company x pump for convection enhanced delivery (ced) market entry validation interim report 2 28...

Company X Pump for Convection Enhanced Delivery (CED) Market Entry/Validation - Interim Research Findings (Primary KOL Qualitative Research) – 2/28/11

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Company X Pump for Convection Enhanced Delivery (CED) Market Validation - Interim Research Findings

I. Preliminary (High Level) KOL Research Findings

Methodology: 19 KOLs (Key Opinion Leaders) have been interviewed, so far, including researchers/clinicians in neurosurgery, neuro-oncology and neurology; Professors of Surgery, Oncology and Cancer Biology; Directors of Neurosurgical Oncology and Neuro-Oncology research. Additional KOLs are scheduled to be interviewed.

What are some of the unmeet needs and/or problems with both CED and other existing approaches?

Existing approaches with respect to CED (alternatives).

Other approaches have yet to match CED in terms of infusion depth, rate and coverage area; spacial penetration is much more limited without CED.

Feedback from the KOLs indicate that there are a number of active agents against brain tumors, but they do not have a good way of delivering them.

None of other approaches have figured out the problem of distribution that is inherent with a liquid medium. Backflows along the catheter, restrictions because you can't get a fluid wave to distribute to the brain, it doesn’t get absorbed.

The CED technique will effectively deliver whether a virus or toxin or tracer drug and will take it to the target destination.

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Existing approaches with respect to CED (alternatives)

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.

For children, chemotherapy has been shown for a number of years quite successful

Only recently chemotherapy has a role to play in adult malignant brain tumors.

There are two major problems with chemotherapy. Many chemos will not cross the BBD, 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.

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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Existing approaches with respect to CED (alternatives)

The KOLs indicated that the CED technique for active agents delivery to brain tumors is now being used. It is an attractive type of delivery strategy for putting drugs, including nano particles, antibodies, viruses, whatever appropriate active agent for the brain.

KOLs noted that CED hasn't been used much recently, however, there has been an effort to use CED for other types of neurodegenerative diseases, with enzyme replacement therapies (trial going on where they are investigating the use of the CED delivery approach-preliminary indications are that the CED approach is safe to do, whether it is efficacious to do, results will follow. The tests are focused on a rare congenital disease which has a deficiency in one of the enzymes. that produces myelin. A child doesn't survive past early childhood.

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.

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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.

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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What are some of the unmeet needs and/or problems with both CED and other approaches?-cont’d.

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.

Unmet needs of existing approaches – not achieving adequate penetration in adequate amount of time.

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.

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.

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Company X Pump for Convection Enhanced Delivery (CED) Market Validation - Interim Research Findings I. Preliminary (High Level) KOL Research Findings

What are the pros and cons to pump and catheter approaches? And to CED delivery of active agents for in-brain drug delivery

A pump and catheter 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.

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.

CED results from a toxin trial; Found that catheter placement accuracy (getting into the tumor, not picking the ideal target with the right precision), especially when you are placing multiple catheters. The recommendation going forward was to have more centralization and some standardized training in terms of catheter placements…(one thing that came out of it). There were no safety concerns that came out of it; 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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What are the pros and cons to pump and catheter approaches? And to CED delivery of active agents for in-brain drug delivery

In some 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.

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..

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.

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.

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I. Preliminary (High Level) KOL Research Findings – cont’d.

Examples of current CED delivery of active agents for in-brain drug delivery clinical trials

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

Title: A Phase I Study of IMMUNOTOXIN, MR1-1NCT Number: NCT01009866Principal 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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Examples of current CED delivery of active agents for in-brain drug delivery clinical trials- cont’d.

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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Examples of current CED delivery of active agents for in-brain (biomedical) drug delivery research discoveries

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.

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

http://www.yalecancercenter.org/education/grand-rounds.html#videotop

http://www.yalecancercenter.org/education/grand-rounds.html#videotop

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Emerging uses of CED and/or emerging disease state opportunities for CED systems

Other diseases to apply CED to include many of the neurodegenerative types of diseases, including getting trophins to penetrate the brain. Focused on diseases such as Alzheimer’s, Parkinson’s, Huntington Chorea, Epilepsy, Multiple Sclerosis. Many of the neurodegenerative are genetic. ACED 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 with out degradation, making its connection and having it absorbed, it would increase its therapeutic potential, greatly.

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.

Intra organ cancer, colon, liver..solid organ structures..would be reasonable to approach with CED. Probably not good for lungs or intestines.

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Emerging uses of CED and/or emerging disease state opportunities for CED systems

Segmental infusion strategies 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.

Could support pancreatic infusion. Complicated, but supported.

Has potential for colon cancer, not breast cancer.

There is potential for CED in uniformly fatal, and hard to treat diseases such as liver and pancreas cancers.

There is significant, non-tumor utility potential for CED.

See a potential use in Parkinson’s disease as a means of pumping up localized, dopamine levels.

See the potential utility 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. Suggestions: To explore uniformly fatal, untreatable diseases that have affectively no therapy , but could be altered.

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Ranked diseases with highest potential to use CED

1-Brain tumors (Glioblastoma...highest consensus) 2 & 3– Alzheimers and Parkinson's Disease 4-Epilepsy 5- Alateral Myotropic Sclerosis (Lou Gehrig's Disease) 6-Solid tumors

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Major barriers to CED of active agents for intra organ, and in-brain drug delivery

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.

Not practical enough

Predicted 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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I. Preliminary (High Level) KOL Research Findings – cont’d. What are some of the key features that a CED Pump and Catheter must have?

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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I. Preliminary (High Level) KOL Research Findings – cont’d. What are some of the key features that a CED Pump and Catheter must have?

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.

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Key features of a CED catheter:

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

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.

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.

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

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 step down used in trying to accommodate this problem to minimize backflow gets into product design issues.

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Key features of a CED catheter – cont’d.

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

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 to see where the catheter is placed.

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

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

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Advantages of purchasing a complete system, both the pump and the catheter

There was a KOL consensus that it would be valuable to have both the pump and catheter, together as one system.

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.

Pumps or caterers? Which is most valuable aspect of this system? KOLs stated that both devices are important.

Some KOLs, however, thought it may be best to unbundle the system so that you could use multiple catheters for any type of pump system. There could also be a separate system for purchasing each separately, or if there was a bundled option, at a discount, that would be appealing to purchasers.

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Will intracranial infusion become the treatment of choice?

Because of the nature of the disease, it will be the method of choice, provided the hardware that is used for the infusion is user friendly. This is not the case, right now.

Some of the KOLs believed this 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 it shows efficacy. The biggest problem is reaching the target effectively.

This approach will not be the sole treatment, not in 5-10 years.

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. 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.

Some KOLs stated that this approach is a very exciting area that can offer a lot to patients a specific local delivery approach.

However, one KOL said NO, due to the expense, uncertainty in value and potentially fraught with huge toxicity issues.

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What are some of the alternatives to intracranial infusions? NOTE: None of these technologies are being practiced, right now.

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

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.

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.

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.

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.

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

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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Could the CED system be used as a post-op immunotherapy treatment?

The overall KOL consensus was yes.

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.

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

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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What will be the impact of selective gene therapy on CED’s?

It would be effective and would be the method of choice for this type of therapy. CED can achieve a predictable and robust gene therapy.

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.

Selective gene therapy could benefit from CED. Without CED it will not work. This type of therapy needs CED.

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How will stem cells impact the treatment of cancer?

As bio protective agents. Stem cells may reduce the toxicities inherent in many approaches. It may prevent chemo brain or toxicity of the brain.

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

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.

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

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.

Other 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.

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How safe is this type of CED system? And, what specific side effects would occur using this type of system?

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.

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

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.

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

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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Will the CED system be inpatient and outpatient?

CED treatment could be both inpatient and outpatient, as well.

Instrumentation needs to be done in the hospital, right now. Delivery of the drug can 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.

The potential for outpatient. Treatment reached a consensus with the KOLs. Extended hospital stays could last approximately two days, and then post-op treatment would be done continually as an outpatient.

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.

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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What is the potential for the adoption of the CED system (pump and catheter) for research?

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.

Pay for it? if it would be available for patients, yes. What is lacking in the field with CED trials is they do not have a system to get off the shelf and run with it. Many KOLs said they would love to have it.

Not high volume. with acceptance and utilization. If you find something that works, especially a solid brain tumor, then it opens up similar solid tumor cancer applications.

Will depend on the cost of the prototype. If it has broad applications, it has to be cost sensitive. How much technology you put into that device, chips to measure flow, and if it delivers therapy at a reliable rate, and eliminates backflow, it would be desirable.

KOLs stated they would not be interested unless it is delivery active, provides effective treatment. This approach will be driven by the success of the agent rather than the technology of the catheter and pump. KOLs 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. They are just now starting to think about this.

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What would be needed to accelerate the development of drugs for CED for in-brain delivery? For intra-organ delivery?

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.

Right now, there are very fragmented studies and companies 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.

Matching the drug to a molecular requirement of the tumor could get very interesting. Targeted therapy, single shot, gets more interesting.

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.

To test drugs, 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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What would be the easiest regulatory/clinical trial pathway for an intra-organ CED system to go from prototype to a marketed product? And, what would some of the regulatory hurdles be?

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 has resulted in negative clinical trials.

There would also be FDA hurdles. 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 the FDA will be getting tougher. And Hospitals are not going to be willing to take the hit and potential complications that could arise. And how would you insure the investment or hospital from catastrophes?

The easiest regulatory pathway to go from prototype to a commercial would be via Glioblastoma according to a majority of the KOLS, since Glioblastoma has a short life expectancy and robust endpoints) compared to Parkinson's disease. If you could demonstrate a survival advantage over conventional treatment, that would be beneficial.

Will need a clinical trial of CED. One positive clinical trial, than the others will follow.

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What has impeded adoption of CED, so far?

Costs, lack of benefits, potential toxicities.

No efficacy, and choice of wrong active agents.

Technical issues and drug agents that are not going where they thought they would go.

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

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.

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How would you get a buy-in from surgeons and other types of medical professionals?

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.

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.

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.

company x pump for convection enhanced delivery (ced) market entry validation interim report 2 28...

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