with viral vectors, immunization strategies.

q  Using ultra sound to cross the BBB. Would create micro bubbles and could focus the ultrasound in a specific part of the brain; would open the BBB. NOTE: A number of ways people tried to open the BBB a number of clinical trials that followed to target brain tumors. However, none have been successful and will not be as powerful as local delivery of active agents to the brain.

q  Immunization, viral vectors and targeted agents, all relatively new.

q  Other CED alternative issues that they do not address: the impossibility of measuring of what you are doing in the brain tumors. without a marker of the efficacy of these agents will be shots in the dark...no better than CED. can't follow what you have done with the tumor.

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n  Potential of a CED system to be used as a Post-Op Immunotherapy Treatment

q  The overall KOL consensus was – YES, there is good potential.

q  Advantage of CED is having the implantable CED system which allows you to access the brain, at will, to help keep the disease from coming back.

q  Yes, certain at this point, especially with using PET scans which will give this type of treatment tremendous flexibility.

q  Some KOLs, however, believed that this type of treatment is a little trickier because the ability to traffic the cells into the brain tumor through CED has been tried in the past without success. if you decided try to immunize a patient against their own tumor, but use CED for the mechanism for immunization, how are you going to traffic the cells into the nervous system? Don't see it as being the means for priming the pump for immune activity.

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n  The Potential of Selective Gene Therapy on CED

q  Gene therapies have been extremely experimental, however, KOLs have stated that selective gene therapy could benefit from CED, would be effective and would be the method of choice for this type of therapy. CED can have an affect on achieving a predictable and robust gene therapy. Without CED it will not work.

q  There are active, ongoing selective gene therapy trials using CED. q  Viral therapy is essential gene therapy. There is great potential for CED development here.

q  The real potential benefit of CED over systemically administered drugs is specifically the development of selective gene and immune therapies.

q  Delivery of herpes viruses will be very complicated through intravenous or intra arterial routes.

Therefore, CED is likely to become an approach to enter viruses into the tumor, and it has been looked at only on an experimental basis. The issue is not settled yet.

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n  Stem Cells Potential Impact on the Treatment of Cancer

q  One stem cell aspect is the idea not all the cells in a given tumor are the same. Cancer cell research may not have anything to do with CED. However, it could replace CED. In 10 years, it is possible. This type of treatment could compete with CED as a delivery agent.

q  Stem cells are being used as delivery agents. They are injected via an IV and know they will find the tumors. The are very mobile and migrate around the body .

q  Research into brain tumor stem cells is very hot. There is a belief that there are brain tumor initiating cells, which may be the reason why we can't eliminate the cancers because the drugs are not targeting the correct stem cells. There is also a belief that drugs could interfere with stem cells. According to the KOL respondents, there is no reason why a CED approach couldn’t be used in stem cell cancer research.

q  Stem cells are perceived as bio protective agents. Stem cells may reduce the toxicities inherent in many

approaches. It may prevent chemo brain or toxicity of the brain.

q  Stem cells can be used as immunization technologies. So you can prime stem cells either in dwelling or externally.

q  Stem cells have the ability to measure circulating stem cells as a marker of chemotherapy. The effects of using stem cells either expanded or protected as a means of avoiding drug related toxicity in the brain or other organs.

q  Stem cells can be used for both immunization purposes or antigen delivery purposes or can be protected to prevent drug related or radiation damage.

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n  Safety of a CED System

q  The side affects of the drugs have not been tested in a large group of patients. And the choice of

drugs to be put into the nervous system is not an ideal one.

q  The site parameters for administration may change from one patient to another depending of the size of the tumor.

q  For some KOLs, this type of system is almost routine. The primary risk is what is the local toxicity of the therapy you are delivering. This will take more research to discover and the dosage levels still need to be tested.

q  There is also worry about seizures, hemorrhage, stroke, infection, increased intracranial pressure, seizures. All areas of potential possibilities.

q  At some point in clinical trials with tumors with higher concentrations of active agents, there may be some non-specific interactions and potential damage to neural tissues.

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n  Potential for a CED Treatment to be Inpatient and/or Outpatient

q  CED treatment could be both inpatient and outpatient, as well. However, there were some KOLs who believe

that CED treatment for malignant brain tumors should be in-patient (in the short-term).

q  For non-brain tumor CED treatments, there is a long term potential of treating various cited neuro-degenerative diseases and a select group of intra-organ cancer treatments on an out-patient basis. An outpatient option would be more acceptable.

q  CED treatment of patients could result in extended hospital stays that could last approximately two to three days, and then post-op treatment could be done continually, as an outpatient.

q  Instrumentation needs to be done in the hospital, first. Delivery of the drug could then be done on an

ambulatory level. Specific volumes of specific infusion rates, time of the infusion, the volume and rate of infusion and specific infusion protocols would call for instrumentation that involved a pump that would have a sensor with warning signs that something is not right, etc.

q  If the pump has a remote controlled pump, everything can be done as an outpatient. It would also be

advantageous if the patient can have the pump refilled. Patients are already using pumps on an outpatient basis.

q  Could also be outpatient with catheters that had some subcanteanous pump or reservoir system that on a regular basis that could release certain volumes of the agents. There would also be monitoring up front to have a certain degree of confidence. The goal would be to try to get to the point of repeated infusions. That type of approach would be the ultimate goal.

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n  Potential for the adoption of the CED system (pump and catheter) for Research Purposes

q  The KOLs agreed that there would be good potential to use this type of system for research purposes. If someone comes up with a fully integrated CED system, a lot of research questions that could be answered.

q  However, the KOLs also agreed that some, not all, researchers/clinical investigators would probably pay for this type of prototype, with the cost factored into the overall clinical trial budget . This budget is usually funded by the clinical trial sponsors, such as the government (through an NIH grant) or a pharma company, for example.

q  Several KOLs stated they would not be interested in this type of prototype unless it is delivery active, and provides effective treatment. They believe that the CED approach will be driven by the success of the agent, rather than the technology of the catheter and the pump. Clinical investigators are now getting to a level to where they have a mechanism to deliver the agent, so now they are starting to think about the catheter and pump systems that have potential applications. What is lacking in the field with CED trials is they do not have a system to get off the shelf and run with.

q  Not high volume (in regard to amount of research facilities that would use the CED system) with acceptance and utilization. However, if you find something that works, especially with a solid brain tumor, then it opens up similar solid tumor cancer applications.

q  The adoption of the prototype would also depend on the cost. If it has broad applications, it has to be cost sensitive. It would also depend on how much technology is put into the devices, such as chips to measure flow, and if it delivers therapy at a reliable rate, and eliminates backflow, it would be desirable.

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n  Acceleration of the Development of Drugs for CED (for in-brain and intra-organ delivery)

q  There would have to be a consortium set up between companies interested in the hardware. Universities

that have a good understanding on how to deliver the molecules would also be beneficial to team up with. A team would have to put together, not one single company or university, but a joint development would accelerate the development of drugs for CED, according to the KOLs. Everyone will benefit.

q  Right now, there are very fragmented studies and companies that have no idea how to optimize the delivery strategy. There is no one out there that has all the critical know -how in one package. There needs to be an effort to get all these parties together under one roof.

q  KOLs stated that the CED delivery system is the main problem. There are lots of candidate drugs that are out there, however, the main bottleneck is the delivery system.

q  Matching the drug to a molecular requirement of the tumor could get very interesting. Targeted therapy,

single shot, gets more interesting.

q  A different approach would need a company that has the money and power to invest into clinical trials. Molecules are available. Clinical development is expensive and would need an industrial partner who is willing to develop the devices and willing to invest into the clinical trials.

q  To test drugs, you would have to go through a variety of animal models from rodents to primates and perform toxicity and distribution studies to see how the drug is getting to the site and measuring the concentration of the drug to where you are delivering it. It is complicated and expensive. Studies would require a big effort by a big pharma or institution to make it a priority.

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q  Competitive Landscape (Outlook)

q  Technologies Currently in Development (Highlights) – (See the Competitive Landscape Section IV in the report for more detail)

q  Competitive Companies to Watch Out For

§  Atanse - Atanse is trying for the 510K clearance for Intracerebral Microinjection (IMI) and Convection Enhanced Delivery System (CEDSYS); Based on two years’ worth of preclinical animal data, Atanse is progressing towards a FDA 510K clearance for their CED system. It is also possible that if FDA approves/clears their device, it could probably serve as a “predicate” to other device manufacturers with similar intent in the loop. Atanse believes they will be able to get this product into the hands of physicians within a year

§  MedGenesis Therapeutix, Inc. has granted Biovail a license to its Convection Enhanced Delivery (CED) platform for use with GDNF (e.g. developing glial cell line-derived neurotrophic factor (GDNF) protein) in CNS indications. MedGenesis and Biovail will initially focus on the development of GDNF for Parkinson's disease, a progressive and debilitating neurological disease affecting close to 5 million patients worldwide. GDNF is a naturally-occurring growth factor capable of protecting and promoting the survival of dopamine producing nerve cells. (They haven’t gotten to human trials, yet, but they intend to conduct the first human clinical study. They also don’t manufacture the pumps and catheters, themselves. The suppliers have not been identified). Will be a combination (drug) product. Will be evaluated by CDIR, and will be subjected to FDA regulatory environment, as a combination product. There is a weak regulatory regime around this type of combination. Will take time for the FDA to figure out the safety (drug and device) requirements.

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q  Competitive Landscape (Outlook) – cont’d.

q  Technologies Currently in Development (Highlights) – (See the Competitive Landscape Section IV in the report for more detail)

q  Competitive Companies to Watch Out For

§  BrainLAB (Germany)- The BrainLAB iPlan Flow is the first FDA approved software in the field of Convection Enhanced Delivery (CED).BrainLAB provides a toolset for stereotactic planning and the placement of fluid delivery catheters (can be customized to a specific catheter). New functionality includes display of patient-specific brain physiology from pre-operative MRI data for better planning of fluid distribution. (NOTE: BrainLAB is also working on supplying a full CED toolkit. They want to sell the kit, pump, catheter, connectors and their workstation. However, they are not designing new catheters, but are working with companies that are.)

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q  Economic/Business Factors – Pricing / Reimbursement Potential

n  For human use there are two components to the costs, to be considered: (1) the drug cost and (2) other CED sytem component costs. If the CED system has proven efficacy, customers will pay more; however, there are concerns that Medicare would balk at paying for Parkinson’s patients (initially) since there are many more Parkinson’s patients that patients with Glioblastoma in the US. The first disease to be considered is Glioblastoma.

n  Research from reimbursement experts suggests a price point of $17,500 USD (to be used on humans). Lower pricing is recommended for prototypes to be used on animals.

n  Costs of the CED surgical treatment procedures, along with an anticipated length of stay in the

hospital (2-3 days) would be a factor in both the pricing and reimbursement of a CED system.

n  Insurance and Hospital/Medical-related Reimbursement Factors:

q  Many insurance companies consider convection-enhanced delivery of drugs into brain parenchyma experimental and investigational because the safety and effectiveness of this approach has not been established.

q  Reimbursement will also be based on the amount of efficacy demonstrated by the CED system. If the

efficacy is in comparison with alternative types of treatments, which do not incur additional hospital and physician costs, it will be much harder to get reimbursed and adopted by the marketplace.

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n  Easiest regulatory/clinical trial pathway for an intra-organ CED system (to go from

prototype to a marketed product)

q  The easiest regulatory pathway to go from prototype to a commercial would be via Glioblastoma according to a majority of the KOLS, since Glioblastoma patients have a short life expectancy (estimated: 2-12 months), compared to Parkinson's disease. If a survival advantage can be demonstrated over conventional treatment, that would be beneficial. One positive clinical trial, than the others will follow.

q  It would have to be a “slam dunk” with unquestioned efficacy. No other way around it. It is anticipated by some of the KOLs that FDA regulations for new devices and/or drug/device combinations will be getting tougher.

q  Would have to establish a molecule that is approved. That molecule does not exist, right now, according to some of the KOLs. There still is an experimental therapy model. The FDA would not approve hardware systems if there is no therapy strategy and no active agent out there treating brain cancers using CED. No drug approval yet because the wrong hardware and/or type of active agent, has resulted in negative clinical trials.

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n  II. Executive Summary – Key Research Findings n  Easiest regulatory/clinical trial pathway for an intra-organ CED system to go from

prototype to a marketed product

q  NOTE: The following includes preliminary data points on CED systems and should be viewed as precursor for launching a thorough research. The following insights “should not be used as is” for final decision making of any sort and necessary iterations should be performed as required.

n  R&D Factors:

q  CED has only gone through initial clinical development, and is currently being evaluated in clinical trials in the US and abroad. However, extensive research is ongoing, focusing on optimizing convection to enhance the therapeutic effect of drugs in various brain disorders. Localization for some diseases remains elusive.

q  Clinical data is often conducted to support PMA (Premarket Application) (e.g. An Investigational Device Exemption (IDE) allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification (510k) submission to the FDA). Clinical studies are most often conducted to support a PMA. Only a small percentage of 510(k)'s require clinical data to support the application. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated.

q  Obtaining FDA clearance or approval is a major barrier before launching a CED system into the market. For first-use devices (e.g. for cerebral drug delivery), where there is minimal data regarding short or long term safety and efficacy, the FDA’s CDRH (Center for Devices and Radiological Health) will usually require prospective randomized controlled trials. The trials represent the largest commercial risk and expense in the development of a new device.

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n  II. Executive Summary – Key Research Findings n  Easiest regulatory/clinical trial pathway for an intra-organ CED system to go from prototype

to a marketed product - cont’d.

q  Transition from Preclinical to Clinical: Need an Investigational Device Exemption (IDE). An IDE allows the new device to be used in clinical study to collect “safety” and “effectiveness” data to support a pre-market approval (PMA) or a pre-market notification (510K).

q  Regulatory Review: How to Market the Device: Make sure that the product is a medical device [meets the

definition of FD&C Act; sec.201 (h)

n  Classify your device (based on safety and effectiveness; class determines 510K or PMA)

n  Gather data for 510K or PMA (clinical data support as required in accord with FDA IDE regulations in addition to marketing clearance)

q  Other Requirements: Premarket Requirements (Labeling; Registration; Listing); Post-market Requirements (Quality System; Medical Device Reporting)

q  Complying with FDA Regulations for Development and Manufacture of Prefilled Drug Delivery Devices:

n  Company X will be required to be well informed about the FDA’s expectations for quality systems controlling combination products. Some uncertainty prevails, and will need to check with FDA.

n  “Single Entity” Combination Product: 21 CFS 3.2(e)(1): Different medical product types (drug and device) are physically combined (check of this CFS is applicable to your case)

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n  II. Executive Summary – Key Research Findings n  Easiest regulatory/clinical trial pathway for an intra-organ CED system to go from prototype

to a marketed product - cont’d.

n  Accelerating the regulatory/clinical trials pathway: (Will need to review the FDA regulations)

q  Accredited Persons Program (FDA): To improve the efficiency and timeliness of FDA's 510(k) process i.e. the marketing clearance in the US.

q  505(b) (2): Drug development; designed to encourage innovation and to eliminate costly & time-consuming duplicative clinical studies (however, check with FDA if this pathway is applicable for your specific design).

q  FDA Acceptance of Foreign Clinical Studies: (Declaration of Helsinki; Country regulations) –may be easier route to perform clinical trials, internationally first.

q  IRB’s: Critical Component: It would be beneficial for a company to team up with several neurosurgeons/academic hospitals to help further the adoption of the CED system via an institutional review board (IRB), also known as an independent ethics committee (IEC) or ethical review board (ERB). This is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the research subjects. In the United States, the Food and Drug Administration (FDA) and Department of Health and Human Services (specifically Office for Human Research Protections) regulations have empowered IRBs to approve, require modifications in planned research prior to approval, or disapprove research. An IRB performs critical oversight functions for research conducted on human subjects that are scientific, ethical, and regulatory.

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n  Getting Buy-in from Neuro Surgeons, Neuro-Oncologists and Other Types of Medical Research Professionals

q  KOLs stated that there would have to be some early victories, and a lot of effort into the first human trials, due to a lot of technical issues that impeded success of the previous trials. Over coming those technical problems with some demonstrated efficacy with an early phase 2-3 trial study would provide a clear indication they need to go forward quickly.

q  Since there isn't much hope with Glioblastoma, they would buy into any technology that is safe and promising and has efficacy and merit. CED has a good tract record in the lab, however, it needs to fix the technical issues.

q  Some KOLs believe that clinicians would not hesitate to use it, since anything that helps survival of brain tumor patients, would help them to try it out. To offer anything to benefit survival advantages would be welcomed by the physicians.

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n  III. Emerging Market Entry Insights

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n  III. Emerging Market Entry Factors (Drivers, Barriers)

q  Clinical Trials (Insights/Profiles)

q  Duke Cancer Institute–The Preston Robert Tisch Brain Tumor Center, Duke Medical Center

Title: A Phase I Study of IMMUNOTOXIN, MR1-1 NCT Number: NCT01009866 Principal Investigator: Dr. David A. Reardon (Participating study KOL) Phase: Phase I

Primary Objective: Determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of MR1-1KDEL when delivered intracerebrally by convection-enhanced delivery (CED) in (human) patients with supratentorial malignant brain tumors. Secondary Objective: Document any radiographic responses associated with intracerebral CED of MR1-1KDEL. Hypothesis: The investigators believe that MR1-1KDEL will be an effective anti-tumor agent for patients with supratentorial malignant brain tumors when delivered by CED. Design & procedures: This protocol is designed primarily to determine the MTD and DLT of a novel, tumor-specific immunotoxin, MR1-1KDEL. MR1-1KDEL will be delivered intracerebrally by CED using 2 intracerebral catheters with at least one catheter placed within the enhancing portion of the tumor. 124I-labeled albumin will be co-infused with gadolinium and PET and MRI images will be obtained at the conclusion of the infusion to monitor volume of drug distribution and leakage into the CSF space.

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§  University of California – San Francisco , UCSF Medical Center (Dept. of Neurological Surgery Research)

Project 3: Imaging to optimize convection-enhanced delivery

Principal Investigator: Krystof Bankiewicz MD, PhD (Participating study KOL)

Clinical trials evaluating the delivery of agents intraparenchymally by using CED has been studied in several phase I trials and phase II trials are ongoing. CED is a promising method of delivery of therapeutic concentrations of drug to the brain while limiting systemic exposure, thereby limiting general side effects. A major barrier to the implementation of CED in clinical practice has been the inability to visualize the tumor and the agent during the procedure to assess the directionality, volume, and distribution of the agent in the brain. Another challenge is the current limited understanding of the differences between the composition of tumor tissue and normal tissue and its effect on the distribution of agents delivered via CED. The aims of this study are to investigate MRI techniques to determine the infusion parameters that are necessary to optimize the delivery of agent to the tumor. Image-based convection modeling and infusion parameters for the distribution of therapeutic liposomes such as nanoliposomal irinotecan will be assessed in canines with spontaneous brain tumors. NOTE: Study is currently focused on animals.

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§  Yale School of Medicine - Neurosurgery KOL source: Dr. Joseph M. Piepmeier (Participating study KOL)

Treating intracranial brain tumors: In vivo delivery of nanoparticles using CED of biodegradable polymer nanoparticles: Yale bioengineers have developed a particle that is small enough that it will diffuse between the cells in the brain, in the space that is between cells, --and once it achieves that, the particle stays there and over a period of weeks, it both degrades and disappears. During that period of time, it can continuously deliver treatment. Therefore, the benefit is that not only getting excellent distribution but a more robust, sustained delivery of treatment. Other applications of regional types of cancer potential...if you can put a catheter in, they can deliver treatment.

q  For more information, review the October 5, 2010 Mark Saltzman, PhD “Degradable Polymer Nanoparticles for the Treatment of Brain Tumors” video link: http://www.yalecancercenter.org/education/grand-rounds.html#videotop

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§  Cornell University, Department of Chemical and Biomolecular Engineering KOL source: Dr. William L. Olbricht (Participating study KOL)

§  Portable Therapeutic Ultrasound System: The motivation is to use ultrasound to improve

the effectiveness of convection-enhanced delivery (CED) of drugs to the brain. Preclinical and clinical studies suggest that the outcome of the therapy depends strongly on the extent of penetration of the drug into the brain, which is determined by the relative rates of convection and elimination. Dr. Olbricht’s lab has shown evidence that ultrasound increases the penetration distance and provides control over the spatial distribution of the infused material in vitro that could significantly improve the efficacy of CED in clinical practice. This work involves both the basic science of transport mechanisms as well as the translational science of scaling the UCED brain cancer therapy into a large animal glioblastoma model at Cornell Veterinary Medical Center. If successful, the lab will transition the technology to human treatment in the next few years, or less.

§  The present invention is a portable system that combines a convection enhanced delivery (CED) device with a pocket sized ultrasound system to enhance the dispersion of injected small molecules. Ultrasound-improved convection enhanced delivery (UCED) uses acoustics that allows for further diffusion of soluble particles from the injection site, as opposed to standard CED systems, which convey limited compound transit distance.

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§  Cornell University, Department of Chemical and Biomolecular Engineering KOL source: Dr. William L. Olbricht (Participating study KOL) – cont’d.

Potential Commercial Applications

q  Increased diffusion of injected substances into target areas for medical, dental, and vet applications. q  Human health applications for dissemination of injected materials. q  Treatment for hard-to-cure diseases.

Technical Merits q  Utilizes acoustic cativation, the most dominant and vital mechanism for ultrasound mediated drug delivery. q  Acoustic streaming can enhance mass transfer of the soluble compound. q  Ultrasound prevents pooling of injected fluid into a cavity that forms around the needle tip.

q  Research Results: The lab studied effects of therapeutic 1.58 MHz focused ultrasound at 1.3 and 5.25 W spatial-average power levels in combination with convective flow on the uptake of Evans blue dye into avian muscle, equine brain and neurological-tissue-mimicking phantoms. Ultrasonic power levels were applied below tissue damage thresholds. Convection velocities were in the range of typical CED infusions in rodent brain. The study showed synergistic effects when ultrasound was combined with CED in all samples at both power levels. The results suggest that CED in combination with ultrasound may enhance the penetration of therapeutics in the brain and increase the concentration of infused drugs over the penetration distance, which may improve the outcome of CED therapy.

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§  Antisense Pharma’s Clinical Phase III study SAPPHIRE in aggressive brain tumors Principal Investigator: Dr. Rolando Del Maestro* (Montreal Neurological Institute & Hospital, McGill University, Montreal, Canada)

§  Study to examine trabedersen vs. current standard chemotherapy in patients with recurrent or refractory anaplastic astrocytoma

§  Trabedersen is a first-in-class targeted therapy. This novel compound acts via inhibition of transforming growth factor-beta 2 (TGF-B2). This treatment acts specifically at the molecular basis of disease by inhibiting tumour invasion, tumour cell growth, the development of tumour vessels called angiogenesis and by improving the ability of the immunological system to combat the tumour.

§  Trabedersen will be administered intratumoral via one single catheter using convection-enhanced delivery (CED) on an outpatient basis. The treatment period lasts up to 6 months consisting of 7-day cycles every other week.

§  The SAPPHIRE study is a randomized, active-controlled, clinical trial designed to confirm the efficacy and safety of the investigational drug trabedersen (AP 12009), observed in previous clinical studies. Trabedersen is being investigated as monotherapy (dose of 10 uM) compared to current standard therapy with temozolomide (alternatively BCNU [carmustine]). The results of a previous randomized, active-controlled Phase IIb study show that the novel, targeted therapy holds significant promise. Currently recruiting study centers will be published on www.anticancer.de

* Dr. Rolando F. Del Maestro is the Director of the MNI’s (Montreal Neurological Institute & Hospital, McGill University, Montreal, Canada) Brain Tumour Research Center.

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§  Antisense Pharma’s Clinical Phase III study SAPPHIRE in aggressive brain tumors – cont’d.

Principal Investigator: Dr. Rolando Del Maestro §  The study objectives will be to assess survival at 24 months. The 14-month progression

rate is the surrogate endpoints for an interim analysis. Patient quality of life is an important parameter of the study.

§  The Montreal Neurological Institute and Hospital is among 100 hospital centers on 5 continents participating in this study. The Montreal Neurological Institute and Hospital received ethics approval in December 2009 to participate in the trial and will be the first site in North America ready to accept patients with recurrent and refractory anaplastic astrocytoma.

n  Patient information available at: http://www.antisense-pharma.com/patientinfo/f_patientinfo.htm

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n  IV. Competitive Landscape

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q  ATANSE n  Background: McLean Hospital and its researcher/inventor, Miles Cunningham, M.D., PhD have formed a start-up

company, named Atanse, Inc., for the commercialization of neurosurgical devices and methods for enhanced delivery of drugs to the brain. Trained at MIT and Harvard Medical School, Dr. Cunningham has created instrumentation and methods that will en-able more precise, better targeted drug delivery to specific brain areas for the treatment of cancer and neurodegenerative disease. Atanse will partner with Frederick Haer Corporation (FHC), a leading provid-er of neurosurgical instrumentation, to complete development and to manufacture instruments for human use. Combined with FHC’s pow-erful patient-customize guidance systems, Atanse’s platform technol-ogy has been described as revolutionary. Development of these products will be complete in 2011 and will require minimal further R&D funding. Initial analysis has estimated a potential US market of approximately $350 M.

n  Market Entry Update: Atanse is trying for the 510K clearance for Intracerebral Microinjection (IMI) and Convection

Enhanced Delivery System (CEDSYS); Based on two years’ worth of preclinical animal data, Atanse is progressing towards a FDA 510K clearance for their CED system. It is also possible that if FDA approves/clears their device, it could probably serve as a “predicate” to other device manufacturers with similar intent in the loop. Atanse believes they will be able to get this product into the hands of physicians within a year. NOTE: The U.S. Food and Drug Administration (FDA) 510(k) review process is a key regulatory pathway for the introduction of new products. It allows medical device developers to bring new products to market based on data from existing devices, known as predicate devices that have already been approved as safe and effective. Most important, it is a long-standing, proven mechanism for ensuring timely access to new and improved treatments for patients in need. In the last year alone, 3,000 new devices were approved under the 510(k) process, benefiting physicians and the patients in their care.

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q  ATANSE (cont’d.)

n  Products/Technology Profiles

n  Technology 1: The IMI: The Intracerebral Microinjection Instrument (IMI) is the only neurosurgical device that has a minimized delivery cannula diameter and allows three-dimensional dissemination of medicine from a single proximal brain penetration and also is capable of electrophysiologically profiling the brain area of interest simultaneously with delivery of therapeutic. The IMI enhances precision and dramatic

n  Technology 2: The CEDSYS: Convection enhanced delivery (CED) is the continuous injection into the brain under positive pres-sure of a fluid therapeutic. While CED has shown promise, it has a number of technical shortcomings associated with drug delivery efficiency. The CEDSYS addresses these problems by utilizing specialized flexible microcannulas that are arranged within the tumor using a computerized guidance system.

q  NOTE: This system has reduced the delivery cannula down to 200 microns and is able to infuse at high rates and with high volumes with absolute minimal reflux -so that the chemo therapeutics stays In the brain. It also allows the drugs to profuse the tumor and surrounding tissues that may be seeded with migrating low cancer cells not normally seen by the cancer surgeon. CED is a way to approaching this issue.

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q  MEDGENESIS Therapeutix Inc.

n  MedGenesis Therapeutix, Inc. has granted Biovail a license to its Convection Enhanced Delivery (CED) platform for use with GDNF (e.g. developing glial cell line-derived neurotrophic factor (GDNF) protein) in CNS indications. MedGenesis and Biovail will initially focus on the development of GDNF for Parkinson's disease, a progressive and debilitating neurological disease affecting close to 5 million patients worldwide. GDNF is a naturally-occurring growth factor capable of protecting and promoting the survival of dopamine producing nerve cells. (They haven’t gotten to human trials, yet, but they intend to conduct the first human clinical study. They also don’t manufacture the pumps and catheters, themselves. The suppliers have not been identified). Will be a combination (drug) product. Will be evaluated by CDIR, and will be subjected to FDA regulatory environment, as a combination product. There is a weak regulatory regime around this type of combination. Will take time for the FDA to figure out the safety (drug and device) requirements.

n  This license of GDNF from Amgen presents MedGenesis and Biovail (merged with Valeant Pharmaceuticals International) with an opportunity to develop a potential therapy for the treatment of patients with Parkinson's disease. They believe their CED approach will result in a targeted delivery of GDNF to the regions of the brain affected by this severely debilitating disease and holds the promise of providing patients with a treatment which could potentially modify the disease.

n  MedGenesis is also considering an approach for their CED system to be permanently implanted. The patient would come in to the hospital to have the infusion done in prescribed intervals, on an outpatient basis.

q  Note: Amgen now holds a small equity stake in MedGenesis. In parallel, Biovail Laboratories International SRL, a subsidiary of Biovail Corporation

(now merged with Valeant Pharmaceuticals), and MedGenesis have concluded an agreement to collaborate on the development of GDNF in Parkinson's disease and potentially other CNS indications. Biovail, which is also a party to the Amgen license for CNS indications and which has a co-exclusive license to exploit GDNF in certain countries (including the U.S., Canada, Japan and a number of European countries), contributes significant development expertise, a broad-based commercialization track record, and a focus on CNS disorders.

MedGenesis is a privately-held Canadian biopharmaceutical company committed to developing and commercializing innovative therapeutics to provide life-enhancing treatments to patients with serious neurologic diseases. MedGenesis is a provider of CED applications, a minimally invasive

technique that provides for targeted, local treatment of CNS conditions such as epilepsy, brain cancer and other severely debilitating diseases of the CNS. Location: Victoria, BC, Canada http://www.medgenesis.com.

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q  DELCATH SYSTEMS

n  Delcath Systems (NASDAQ: DCTH) is an emerging, small-cap medical device company that is developing a regional treatment system for cancer in the liver. Delcath's Percutaneous Hepatic Perfusion (PHP) technology allows physicians to deliver significantly higher doses of existing chemotherapy drugs to the liver without exposing each patient's entire body to the anti-cancer drugs, representing an elegant solution that promises to increase the effectiveness of approved anti-cancer drugs while reducing systemic side effects.

n  In 2009, Delcath announced that the FDA granted orphan drug status to doxorubicin, an approved chemotherapy agent, for the treatment of primary liver cancer. The Company said it tested doxorubicin with its unique drug delivery technology, Percutaneous Hepatic Perfusion (PHP), which results in significantly higher doses (e.g. 10X the FDA approved standard dosing with 100X exposure of drug to the tumor site) of anti-cancer drugs such as doxorubicin to the liver without exposing the patient's entire body. Delcath plans to carry out the necessary clinical work for a regulatory submission of PHP with doxorubicin.

n  Clinical Trial: The Phase 3 Metastatic Melanoma Trial met its goal of 92 patients and was fully enrolled. This clinical study is evaluating the Delcath PHP System for the regional delivery of melphalan to the liver to treat patients with metastatic cutaneous and ocular melanoma who have unresectable tumors in the liver. Enrollment in the Phase 2 clinical study of the Delcath PHP System with melphalan for patients with inoperable liver metastases from neuroendocrine tumors reached 25 patients last fall and continues to enroll patients with guidance at that time for data to be reported in the coming months.

Delcath Systems, Inc. is a development stage specialty pharmaceutical and medical device company focused on oncology. They are developing a proprietary system for Chemosaturation Therapy that is designed to administer high doses of chemotherapeutic agents to a diseased organ or a region of the body while protecting the patient from potential systemic side effects. The Chemosaturation Therapy system is designed to be a repeatable, minimally invasive procedure that isolates the blood flow of the targeted organ, saturates the isolated organ with therapeutic agent, and then filters out toxic levels of the drug before returning it to the patient. The Delcath Chemosaturation system is not currently approved by the FDA or any other regulatory body, and it cannot be marketed in the United States or elsewhere without regulatory approval.

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q  CMA MICRODIALYSIS (Sweden)

n  CMA Microdialysis: CMA Microdialysis (“CMA”) is a Swedish medical device and research company founded in 1984 as a spin-off from the Karolinska Institute. Unique and market leading solutions are developed, produced and sold to clinicians and researchers to enable optimized patient care and accelerated drug development. CMA’s complete line of instruments, consumables and computer software are used globally by universities, hospitals and pharmaceutical companies as unique tools for in vivo sampling and monitoring of organs and blood.

n  The core competence lies within solutions based on the Microdialysis technique. The products are produced in Sweden under ISO 13485 and according to FDA standards. With a highly specialized and skilled staff, consumables are manufactured in a Class 8 clean room environment. CMA also offers OEM manufacturing services.

n  PRODUCTS:

q  Catheters designed to monitor mitabollityes in real-time in a patient’s brain. q  Catheters for Clinical use q  Catheter Accessories q  Pumps for Clinical use q  Analyzers Software

n  The head office is located outside Stockholm, Sweden, with a subsidiary north of Boston, USA. CMA has distributors

across the globe, responsible for local sales, service and support.

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q  BrainLAB (Germany)

n  The BrainLAB iPlan Flow is the first FDA approved software in the field of Convection Enhanced Delivery (CED).

q  BrainLAB provides a toolset for stereotactic planning and the placement of fluid delivery catheters (can be customized to a specific catheter). New functionality includes display of patient-specific brain physiology from pre-operative MRI data for better planning of fluid distribution.

(NOTE: BrainLAB is also working on supplying a full CED toolkit. They want to sell the kit, pump, catheter, connectors and their workstation. However, they are not designing new catheters, but are working with companies that are.

q  Pre-operative patient-specific simulation of fluid distribution q  DICOM import and analysis of magnetic resonance (MR) diffusion tensor imaging (DTI) q  Fusion of DTI data to anatomical data q  Pre-operative analysis of brain hydraulics and visualization of hydraulic properties and fluid pathways q  Easy-to-use placement guidelines: Visualization and “instant availability” in surgical planning q  Significantly reduced planning time compared to conventional methods Dynamic computation of backflow regions

based on catheter type and flow rate q  Seamless integration with navigation technologies and a variety of stereotactic frames q  iPlan Flow is an integral element of a comprehensive treatment strategy for brain tumors and a significant step towards

the future of oncology. q  iPlan Flow is the first FDA approved software in the field of Convection Enhanced Delivery (CED). **iPlan Flow (CED) Video Link:

http://www.brainlab.com/module/FlashVideoGallery/flashVideoIframe.asp?media_id=1265

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q  BrainLAB - cont’d.

n  Brainlab develops, manufactures and markets software-driven medical technology that supports targeted, less-invasive treatment.

n  Brainlab technology focuses on facilitating collaboration between hospitals and clinicians from a wide variety of subspecialties—from neurosurgery and oncology to orthopedics, ENT, CMF and spine & trauma. This integration is touted to deliver better access to improved and more efficient treatment.

n  Founded in 1989, the privately held Brainlab group has 5,260 systems installed in over 80 countries. Based in Munich, Germany, Brainlab employs 950 people, including 240 R&D engineers on the product development team, in 16 offices worldwide.

n  With a diverse workforce from over 30 countries, the official language at Brainlab is English.

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q  Renishaw (UK)

n  Renishaw, based in the UK, provides advanced engineering solutions for stereotactic neurosurgery. The company’s initial range of products is designed to enable surgeons to implant Deep Brain Stimulation (DBS) electrodes to targeted brain anatomy. They are also working with a number of medical technology and biotech companies on the development and optimization of next-generation drug delivery systems for the treatment of serious Central Nervous System diseases.

n  According to feedback from one study KOL, Renishaw is also creating applications for CED.

n  Products: Implantable Therapeutic Delivery Devices

q  The Neuroguide™ electrode introducer kit- Neuroguide™ can be integrated into existing practices, used either in combination with or instead of microelectrode recording. By requiring fewer trajectories through the approximate target volume, surgery times and the risk of hemorrhages are both reduced. In the event of a revision, Neuroguide™ remains in place so it can deliver positional accuracy without having to repeat the full stereotactic procedure, saving time and benefiting the patient. This device is designed to obtain greater precision and accuracy in cases where a surgeon is targeting the Subthalamic Nucleus, the Globus Pallidus Interna, the Thalamus or the Pedunculopontine Nucleus.

q  Link: http://www.renishaw.com/en/implantable-therapeutic-delivery-devices--6725

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n  V. Recommendations

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q  #1: Primary Target Disease State Opportunities

n  It is recommended that Company X focus on Glioblastoma as the primary disease state target, followed by Parkinson’s disease.

§ The study KOLs see a strong potential use of a CED treatment in Parkinson’s disease, as a means of pumping up localized, dopamine levels. Although there are multiple treatments for Parkinson’s, to some extent they help in reducing the symptoms and enhance the quality of life, they are not curative. None of the treatments stop the brain degeneration that is occurring. Ultimately, the patients succumb to the disease at the end stage. There is still is a need to slow the progression of the disease.

n  Recommendations n  Drivers

n  There still is no cure for Glioblastoma patients, who have an approximate life expectancy of 2-12 months.

n Personalized healthcare market growing

n Changing healthcare service paradigm that will be geared more toward home-based consultations, disease and health maintenance

n Aging populations (global) who are more prone to CNS and intra-organ cancers (e.g. liver, pancreas, etc.)

n Advancements in out-patient, home-based medical services potential (e.g. mobile, home-based applications, medical devices, smart drugs, advanced simulation technology, etc.)

n Parkinson’s Disease has a much larger patient population, than Glioblastoma, particularly in the US. Approximately, 1.5 Million people in the US have this disease, according to the Parkinson’s Disease Foundation.

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q  #2: CED System Component Focus

n  It is recommended that Company X focus on either developing an advanced type of catheter with the following qualities (not exclusive to) and/or partnering with a company and/or academic research community that is developing an advanced type of catheter to be used in a CED system.

q Any marriage between the CED technology and actual measurements of in situ drug levels, would be hugely valuable. It would help to reduce the risk of the physician getting sued for drug related toxicities or the amount of drugs are being put into the patient. Therefore, measuring how much drugs that are being put in the catheter tip would be good.

q Some catheters get clogged and some have blockages. Being able to minimize the blockage factors that would prevent the infusion being conducted with the catheter would be advantageous.

q A catheter could be implantable to accommodate not just a one -time infusion, and to be used for potential out-patient treatments.

q Would like to see catheters have antibiotic impregnation, radio opaqueness, MRI capability and opportunity that after surgery you can track where the catheter is placed via x-ray

n  Recommendations

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q  #3: Packaging of a CED System

n  It is recommended that Company X focus on packaging its CED system with both the pump and the catheter, since the KOL consensus believed that a complete system approach would be more reliable (mechanically and support wise.)

n  Other options could include: - A pricing (discount) option for a complete and/or separate system component packaging.

- A complete CED toolkit system, which could include a pump, catheter, connectors, additional catheters, and BrainLAB software/workstation. NOTE: Company X could become a reseller for BrainLAB’s CED workstation and potentially its CED toolkit , which is not yet on the market. See BrainLAB’s profile on page 60-61.


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q  # 4: Acceleration of Drugs for CED

n  It is recommended that Company X consider creating a consortium between companies interested in the hardware. In addition, universities that have a good understanding on how to deliver the molecules would also be beneficial to team up with. A team, therefore, would have to put together, not one single company or university, but a joint development which would have the potential to accelerate the development of drugs for CED.


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q  # 5: Factors That Will Impact Pricing & Reimbursement

n  It is recommended that Company X focus on packaging its CED system with both the pump and the catheter, since the KOL consensus believed that a complete system approach would be more reliable (mechanically and support wise.)

n  Other options: A pricing (discount) option for a complete and/or separate system component packaging should also be considered.

n  It is recommended that a “permanently implantable” approach to the pump and catheter be considered. Both from a competitive and cost benefit ratio perspective.

n  For example: The patient would come into the hospital to have the infusion done in prescribed intervals, on an outpatient basis. This type of approach could result in considerable hospital and physician costs that would incurred if the treatment had to be in-patient. If the hospital considers a CED approach to cost more than a systemic type of drug treatment, the market adoption of the CED system could be more of a problem. Certainly, a cost-benefit analysis would have to be considered.


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q  #6: CED (Standardized) Training - (Customer Education)

q  Going forward with CED would require more centralization and/or standardization of the CED (in-brain catheter placement) technique, particularly for neuro-surgeons/investigators conducting clinical trials that utilize the CED. Therefore, standardized training in catheter placement, along with additional training on the use of the pump and related connecters is recommended to be included with a CED system that is both being trialed and eventually commercialized.

q  It is also recommended that an extensive training manual (video) should be developed to train prospective clinical trial investors and eventual customers, along with additional customer service support.


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q  #7: Utilize Academicians As Product Champions q  For successful market adoption, it is recommended that not only will you need clinical evidence (efficacy), you will also champions, such as leading academicians, that will test it and teach other people how to use the system and related surgical technique.

q  Suggested Champions: Dr. James T. Rutka, Toronto, Canada and Dr. Krys Bankiewicz, University of California, San Francisco, CA


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n  VI. APPENDIX

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Company X Pump for Convection Enhanced Delivery (CED) Market Entry/Validation – Final Report n  VI. APPENDIX

n  List of KOL Study Participants

q  Sandeep Kunwar, MD, Neurosurgeon, Associate Clinical Professor of Neurological Surgery, Surgical Director, California Center for Pituitary Disorders at UCSF, San Francisco, CA

q  Miles Cunningham, MD, PhD, Neuropsychiatrist, Director, Laboratory for Neural Reconstruction Chair, ANPA Scientific , Program Committee Executive Director, McLean Fellowship in Behavioral, Neurology and Neuropsychiatry , Mclean Hospital, MA and Founder of Atanse

q  Daniela A. Bota, MD, PhD, Neurological Oncologist at UC Irvine Healthcare Comprehensive Brain Tumor Program, Irvine, CA

q  John H. Sampson, MD, PhD, Neurosurgeon, Division of Neurosurgery/Department of Surgery Duke University Medical, Durham, NC

q  William Olbricht, PhD, Professor, Cornell University, School of Chemical & Biomolecular Engineering, Ithaca, NY

q  Yael Mardor, PhD, Chief Scientist, The Advanced Technology Center Sheba Medical Center, Tel- Hashomer, Ramat-Gan, Israel, Israel (Research in the area of Convection-Enhanced Delivery of High Viscosity Nano-Particles)

q  Michael Weller, MD, Clinical Neurologist, Chairman of the Department of Neurology at the University Hospital Zurich, Switzerland

q  Bharath R Somayaji, PhD, Research Scientist, Chemical Engineering, CFD Research Corporation, Huntsville, Alabama.

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n  VI. APPENDIX

n  List of KOL Study Participants – cont’d.

q  David T Durack, MD, D Phil, FACP / Senior Vice President, Corporate Medical Affairs, Company X; Consulting Professor of Medicine, Duke University, NC

q  Richard Finn, MD, Medical Oncologist/Internal Medicine, Department of Surgery, Dumont-UCLA Liver Cancer Center, UCLA, Los Angeles, CA

q  Fred H. Hochberg, MD, Neurologist, Associate Professor, Department of Neurology, Harvard Medical School, Neurology Department, Massachusetts General Hospital, Boston, MA

q  Warren P. Mason, MD, FRCP, Neuro-Oncologist, Staff Physician at Princess Margaret Hospital, Toronto, and an Associate Professor of Medicine at the University of Toronto, Canada . He co-chairs the Brain Disease Site Group of the National Cancer Institute of Canada Clinical Trials Group. His main research interest is in the treatment of brain tumors, particularly glioma, with an emphasis on novel drug evaluation for glioblastoma.

q  John Mikszta, Director of Parenteral Technologies at Company X; Research Triangle Park, North Carolina

q  Charles Shermer, P.E. - Company X Technologies

q  Krystof Bankiewicz, MD, PhD, Professor of Neurosurgery and Neurology, Kinetics Foundation Chair in Translational Research, University of California, San Francisco Neurological Surgery, San Francisco, CA

q  Linda M. Liau, MD, PhD, Neurosurgeon, Professor & Vice Chair, UCLA Department of Neurosurgery, Director, UCLA Brain Tumor Program, David Geffen School of Medicine at UCLA, Los Angeles, CA

q  Martin J. Van den Bent, MD, Neuro-Oncologist, Department of Neuro-Oncology, Erasmus MC Daniel den Hoed Oncology Center, Rotterdam, Netherlands

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n  VI. APPENDIX

n  List of KOL Study Participants – cont’d.

q  Maciej S. Lesniak, MD, MHCM, FACS, Neuro-Oncologist, Professor of Surgery and Cancer Biology , University of Chicago Medical Center, Chicago, IL

q  Manish Aghi, MD, PhD, Neurosurgeon-Scientist (specializing in adult brain tumors), Associate Professor, University of California, San Francisco, Dept. of Neurological Surgery, CA

q  Stuart A. Grossman, MD, Internal Medicine/Medical Oncologist, Professor of Oncology, Medicine & Neurosurgery The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins , MD

q  James T. Rutka, MD, PhD, Neurosurgeon/Pediatric Neurosurgery, The Hospital for Sick Children, Toronto, Canada

q  Michael Lim, MD, Assistant Professor of Neurosurgery, Oncology and Institute of Nano Biotechnology, Director of the Brain Tumor, Immunotherapy Program Director of the Metastatic Brain Tumor Center, Johns Hopkins Hospital, Baltimore, MD

q  Joseph Piepmeier, MD, Neurosurgeon, Professor of Neurosurgery, Yale University School of Medicine , New Haven, CT

q  David A. Reardon, MD, Pediatric Neuro-Oncologist, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC

q  Nathan R. Selden, MD, PhD, Neurosurgeon, Neurological Surgery, Oregon Health & Science University, Portland, OR

q  Michael A. Rogawski, MD, PhD, Neurologist, Professor and Chair, Department of Neurology University of California, Davis , CA

Presentations & Public Speaking

CED Tight Space Innovation Market Entry- final report