In this webinar, we will: Answer questions and understand parent needs to make participation in a pivotal trial as easy as possible Share information on the path to drug approval and pivotal trial Learn about Vtesse Establish communication channel with Vtesse Agree on a mutual sense of urgency to demonstrate safety and efficacy of VTS-270 to ensure wider availability Clinician perspective on the drug development process Why drug development process is necessary for NPC community Parent perspective of having a child treated with VTS-270

1. Vtesse Welcomes the NPC Community
Determined
Community
NIH TRND
Academic
Scientists
Janssen
R&D
NICHD
NINDS
Consultants
Parent-Led
Foundations
APMRF, DART,
Hide & Seek,
SOAR-NPC, Addi
and Cassi Fund,
Hadley Hope
Parent
Scientists
US, EU, Brazil,
Rest of World
Parent
Advocacy
Groups
NNPDF, NP-UK,
INPDA
VTESSE
Manufacture the
Highest Quality Product
Pursue Rapid Path to
Approval for VTS-270
Drive innovation and
next-generation
products
1

2. 2
Good evening. My name is Ben Machielse, I am the CEO of Vtesse. Thanks so
much for participating in this webinar.
It is an honor to host this webinar. I'm going to take a step back and think about
how this cyclodextrin project came to fruition. Actually it all started as an
initiative fueled by parents, supported by parent advocacy groups and parent-
led foundations. There was significant involvement of many, many academic
scientists, NIH TRND and NIH NCATS really played a major role. We should
not forget to mention Johnson & Johnson who actually supplied the drug.
We are honored that we actually can take this program to the next step and
focus on getting this drug approved.

3. CONFIDENTIAL & PROPRIETARY
VTESSE & THE PATIENT COMMUNITY
WORKINGTOGETHERTOBRINGNEWSOLUTIONSFORNPC
2015

4. Webinar Goals
• Answer questions and understand parent needs to make
participation in a pivotal trial as easy as possible
• Share information on the path to drug approval and pivotal trial
• Learn about Vtesse
• Establish communication channel with Vtesse
• Agree on a mutual sense of urgency to demonstrate safety and efficacy of
VTS-270 to ensure wider availability
• Clinician perspective on the drug development process
• Why drug development process is necessary for NPC community
• Parent perspective of having a child treated with VTS-270
We will plan future webinars to inform and update the community
4

5. CONFIDENTIAL & PROPRIETARY
INTRODUCTION
Ben Machielse, Drs.
Vtesse President & CEO
5

6. 6
I want to emphasize before we go into the presentation that this is not a patient recruitment
seminar. We are actually trying to learn from the parents and families, what their thoughts are
about our activities, and about the trial. As I mentioned on January 7th, we are very much
interested in listening and learning from your perspective to actually move this program
forward.
We hope that we can establish an effective communication channel with you, and hopefully we
can all agree on the mutual sense of urgency to demonstrate the safety and efficacy of VTS-
270 to ensure the widest availability possible.
I am very pleased that Marc Patterson, as a clinician, will share his perspective on the need
for drug development and why a drug development process is necessary for the NPC
community to get the drug approved.
Also, Phil Marella will speak on his perspective and his experience with his son Andrew, who is
being treated with VTS-270 in the NIH Phase I trial.
As I said before we plan future webinars to inform and update the community.

7. Vtesse Core Values
• We care about the NPC community
• We are committed to help NPC patients and their families
• Singular focus – develop and seek regulatory approval for VTS-270 (2-
hydroxypropyl-b-cyclodextrin) to treat NPC
Put NPC
patients and
families first
• With you, we will do everything possible to answer how well VTS-270 works
• We operate with a sense of urgency
Think
beyond
limits
• We have a solution-oriented mindset
• We will listen and communicate openly where we can
• We aspire to deliver on our promises
Hold
ourselves
responsible
7
A privilege to serve this community by developing and seeking
approval for VTS-270 for the treatment of NPC

8. 8
First, just a little bit about Vtesse. When we started working on this opportunity what I
sensed was the commitment of the community to actually do whatever is possible to seek
a solution for their children. We are committed to help the NPC patients and their
families.
As a company, we focus on VTS-270 only, and really accelerate that to seek approval for
VTS-270 as soon as possible. We think beyond limits.
With you, we will do everything possible to answer how well VTS-270 works. Having good
data and understanding how VTS-270 works is absolutely essential to develop the best
future treatment paradigm for these patients.
We operate with a sense of urgency. We started January 7. We have had our first
interactions with the regulators already, and we have hired our CRO (Clinical Research
Organization who will run our clinical trial), and we are really marching forward to start the
study as soon as possible.

9. 9
As a team we had hold ourselves responsible. We have a solution-oriented mindset. We
know that this will not be an easy project, but with our shared commitment to find a
solution for the NPC children we think and we hope that we can contribute to a solution.
We will listen and communicate openly where we can. I hope you understand that we are
still in active discussions with the regulators, and sometimes it is difficult to share
everything because some things are simply not yet decided, or not yet approved. To
protect the open dialogue with the regulators, we also sometimes have to be a bit
cautious.
We aspire to deliver on our promises. We hate to make commitments we cannot fulfil.
Sometimes it will lead to us being a little bit careful on what we share because sometimes
we are not yet sure, but I promise you we will always be honest.
It is a privilege to serve this community, we see it as a challenge and we hope to
contribute to the development and the approval of VTS-270 with the treatment of NPC.

10. Introductions
Vtesse Team
• Our team has developed and
sought approval for 20
compounds
• Two major R&D functions –
clinical research and technical
operations
• Clinical research: launch a global
pivotal clinical study for VTS-270
• Technical operations: improve the
drug and method of
administration
Our Panel Today
• Ben Machielse, Vtesse
• Marc Patterson, Mayo Clinic
• Paul Gissen, GOSH (EU Session)
• Liz Berry-Kravis, Rush University
(US session)
• Phil Marella, Parent
• Will Evans, Parent (introductions,
EU session)
• Participating: Ravi Venkataramani,
Sarah Frech, Jehan Rowlands, Carol
Tressler, Siren Interactive
10

11. I’ll pass the torch to Will Evans for introductions.
Will: Thank you. So I’ll start by introducing myself, many of you may have met me. I’m
Will Evans, the father of Sam Evans. He’s 7 and he has Niemann-Pick Type C. I also
have 2 other children who are unaffected.
I’m a trustee with Niemann-Pick UK and in my day job I’m also a General Practitioner, a
family physician in England. We live in Northern England.
So it’s important for me to give a brief intro and tell you a little bit about things before we
hear more about things we’ve been looking forward to. I have to share with you the
excitement of hearing the announcement of the long awaited and hopeful cyclodextrin
trial. I know many people on this call, myself included, have spent a large amount of time
finding out about what’s going on with the Phase I trial, with the work done before that -
the preclinical work, and all the excitement that came with the impressive results that
we’ve seen.
We’ve also, myself included, explored compassionate access and other options to
access this therapy; but, the key thing was, and certainly what I wanted was to get a
clinical trial in Europe where we can get a definitive answer and proof that the drug
hopefully works and we can all get access for people with NPC across the world.
11

12. Throughout the process myself as a representative of NP UK, but also the INPDA have
been in contact with the NIH for a long time, and having regular teleconferences with
them and also with Vtesse, the company, right from the outset of the formation of the
company and actually before then. So Vtesse have actually been engaging us as a
patient group in Europe as of summer of last year. And, they have been at pains to try
and keep us informed of what’s going on and have listened and valued our input
throughout this process to try and achieve what they truly do see as a multi-nationals trial
with EU having equal footing as the US, which I am greatly encouraged by; and, I’m sure
you will hear more about that later.
Today’s webinar is a start and further demonstration of this willingness to engage with us
as a patient and parent group, as well as a chance for us to learn more about Vtesse’s
intentions. It’s a way to learn more about us as a patient group in Europe and how they
can help us facilitate this trial and address some of our needs as well.
There are things they can share and some they can’t because it’s still a process as they
are still deciding what needs to be done and they are still in contact with regulators and
centers. So I think it’s important to emphasize, and we would hopefully gain lots of
information today; but, maybe not as much as we first hoped.
12

13. The key thing to say is that we are all painfully aware of the urgency of this. We all have
loved ones affected by this. I also feel from conversations with Vtesse that they
appreciate this; and, they really do value and know that this is something they can’t hang
about with, and they need to get answers quickly so we can definitely know if cyclodextrin
works, and therefore hopefully have an approved compound that we can all access for
our patients.
I look forward to the discussions.
13

14. 14
Ben: Let me talk about the Vtesse team. Our team has developed jointly and sought
approval for over 20 compounds which are currently used in the field. We understand the
interactions with the regulators, and we understand also how to develop a label which is
meaningful for the patients who actually will receive the drug in the future.
As a company, we have two major R&D functions: clinical research led by Sarah Frech,
that is focused on the launch of the pivotal clinical study. They have developed the
protocols, they have sought scientific advice, and they are actively interacting with the
CRO to accelerate the development of the clinical plan at the highest pace possible.
Then we have a technical operations function led by Allan Darling. Their focus is to
further improve the drug and also improve on the method of administration. We see this
as part of our long-term commitment to continue to optimise the current drug
cyclodextrin, and possibly develop new drugs for the treatment of NPC.

15. 15
Our panel today consists of myself, Marc Patterson from the Mayo Clinic, you probably
all know him but Marc is on our SAB and has been working on NPC for many many years
and he is considered one of the major experts in the world on NPC.
We also have here Liz Berry-Kravis from Rush University. She is also a neurologist and
she treats some patients under iIND, and has tremendous experience with the NPC
patients; and, we are collaborating with Liz to learn where we can.
Also, Phil Marella, he will present as a parent on his experience in the Phase I trial.
Last but not least, and I forgot to put them on the list and I take the blame for that, Denny
Porter is here also as a panellist to share his experience. Denny Porter of NIH with his
team has driven forward the development of cyclodextrin for the treatment of NPC to a
point where we now can take it to a pivotal trial. We are building on the foundation which
has been laid by the parents, by the iIND parents, and by the work at NIH and academic
institutions to design the best possible study.
Other people participating are Ravi Venkataramani, our Chief Business Officer, Sarah
Frech, Head of Clinical, Jehan Rowlands, Head of Regulatory Affairs, Carol Tressler, our
Office Manager, and Siren Interactive.

16. Where We Stand Today
• We have the right ingredients to drive this program forward
and seek approval for VTS-270 to treat NPC
• Licensed rights from the National Institutes of Health (NIH)
• Transferred Investigational New Drug (IND) application and the Orphan
Drug Designations for US and EU
• Raised money from investors to conduct the pivotal clinical trial
• Completed initial interactions with US and EU regulators
• Our immediate goal: initiate a pivotal clinical study to seek
approval for VTS-270
• Longer term vision: evaluate potential second-generation drug
• Method of administration that decreases burden to patient
16

17. 17
Where do we stand today? We have combined the right ingredients to drive this program
forward and seek approval for VTS-270.
We have licensed the rights to cyclodextrin and other compounds for the treatment of
NPC from the National Institute of Health, and that gives us a wealth of data which helps
us to analyze the historical data, and the data on Phase I which allows us to optimize the
design of the clinical study.
We transferred the IND (the investigational new drug application) and the Orphan Drug
Designations to Vtesse for the US and EU, and this will allow us to actively interact with
regulators to discuss our clinical development plan.
Absolutely important too is that we raised enough money from investors to conduct a
pivotal trial and we are very confident that we are very well equipped from a resource,
knowledge, and know-how point of view to start and complete this clinical trial.
As said before, our one single goal is to initiate the pivotal clinical study to seek approval.
The longer term vision is evaluate, based on what we learn from cyclodextrin, second
generation drugs and improve the method of administration so that we decrease the
burden of the patients in case we demonstrate that cyclodextrin works.

18. VTS-270
About VTS-270
• A formulation of 2-hydroxypropyl-
b-cyclodextrin (HPbCD)
• Extensive safety profile in multiple
applications
• Deep preclinical knowledge
• HPbCDs are complex mixtures
• Currently in Phase I testing in the
US
Efficacy
• Strong efficacy results in mice and
cat models of NPC disease
• Prevents cerebellar dysfunction such as
ataxia
• Preserves Purkinje cells
• Prolongs lifespan
• Route of administration is
important in treating the
neurological disease
• In cats, administration directly into the
brain improves neurological disease
more than injecting into the body
• Intrathecal/intracranial is better than
intravenous/subcutaneous for
neurological disease 18

19. 19
What is VTS-270? VTS-270 is the formulation of 2-hydroxypropyl-beta-cyclodextrin. It
has been studied over many, many years. It has an extensive safety profile in multiple
indications.
Fortunately, we have a very deep preclinical knowledge of 2-hydroxypropyl-beta-
cyclodextrin that we are using in our trial.
We do realize that cyclodextrins are complex mixtures, and one mixture is not necessarily
the same as the other mixtures.
Currently VTS-270 is in Phase I testing in the US at the NIH site.

20. 20
From an efficacy point of view, we are really optimistic because the efficacy results in
mice and cat models of NPC show that there are clear indications that VTS-270 prevents
cerebellar dysfunction such as ataxia.
Also it has been demonstrated that VTS-270 preserves Purkinje cells.
Very importantly in both the mice and the cat model, it is a clear prolongation of life span
and that set of data in combination with what we have learned from the Phase I study
and the natural history study gives us a sense of optimism.
I must mention that the route of administration is very important in treating the
neurological aspects of the disease. In cats, administration directly into the brain
improves neurological disease more than injecting it into the body. Therefore we have
elected to administer this drug intrathecally (lumbar puncture). Based on the data in the
preclinical study as generated by many academic institutions, it is better than intravenous
administration for the treatment of the neurological disease.
Having said that, this is an initial introduction of where we stand today, who we are as a
company and our initial plan. I would like to actually pass the torch to Marc Patterson who
is going to share a clinician’s perspective.

21. A CLINICIANS’ PERSPECTIVE
Marc C. Patterson, MD, FRACP, FAAN, FANA
Professor of Neurology, Pediatrics and Medical Genetics
Mayo Clinic Children’s Center
21

22. 22
Thank you very much. Just to introduce myself to people who may not know me, I am a
Pediatric Neurologist.
I got involved in this field about 25 years ago when I was at NIH. I had the privilege of
being involved in the first randomized study in Niemann-Pick C which was a study of
cholesterol lowering agents subsequently in the study of Miglustat.
I have had the greatest privilege of caring for many, many patients over many years now.
So, I am as eager as everyone else that we have the best and the safest treatments
available to treat children and adults who are afflicted by this disease.

23. Unmet needs and challenges in NPC:
April 2015
• No approved disease modifying therapy in the US
• Delayed diagnosis – significant disease burden before
interventions can be pursued
• Unclear which measures will be accepted globally by regulators
as evidence of efficacy of treatment
• Animal studies provide strong data supporting benefit from 2-
hydroxypropyl-b-cyclodextrin (cyclodextrin) in NPC - but there
is no controlled data yet on efficacy of cyclodextrin in humans
23

24. 24
I just want to take a moment to talk about the unmet needs and challenges in Niemann-
Pick C in April of 2015. For those of us in the US we have no approved disease modifying
therapy, and this is a problem. There is a therapy which is approved elsewhere which has
shown evidence of efficacy, but because it is not approved by the regulatory agencies it is
not freely available to everyone, so this is a considerable problem.
An even bigger problem is the delayed diagnosis. A number of studies have been done in
different centers, and typically the average delay in diagnosis for this disease is five
years. In some cases, in adults it has been as much as 20 years. In fact, the oldest
patient I diagnosed was 65 and had first developed symptoms at 40 years of age. This is
a huge problem because it means when we have potentially effective therapies, the
patients to whom we can administer these therapies already have a significant burden of
disease. What that translates into is a loss of neurons. Neither cyclodextrin nor any other
therapy that is proposed at the moment can replace neurons that are lost. So, it is
absolutely critical that we make this diagnosis as soon as possible so that we can have
the most effective interventions.

25. 25
Another problem which is not unique to Niemann-Pick C that is common amongst rare
diseases that affect the nervous system is that it is difficult to know exactly what to
measure that will demonstrate to the satisfaction of parents and academic investigators,
and in some ways most importantly, regulators that the treatment is truly effective. In
certain diseases such as cancers, survival is the outcome measure that is most widely
used. That is not in any way appropriate for Niemann-Pick disease type C. We could
never conduct a clinical trial which would give us data in any sort of reasonable time
frame.
So, we need to look at manifestations of the disease that can be measured objectively
and consistently and which are not subject to what we might call noise. That is, variations
which are not due to the progression of the disease itself, but to other factors such as
drugs that are being administered to patients or into current illnesses and so on.

26. 26
Fortunately, thanks to the wonderful work of Denny Porter and his colleagues at NIH, we
now have something that did not exist in the past when we were trying to design studies,
and that is a large Natural History database which is now linked to a number of
compounds which can be measured in different bodily fluids, in other words, biomarkers.
This is a tremendous resource and it has really been essential to make progress in this
disease. One of the most valuable biomarkers to come out of these studies has been the
recognition that a specific trial Oxysterol is a very valuable diagnostic tool for Niemann-
Pick C. Prior to the availability of this blood test, we needed to rely on tissue biopsies,
genetic tests, both of which are expensive and cumbersome and have significant false
positive and false negative rates. This is going to make a huge difference in our ability to
diagnose this disease better.
Of course as you have already heard from Ben, animal studies have provided very strong
data supporting benefit from cyclodextrin in mice and cats, and although the drug has
been administered to humans we do not have any controlled data yet on its efficacy. Let’s
expand a little bit more on that.

27. Why pursue a controlled clinical trial?
• To determine if perceived benefits in animal studies
(“preclinical studies”) also occur in humans under controlled
conditions
• To determine if the agent is safe in humans
• Both control and intervention groups studied using appropriate
statistical methods are essential to ensure that variations in
outcomes are related to the agent being tested, and not just
chance
• To provide data for regulatory approval (by the FDA in the US,
different agencies in other countries)
27

28. 28
Really the question is why pursue a controlled clinical trial? We have seen the best
results from any intervention in the animal models of Niemann-Pick C with cyclodextrin.
So, it would be very reasonable for people to say why not just treat people? Why not just
treat humans with this drug?
The reason is that we don't know if it works in humans yet. We do know that humans,
and this sounds trivial, are not mice and are not cats and there are many examples in
science where promising agents produce what look to be impressive results in animals
but don't translate to humans.
The other big problem in is in humans the disease is very variable. It is absolutely
essential that we have controls so that we can demonstrate that apparent benefit is true,
and not just a result of random variation.

29. 29
In other words, the reason to pursue a controlled clinical trial is to determine if the
perceived benefits in animal studies, these are the preclinical studies that have been
referred to, also occur in humans under controlled conditions. Of course it is important to
determine if the agent is safe in humans.
We also have many examples in clinical studies where small numbers of humans are
exposed to a drug early in the course of its development and then later when larger
numbers are exposed adverse events which were not previously recognised or expected
can become apparent.
When we talk about controls it means that we need two groups of patients who are as
closely matched as possible in terms of age and severity of disease, and other factors
who can be compared. One will receive the active agent, one group will not.

30. 30
We know that when we are studying or performing these sorts of studies to account for
variation that occurs naturally, we need to use statistical methods.
The factors that have to be taken into account when designing a clinical trial are first of all
the size of the effect, and so before investigators begin a trial they have to decide what
they will measure, and what they will regard as a clinically significant change in that
measure using that measure of effect size. It is then possible to calculate how many
patients will be needed to participate in this study to have a reasonable chance of finding
an effect, if it is there.
And this number that is calculated, it is called the power of the study. For example, you
may say that a study has an 80% power of detecting a 5% difference between the
intervention and control groups.
This is an absolutely critical number because in rare diseases one of the enormous
problems we face is that agents which may produce clinically significant effects may not
reach statistical significance because the numbers of patient studied are too small.

31. 31
This is called a Type 2 error in statistics. It is an incorrect or a false negative result.
This is one of the reasons why selecting patients carefully, matching them as carefully as
possible and limiting the variability are all absolutely essential in designing a study that
will answer the question as clearly as possible. I can't over emphasize the importance of
that.
When you see detailed criteria for inclusion and exclusion from studies, these are not
something that has been decided upon in a random fashion. This has been carefully
thought out to ensure that this study is going to get the answer that is required.
A very important reason to pursue a controlled clinical trial is that this is the only way that
we will get data that will be acceptable for regulatory approval by the Food and Drug
Administration of the United States and by the different agencies in other countries.

32. How drugs are developed and approved
• Mission of regulatory agencies
• FDA: “The mission of FDA's Center for Drug Evaluation and Research (CDER) is
to ensure that drugs marketed in this country are safe and effective”
• EMA: " to foster scientific excellence in the evaluation and supervision of
medicines, for the benefit of public and animal health"
• Regulatory agencies typically do not test drugs
• Although they sometimes conduct limited research in the areas of drug
quality, safety, and effectiveness to help with enforcement activities
• “Clinical trials are experiments that use human subjects to see
whether a drug is effective, and what side effects it may cause. ”
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/
32

33. 33
I wanted to say a word or two about how drugs are developed and approved. Now, I am
not an expert on this by any means. There are people participating here who are, and
could answer many more detailed questions; but, I have painfully learned some details of
this and I will certainly share them with you.
First of all, what is the mission of the regulatory agencies? The Food and Drug
Administration states that the mission of the Food and Drug Administration’s Center for
Drug Evaluation and Research (CDER) is to ensure that drugs marketed in the United
States are safe and effective.
Now, the European Medicines Agency has a slightly different statement. They state that
their mission is to foster scientific excellence in the evaluation and supervision of
medicines for the benefit of public and animal health.

34. 34
Now, whilst it is true that in many situations, the evaluations of these two agencies will
coincide, and they are beginning to cooperate more and more, they are not the same.
They have their own rules and requirements.
When conducting an international or global study, which is really important for rare
diseases such as Niemann-Pick C, one has to take into account the requirements of
these different agencies.
It is also important to remember that regulatory agencies do not do the pivotal drug trials
themselves. Sometimes, they conduct research or fund research in terms of drug quality,
safety, and effectiveness to help with their enforcement activities, but they typically do not
fund the pivotal trials.
I want to emphasize this final statement, clinical trials are experiments that use human
subjects to see whether a drug is effective and what side effects it may cause. I
emphasize this, they are experiments. You can't refer to the drug as a treatment until you
have evidence that it actually does something in humans.

35. 35
It is very important that I think we use this language carefully in talking about the
experimental agent or the experimental drug because if we call it a treatment, people
tend to think somebody is getting treatment and somebody is in the control, but it is not.
Both are participating in an experiment.
In fact, the way I believe this trial will be designed, everyone will have the opportunity to
receive the interventional agent after a period of time; but, I can't over emphasize the
importance that clinical trials are experiments.

36. Regulations – why expert guidance is needed
36

37. 37
I do not expect you to be able to read this slide unless you have much better vision than I
do; but, it is just to give you a very graphic sense of the complexity of this process.
The drug regulatory process is a thicket of rules and regulations and this is not something
for amateurs to do. You need professionals such as those who are involved in Vtesse
who have already passed along this way who know how to negotiate these agencies.
They are very strict with requirements. If you go to these web pages, you will see that
each one of those blue lines represents a link that links on many pages, many
regulations, many forms, and these all have to be right. These people are worse than the
IRS.
You've got to get everything exactly right if you are going to move along this path
correctly. This takes experience.

38. Why pursue drug approval?
• The cost of approved drugs is (usually) covered by insurance,
meaning that most patients should be able to gain access to
agents regarded as safe and effective
• The drug approval process will also provide a better
understanding of the objective efficacy of the drug
• Regulatory agencies continue to monitor drugs for safety after
approval
• Approval of one drug provides a road map for subsequent
studies of new drugs to treat the same condition
38

39. 39
I guess, a final question is, if you can show that this agent is effective, why is it so
important to get the drug approved?
The reason is very simple. In most countries, the cost of approved drugs is covered by
insurance. That means that if a drug is approved most patients should be able to gain
access to agents which are regarded as safe and effective in treating their illness. Now of
course, if you go through this very rigorous drug approval process, it should provide
better understanding of the objective efficacy of the drug.
In addition, as I mentioned before, sometimes unexpected adverse effects of drugs can
occur after initial studies. The regulatory agencies will continue to monitor drugs for
safety and they will detect signals and intervene if necessary.
One important point is that when any agent is approved for the treatment of specific
manifestations of a disease, then certain criteria are established. This provides a
roadmap for subsequent drug development. We know that although cyclodextrin has
provided the most impressive results in animal models of this disease, it is not a cure.
These animals still succumb to their illness. They survive much longer than animals
treated with other agents but they still succumb. Ultimately, cyclodextrin is not going to be
the final answer, but we hope it will prove to be a very important step towards that.

40. 40
I just want to make a couple of closing comments.
As I mentioned, this trial as proposed by Vtesse for cyclodextrin is not the first trial of
drugs in Niemann-Pick C. It is not the first controlled trial. There was a randomized trial of
cholesterol lowering agents that was published in 1993. We did a controlled trial of
Migulsat with small numbers on a population of very sick patients without the database of
clinical information and with very limited funding which was published eight years ago.
Now, the unique aspect of this trial is that we have a beautifully gathered and analyzed
cohort of patients from Denny Porter’s study at NIH with linked biomarkers that provides
the basis for designing a clinical trial. This was never available before. There was no
funding to support it. It has been done and executed in a superb way. We have this basis.
We have an agent which has been very effective in animals.
I think this is an exciting time for everyone in this community, but it has already been
stated this is still not an easy study to do. With all of these factors in our favor, it is a
tough disease that is difficult to study.

41. 41
It is absolutely essential that this study is designed to be as likely as it can be to show a
true benefit if it exists. And so, that requires rigor; and that rigor of course, means that not
everybody is going to be able to participate in the study and not everyone will qualify.
But it is very important that everyone understands why this is the case. Ultimately, this is
their best chance to get a clear-cut answer and we hope to have an approved therapy.
I am going to conclude my remarks there but I do want to take this opportunity to thank
you for the opportunity to speak.

42. 42
Also, if I may introduce Phil Marella, I have had the opportunity to get to know Phil and
his remarkable family since their journey with Niemann-Pick C began many years ago
now.
Phil is a really extraordinary person as are his family members. In addition to coping with
the burden of this illness, they have been extraordinary fundraisers and intellectual
leaders within the patient care community. They really are one of many people who I
found very inspiring over the years.
Again, thank you for the opportunity to speak and I'll pass the torch to you Phil.

43. CONFIDENTIAL & PROPRIETARY
A PARENT’S PERSPECTIVE
Phil Marella
Father of Dana and Andrew

44. 44
Thank you for that Marc. I greatly appreciate it and thank you for all that you have done
for the kids and the families over the long period of time you have been helping with
NPC.
I will introduce myself, I am Phil Marella. I live in Connecticut with my family. Many of you
know our story. For those of you that don't, two of my wife Andrea’s and my children were
born with Nieman-Pick C. Sadly in 2013, we lost our daughter Dana right before her 20th
birthday. Our son Andrew who also has Nieman-Pick C, is going on 16 now and he is
actually doing pretty well though he is battling daily seizures which started not too long
after Dana’s passing.
Before we turn the slide and I get into some discussion about our experience in the
Phase I trial, I would like to tell you all how important we feel this trial is for all of the kids
and for the adults as well with NPC. We have dreamed of an approved therapy as a
collection of families. The NIH has provided amazing support in this effort and the US
FDA has listened to our pleas. Those of you who have been to our fundraisers have
heard me say that I like to describe this community as an extended family, a committed
family, and I hope with this trial, we will continue to show that to everyone.

45. Potential Impact on Hearing
Anunsettlingrisk;decisiontoacceptornot
45
• March 2015: our son, Andrew, received 1st dose at 900mg
• Andrew had a significant loss of hearing in the mid-conversational range
• For Andrew’s April visit, we’re thrilled his hearing has come back nicely
• Hearing impact was a Grade 1 loss
• Realizing NPC is already taking Andrew’s hearing, we bought hearing aids for Andrew
• Andrew is hearing things he has not heard in years
• Hearing aids are usually covered by insurance for children
• We worried non-stop about risking Andrew’s hearing
• Now feel comfortable that the loss can be addressed
• Excited to see Andrew more talkative and walking better
• It’s a very personal decision, but it is important to remember that NPC is impacting
hearing anyway, and it’s the other, devastating, mental and physical deterioration we
hope to dramatically show down

46. 46
The first thing that I thought I would address is the issue that we all worry the most about
which is the hearing. As you know, the mice and the cats are completely deaf and
irreparably deaf. And so, that became much more of a concern particularly as we started
approaching higher doses this past fall. I'll tell you a little bit about our experience.
Our son Andrew has been receiving an increasing amount of cyclodextrin for 17 months
now. Last month in March, he received 900mg for the first time. As was expected,
Andrew had a significant hearing loss mostly in the midrange sound. If you have learned
about this at this point, it is very important for conversation.
In the time between our April and March visits, we went ahead and got Andrew hearing
aids. Last week we returned to the NIH for the second dose of 900mg. We learned that
Andrew’s hearing had actually recovered pretty nicely. When we left after the first dose of
900mg, his hearing was graded as a grade 3 loss but by last week it had recovered to a
grade 1. That was a great bit of news.

47. 47
Now, I mentioned that we had already gotten Andrew hearing aids. We were actually
inspired by Tonya Kains' story, which she told to my wife Andrea in March. The Kains' had
gotten their daughter Julia, who is about Andrew’s age and a wonderful young lady,
hearing aids. Tonya was telling us the story that Julia got up one morning, put in her
hearing aids and gleefully came downstairs to tell her mother she heard the birds chirping
outside for the first time.
That was when we realised that we had sort of been depriving Andrew of some of the
pleasures of the world. He had already had some fairly significant high range hearing loss
and that was something that we had just sort of thought that he could get by without the
hearing aids. I have now gotten him hearing aids. I have to tell you his hearing is almost
perfect at this point. These hearing aids are now so sophisticated they can literally tailor
them to the loss that he has.
We were there this morning adjusting them for the increased recovery in his hearing over
the last month. They actually tuned in two programs so that when we go back we can
push this little button three times and it will increase the benefit for him for a period of
time after he gets the next dose. When it gets a little better, we can press the button
three more times and it will go back to the original setting. It is absolutely amazing what
you can do with the hearing aids now. The good news for families with children
is that it is usually paid for by insurance whereas, not for adults.

48. 48
I can't really express the fears that we had going into that 900mg LP. It is very easy to
take a logical approach and say, I'm giving this medicine, it is going to improve his life,
and it is going to give him a longer life span; but, the moment before you give your child
something that may rob their hearing the next day, your heart is going to stop to beat.
But having taken the step, having had a much better result than we thought was likely,
we really feel some relief at this point about cyclodextrin. We’re not concerned about
going to 1200mg any longer. I think that with the hearing aids, it is just amazing what we
have been able to do for Andrew. And of course, we are hopeful that the cyclodextrin is
going to have great benefit for his overall quality of life.
We are actually encouraged over this past year. He is talking more, he's walking better.
He was at physical therapy this morning and his physical therapist is very pleased with
his increased balance, strength in his legs, and his gait is better. It is certainly looking
positive and I think everyone has the same kind of hopes for cyclodextrin.

49. 49
But needless to say, this is a very personal decision that everyone has to make for their
family, for their child, and for themselves about whether to take the cyclodextrin and risk
what is still an undefined potential risk with the hearing.
I think it is important to note though that, as I said, Andrew already had some significant
high frequency loss and the NPC is taking the children’s hearing anyway; so, when you
put that up against the potential benefits, I think the goal is to dramatically slow down the
rest of the horrors of this disease because we are losing the hearing anyway.

50. Lesser Challenges
Thingsthatarenotasbadastheyseem
50
Having reconciled what our family sees as the greatest challenge, we face the lesser
challenges
• Lumbar punctures
• Andrew has had almost 25+ LPs since 2006, and only 1 with some post-LP nausea. The last 3
were with just local anesthesia, and he did great.
• To move quickly with the treatments, which is so crucial for all of these children, LP seems
the best way to go. Ommaya reservoir was a clever idea, but it cost us all critical months of
delay.
• Frequent travel to the site
• A necessary sacrifice to have the proper control, but hopefully enough approved locations
to make it as convenient as possible. The locations have to be facilities that can meet the
standards for potential approval.
• Control arm in the experiment – Promised my family I’d always work to avoid another
“Zavesca Situation”
• During the controlled trial portion, there is a chance that your child will not get the drug for
the first year
• After that everyone will be enrolled in an open label extension where they will get the
treatment

51. 51
I would like to address some of the other issues that I see as less problematic. They are
somewhat obviously traumatic in our minds, but I think having faced down the biggest
challenge of the hearing, we're not quite as concerned about these.
That is the lumbar punctures which no one particularly likes; but, if we want to move this
trial forward quickly, this is the best way to go. I will tell you that Andrew has had over 20,
maybe 25 lumbar punctures since 2006. He was one of the first children enrolled under
the natural history study. In all that time, he has only had one lumbar puncture that
resulted in some post LP nausea. He didn’t even have a serious headache from it. The
last four LPs with the cyclodextrin were done with local anaesthesia and he did really,
really well.
To move forward with the treatments which are so critical for all these kids, LP seems to
be the best way to go.

52. 52
I was very excited about the concept of the Ommaya resevoir when it was first presented,
but obviously when we developed some difficulties with it, it cost us critical months of
delay. Anything that we would do along those lines again would likely lead to further delay
and deterioration of children unnecessarily.
Anytime you are in a drug trial, you just don't do this at your local hospital. There are
going to have to be limited number of sites. There will be frequent travel. It is certainly
going to be easier with multiple sites. It will be easier than going to the NIH once a
month, but we are not going to be able to do this everywhere and we are going to have
lots of number of sites and that will hopefully help us create the right environment to get
the approval. I am told that there will be a number of sites and they are working very hard
to make this as convenient for everyone as possible.

53. 53
Ben and Marc talked about the control arm in a trial, which again we all wish was
unnecessary in any drug trial.
I have to say that I promised my family after the Zavesca fiasco, that I would always work
for this community to avoid that again. I was one of the three parents that spoke before
an FDA panel that was charged with recommending one way or the other whether to
approve Zavesca or not. I will tell you that listening to the onslaught of complaints about
Zavesca from the FDA was devastating. I was just completely overrun with the
complaints. The sad thing was we knew it had helped the children, but we couldn’t prove
it.
Here we are with a situation in this country (US) where about half the kids can get
Zavesca and half the kids can't. That is a shame and that is something we have to avoid
for all of our potential therapies or hopefully approved therapies in the future.
During the controlled trial, there is a chance your child will not be getting the drug for the
first year; but, there is a commitment that after you have been in the trial for 12 months,
you are going to be enrolled in open label extension where you will actually get the
treatment as long as it takes to get approval. Hopefully, we get the approval.

54. Our Hope
• Quality-of-life and longevity that we have seen in mice and in cats is
the strongest that we have seen with any drug
• This drug has been used safely in several other drugs as a carrier –
has a large safety record behind its use
• Controlled experiment
• Only a clinical trial will demonstrate if we can see the kind of success in
children with quality-of-life and longevity that we have seen in cats
• We cannot have ANY more treatments which some of the children can get
and other children cannot. That takes FDA approval
• The Zavesca approval process underscores this – the panel even accepted
that there was a “suggestion of benefit”, there was plenty of personal
evidence but not enough scientific evidence for approval
• Controlled clinical trial will help get that evidence and accelerate the
approval process
54

55. 55
Let’s look at the positive side of this. What are our hopes as parents, as patients, and as
the doctors of patients?
We’ve hoped forever for an approved therapy. The quality of life and longevity that we
have seen in the mice and in the cats is the strongest that we have seen from any drug
ever. cyclodextrin has been used safely to deliver other medicines. It has a large, long
safety record. We are conducting a controlled experiment approved by the FDA and the
EU and only a clinical trial can demonstrate if we are going to see the kind of success in
children that we have seen for example in the cats.
We can't have any more treatments where some of the children can get the medicine and
some of the children cannot. That takes FDA approval. The Zavesca approval process
underscores this. The panel even accepted that there was a suggestion of benefit. That
afternoon, we convinced 10 out of 13 panelists with our hearts to recommend the
approval of Zavesca.
A controlled clinical trial will help get the evidence and accelerate the approval process.

56. 56
A couple of closing points.
I think it is important to remember as Marc said, cyclodextrin presents the greatest
possible benefit we've ever seen for the kids, but it is not a cure. This is just a first step;
but, clearly an important step in what we hope will be an approved combination therapy, a
drug cocktail if you will.
Hopefully by the time this trial is over, we will have something else, maybe more than one
item ready to roll into another trial - something that we can build on. We have developed
a lot of goodwill with the NIH, and with the FDA. I hope that we can follow through on the
earlier enthusiasm we all showed and make this trial a success. Thank you.

57. How Do We Get VTS-270 Approved?
• Clinical trials are experiments to answer several key questions:
• Does the drug work?
• Which aspects of the disease does the drug treat?
• What are the risks and side effects?
• What is the dose where the drug works best (best efficacy) and has the
lowest risks/side-effects (best safety)
• Current Phase I will provide initial answers for some of these
questions; provides the basis for Phase II/III clinical trials
• Vtesse will conduct a combined Phase II and Phase III clinical trial
that will seek to provide definitive answers to these questions
• Regulatory bodies will review our data to see if we have established
safety and effectiveness of the drug to support approval
57

58. CONFIDENTIAL & PROPRIETARY
VTS-270: PATH FORWARD
Ben Machielse, Drs.
Vtesse President & CEO
58

59. 59
Thank you Phil. Let me talk a little bit on how do we plan to get VTS-270 approved.
As Marc said, clinical trials are experiments and they are designed to answer several key
questions. First of all, does the drug work?
Second, we plan to actually set up a study such that hopefully at the end of the study we
understand a greater aspect of the disease, if the drug works. Hopefully we will find out
about certain key aspects - that cyclodextrin has a positive effect on NPC but in other
aspects, it probably will not.
By doing the study, we may be able to provide a benchmark and understand where
cyclodextrin works and where it does not work. That would open up the way for future
development of drugs which cover the aspects of treatment where cyclodextrin doesn’t
work.
Also very important is will we understand the risks and the benefits and the side effects of
the drug? We have talked about ototoxicity, but we need to make sure that there are no
other side effects and risks involved with administering this drug.

60. 60
Also very importantly, what is the best dose? What generates the best efficacy
and has the lowest risk side effects? We need to carefully balance that and we
plan on doing that in this study and I will explain that somewhat later.
Fortunately, the current Phase I study as conducted by NIH will provide initial
answers for some of these questions and it will provide a basis to actually build
clinical protocol for the Phase II/III trial.
We focus on a single trial which hopefully provides definitive answers and can
help us to seek approval of this drug. After completion of the clinical trial we will
work rapidly to submit the documentation to regulatory agencies in both the US
and Europe and other territories to seek approval.

61. Our Current Thinking for a Pivotal Clinical Trial
• Global, 50 patient, multi-site study will be launched no later
than second half of 2015
• Controlled study (treatment and control arms) in 2 stages:
• 1st stage to select best dose
• 2nd stage patients get the best dose
• Intrathecal, bi-weekly administration of VTS-270 with 1 year
duration
• Followed by an open label extension until the time of approval
• Both the treatment and control arms will get the drug
61

62. 62
I would like to talk to you a little bit about our current thinking for our pivotal clinical trial. I
just want to preface this: that we cannot disclose everything yet because we are still in
active discussions with the regulators, but what we can disclose is the following: we plan
on a global clinical trial which means that we will design such as capture the patients as
quickly and as efficiently as possible.
We plan on possibly somewhere between 15 and 20 sites worldwide to actually conduct
this study. It will be a multi-site study in multiple territories, and we also will provide
support to travel to the sites. We understand that even with 20 sites there still will be
travel involved and we will do our utmost best to make it as easy and as convenient as
possible for you.
We plan on launching the site no later than the second half of 2015 and I'm optimistic that
we actually can start this trial for you in Q3 of 2015.
We also will capture a lot of other data. We will evaluate what biomarkers could be
indicative of efficacy and those kind of things, but of course the most important thing is
that we look at clinical phenomena which could be indicative of efficacy of the drug.

63. 63
We plan on a controlled study and as Phil said, a certain number of patients will not
receive the drug for a year. We are not thinking about one to one randomization, but we
are currently thinking about a two to one randomization, because we are very sensitive
about the fact that certain patients will not receive the drug for the first year.
It also will be a blinded trial, and as you may hear I'm not using the word ‘placebo’
anywhere here. We are doing a controlled trial where we basically will simulate
everything for each patient in the trial. Patients in the control side of the study will not
receive the lumbar puncture in the lower part of the back.
We are also evaluating what we call the implementation of a rescue option. If there is
unexpected decline in some of the patients, we are evaluating if it would be possible to
implement an option where those patients are lifted out of the trial and put on drug.
That is what we are evaluating, this is not yet a hard commitment, but we are working on
it.

64. 64
The study consists of two stages. The first stage is to actually select the best dose. We
will assess safety tolerability and side effects of the doses so that we actually have an
indication that we can enroll the remainder of the patients in Phase II. As I said before, it
will be an intrathecally administered product. We will administer it every two weeks for the
duration of one year.
I also want to emphasize that we looked at multiple dimensions of this. We are not
scoring people only on one particular aspect; but, we have designed the study such that
we will evaluate in what aspects patients will stabilize or maybe even improve.
After a patient is enrolled for one year, each and every patient in the clinical trial will be
allowed to participate in the open label extension study until the time of approval.
That means people who were treated and also people who were in the control arm will
receive the drug after that first year of study until the time the drug is approved.
We try to be very sensitive to your needs. We do believe that a controlled study is
required given the fact that the disease progression is relatively unpredictable and we
must be able to accurately measure any effect of cyclodextrin.
That concludes our presentation and I would now like to answer some of the
questions we have received during this session.

65. Discussion
• Questions from the community
65

66. 66
We did receive many questions. As we indicated earlier we cannot answer all of them
here. There are quite a few questions around the lumbar puncture.
I will try to do so and you know fortunately we have people here on the panel with
significant experience with these repeat lumbar punctures and two of those are here, Liz
Berry-Kravis and Denny Porter. I would like to ask their opinion about their repeat
administration of lumbar puncture. How patients perceive it and what you consider be the
risk of that? Maybe Liz you can start and comment on this.
Okay. Hi, thank you for letting me participate in this webinar. We have an iIND in which
we have three patients enrolled and two of our patients have been enrolled for about 16
months now. We have been doing LPs every two weeks on these patients and in general
this is really very well tolerated.
The process itself is really not that difficult. It is mostly a matter if the person doesn’t
understand what is going on, they can show that they can be still for it and not move
during the process. In many cases doing an LP on a child is almost easier than drawing
blood because the spaces between the bones and the spine are quite wide and you don't
have problems with arthritis and it is really pretty easy to do.

67. 67
What we do when our patients come in is we have Lidocaine that we put on the back. It is
a cream and kind of numbs them up and then when we do the spinal tap, we inject some
additional Lidocaine, but they don't feel the needle so much because we have already
numbed up the back with the cream and then just put the needle into the back, get fluid
out and then do the infusion.
As long as the patient is lying still, they are actually pretty comfortable. Our patients joke
around with us, talk with us and we talk about movies during the procedure.
Our patients have been good afterwards. They haven’t had any problems. We did have
some problems with post spinal tap headaches and a little bit of vomiting initially; but, we
switched to a special kind of needle called the Whittaker needle which doesn’t cause as
much damage to the covering of the spinal cord when it goes in, and we haven't had any
problems really with those kinds of side effects afterwards.
We do the procedure in the outpatient clinic with our patients. It takes about 15 to 20
minutes and our patients are in and out. They come in the morning and they are out by
early afternoon. It takes some getting used to but once you get used to it, it is kind of an
aggravation but it is not really a big difficult thing.
Okay thank you Liz. Denny would you be able to share your perspective?

68. 68
Yes. Lumbar punctures are one of the items when we go through the consent that we
always end up focusing on because almost always the parents or guardians are
concerned about it.
It really is a simple procedure and Liz described it well. Now that is coming from the
perspective of a paediatrician, not a parent. It tends to be scarier in concept than it is in
actuality and what the risks are. The risks are really the post LP headache, plus or minus
some vomiting or nausea associated with it.
We've done LPs in the Natural History trial and now in the cyclodextrin trial. We have
done hundreds in NPC kids and young adults. Phil talked earlier about his son’s
experience and that’s pretty typical. One episode of nausea with about 25 LPs. Our
numbers are somewhere around that 5% mark.
The headaches or the nausea tend to be self-limited and relatively short in duration. Very
rarely do they last beyond the day. It is something that, yes it is an adverse event, it will
happen if we do enough of these, but it is a very minor problem.

69. 69
The kids tolerate the procedure very well. At least half of our kids do it at the bedside as
Liz described.
They are very used to it and the teenagers will sleep through it. The younger kids we do
have to sedate, but again, it is a quick, relatively easy procedure with very little actual
risks that occur. It’s tolerated very well.
Kids tend to let you know when they don't like something. We have some kids that
obviously get nervous, but they are nervous in general. But we don't have kids objecting
to this being done and as every parent knows if your kid doesn’t want something they
tend to let you know.
Thank you Denny. Marc anything to add?

70. 70
No I would support exactly what my colleagues said.
I would just emphasize the fact that I think the general public has a misunderstanding of
this procedure, and as I said in the earlier webinar, it is often done in emergency
situations in less than ideal circumstances. Sometimes by people who are not very
experienced at doing it.
That is very different from the situation in a clinical trial or in a diagnostic setting where
you have operators who do this all the time. In our institution we have a service actually
run by nurses who spend all day doing spinal taps. They do thousands of them and as
Denny pointed out the rate of headaches afterwards is about 5% and otherwise, we really
don't see major problems with this.
I have probably seen most children who have had a chemotherapy for leukaemia and
these children have the intrathecal chemotherapy and then jump up off the bed and then
go and play.
They get used to it, and I would agree it is really not that much worse and in some ways,
easier than drawing blood from some children.

71. 71
Thank you Marc. I would like to add that when we evaluated the development of this
drug, we also evaluated if it made sense to first develop the alternative delivery device
and then start a trial.
But we came to realize that it could take a year to two years to do this and we really
believed that getting an answer on cyclodextrin quickly is absolutely essential.
I can also assure you that Allan Darling, our head of technical operations is working
actively on evolving this device. We are currently in the process of identifying those
devices and doing the initial evaluation. I cannot guarantee when it will be done but it is
one of our priorities, just wanted to add that.

72. 72
Many of the questions are around a controlled trial. Why is a controlled trial important?
We believe that a controlled trial will give us the objective evidence that the drug works
and it shows us that it is effective.
This is a disease which has highly variable disease progression and finding out what the
drug is actually doing without the control is very difficult because you do not know what
your reference point is. We believe that it is very important to make the most accurate
assessment possible about the efficacy of cyclodextrin.
In turn, this improves the probability of success which is of long term interest to the NPC
community. I do believe that running a controlled trial will also allow you to shorten the
duration of the trial because you have an immediate direct comparator.
In addition, it will give us the opportunity to identify specific effects of the drug. We talked
about that. This will be important for patients and caregivers to exactly understand what
the drug will do and what it will not do.

73. 73
Because it is important to develop the best treatment regiment possible for the children
who have NPC, we believe that it is important to do a controlled trial.
We also understand that there is concern about the controlled trial; but, we think that
from a long-term perspective it is the best thing to do.
Again, the study itself will take a year. We will administer the drug every two weeks and
we are also considering the rescue option to minimize the risk to the patients who are not
treated, and we have the open label extension study.
We are sensitive to this concern but we are also actually asking you to take a long-term
view on how to develop this drug and make it available to all children.

74. 74
There is one last question we can take and I would like to answer that and that is the
question on the travel, and the burden of the travel and support.
Our strategy is to actually be very opportunistic in defining where sites will be located. It
will be driven by where the patients actually are. It will be determined by the quality of
what else we can find in the vicinity, and we will do our outmost best to make sure that
everybody that’s interested in the study and qualifies, can participate in the study with our
support and with reasonable access to the sites.
Of course we are currently working with our CRO. We actually tried to map out where the
patients are, and that will drive to where we will locate the study sites.
Having said that, I think we have come to the end of the webinar. I would like to thank
you for your time. I hope that you realize that this is the first webinar, of hopefully many to
come. We would love to hear from you. I promise you that as soon as we have more
information, we will schedule the next webinar.
Thanks again for all your time. Have a good evening and hope to speak with you soon.