Educationalbooklet

2020

Written by a doctor. Explained by a patient.

Introduction

The power of stem cells 4

What is a stem cell? 5

What are the different types of stem dells 6

How do stem cells work? 9

Conditions we treat with stem cells 12

Do stem cell therapeutics work? 13

The Novastem difference 15

Next steps and the patient journey 16

Other FAQs 17

Contents

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Stem cells control the body’s ability to regenerate and repair. Stem cells also produce an array of signaling molecules and growth factors that can stimulate amplify healing activities.

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The human body is comprised of hundreds of different cell types, each performing

unique roles that are coordinated to provide broader organ system function. While

these organ systems enable a remarkable range of biological activities, maintaining this

diverse population of cells poses a significant challenge. Stem cells provide an efficient

solution and fundamentally control the body’s ability to regenerate and repair.

The power ofStem Cells

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Stem cells control the body’s ability to regenerate and repair. Stem cells also produce an array of signaling molecules and growth factors that can stimulate amplify healing activities.

With this power to trigger cellular proliferation and grow

into different cell types, stem cells provide a simple

and efficient solution to the challenge of repairing and

maintaining a diverse population of cell types. Simply

put, stem cells control the body’s ability to regenerate

and repair.

When we are very young, the body has a large reser-

voir of healthy, active stem cells. As a result, children

have remarkable regenerative powers. They heal more

quickly and recover more effectively from severe injuries

and diseases. As we age, this regenerative capacity is

dramatically diminished. First, the reservoir of stem

cells is gradually depleted, such that by adulthood, we

have perhaps 10% of the stem cell quantity of a toddler.

Second, the functionality of the stem cells themselves is

compromised with age. Adult stem cells produce fewer

growth factors and respond less aggressively to chemical

‘repair’ signals. While we all experience this deterioration

in regenerative capacity as we age, understanding the

direct role of stem cells in tissue repair introduced the

concept that cells could be injected as a therapeutic

agent to help promote healing and recovery.

The therapeutic use of stem cells has its origins in bone

marrow transplantation in the 1950s for leukemia patients,

and later cord blood transplantation in the 1980s.

These early stem cell transplants have revolutionized the

survival outlook for blood cancers, and today stem cell

banks store millions of doses of life-saving cord blood.

Broader applications of stem cell therapeutics were

enabled in the 1990s, and 2000’s when advances in cell

biology allowed scientists to identify and harvest stem

What are stem cells?

10%By adulthood we have perhaps 10% of the stem cell

quantity of a toddler.

1950sThe therapeutic use of stem cells has its origins in bone

marrow transplantation in the 1950s for leukemia

patients.

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cells, expand them in the laboratory, and then re-inject

them into patients to enhance or restore the body’s

regenerative engine. In early 2000, scientists reported

the first use of stem cells to restore functioning heart

muscle in humans following a heart attack. Over the

next decade, pioneering cell-based therapies were

developed to treat damaged tissues across nearly every

medical discipline- heart failure, stroke, neurodegenerative

diseases, peripheral arterial disease, spinal cord injury,

cerebral palsy, osteoarthritis, etc. Despite rampant

optimism throughout the scientific and medical community,

the simple reality is that effective stem cell treatments

are evolving slowly. While stem cell therapies have been

overwhelmingly proven to be safe, patients should

recognize that meaningful improvements in most clinical

studies are only observed in 5-25% of the cases. Many

would consider these outcomes spectacularly good

given that most of these clinical trials treat ‘no option’

patients with catastrophic damage to major organ

systems, but we believe it is our ethical responsibility to

accurately represent the status of stem cell research,

and the likelihood for ‘miracle cures.’

What are the different types of stem cells?

It is important to recognize that there are many types of stem cells, each with unique capabilities and each with different clinical and ethical considerations.

The most powerful cells are pluripotent stem cells- cells that can differentiate into every tissue type. Embryonic stem

cells are an example of pluripotent cells. These cells are highly controversial, are infrequently used. Novastem does not

use embryonic stem cells in any research or clinical activities. More recently, scientists developed a way to genetically

modify adult skin cells to ‘revert’ them back to an embryonic stage. These induced pluripotent cells (IPScs) have exciting

therapeutic potential and were the subject of the 2012 Nobel prize. However, risks associated with genetic modification

and the potential for uncontrolled cellular proliferation has slowed clinical development. To date, only a few patients

have been treated with IPSCs. Most stem cells used clinically today are multipotent stem cells, meaning that they can

differentiate into several tissue types, but not all. Multipotent stem cells can be found in most tissue types throughout

the body, and in general, the origin of the stem cell will largely predict the type of tissue it is most well suited to repair/

regenerate. Fat derived stem cells, for example, do not readily differentiate into liver cells. Similarly, hematopoietic stem

cells from the marrow cannot form cartilage tissue.

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While all stem cells are capable of producing growth factors and other signaling molecules that trigger innate healing, we believe that stem cell sourcing is a critical consideration in developing the most effective, tissue-specific treatment protocols.

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So while all stem cells are capable of producing growth factors and other signaling molecules that trigger innate healing, we believe that stem cell sourcing is a critical consideration in developing the most effective, tissue-specific treatment protocols.

Most clinical protocols use cells that are harvested from either blood, fat, marrow, or birth tissues (placenta or cord-derived cells harvested from discarded tissues after a live, healthy birth). All of these sources provide an ample number of cells from relatively simple biopsies, and in most cases, the stem cells can be expanded in culture to provide many doses (in some cases, thousands of doses can be generated from a single biopsy). There is significant scientific debate surrounding which cell source is ‘best’. It is likely, however, that the definition of ‘best’ varies from patient to patient, and almost certainly varies by disease target.

One metric by which scientists define the potency of stem cells is the quantity growth factors produced by the cells. The academic literature is replete with examples of these quantification studies, and there is a natural tendency to gravitate toward cells that produce the most growth factors. This ‘more is better’ mentality

has, in part, led to an increasing consensus that birth tissue-derived cells have the most therapeutic potential.

Placental derived cells, in particular, are not only powerful growth factor producers, but also demonstrate broad differentiation. Placental derived cells are the primary pillar for many of our treatment strategies; however, we do not believe that this ‘more is better’ approach is appropriate for all clinical indications. We use specialized neural stem cells for spinal cord injury and neurodegen-erative diseases, while we use marrow-derived mesen-chymal stem cells for orthopedic treatments. For other more complex diseases, we use a serial dosing strategy alternating between marrow and placental derived cells. We believe that using multiple stem cell types mimics the body’s natural response to damage and maximizes the likelihood of a strong positive response. This individual-ized approach is unique in the stem cell industry and is in contrast to most stem cell clinics that traditionally specialize in a single harvest strategy and a common cell type used across all therapeutic targets. This focus on a single cell source is not driven by a scientific rationale. Rather, it is driven by commercial practicalities. That is, most clinics have access and expertise in a single harvest strategy and deploy that across all disease targets.

Recognizing that stem cell source can have a dramatic impact on efficacy,

Novastem uses different types of stem cells to match the therapeutic target.

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How do stem cells work?

Irrespective of their origin, all stem cells perform two basic roles in maintaining and repairing cellular systems.

First, they can home to areas of disease or damage, where they release proteins that spur growth and proliferation.

Second, they can recognize the mechanical and chemical signals of their local environment and then differentiate into

the specialized tissue to restore organ function. Originally it was thought that this second pathway was most important.

Over the last five years, however, it has become increasingly apparent that the first pathway, termed paracrine

signaling, is the primary mechanism of action for stem cell therapeutics.

Stem cells and your immune system Patients generally have an option of being treated with

their own cells (autologous approach) or cells harvested

from a young, healthy donor (allogeneic approach).

Like the tissue source issue, there is ample debate over

which approach is best. Autologous cells have one

obvious advantage in that they immunologically matched.

As a result, they can not only home to damaged tissue

and produce a paracrine signaling cascade (triggering

innate healing). They can also differentiate into functional

tissue. Many patients are also more comfortable in

receiving their own cells. Autologous approaches have

several disadvantages that must also be evaluated. First,

cells harvested from older, sicker patients tend to lack

therapeutic potency. That is, they generally produce

weaker paracrine signaling. Autologous cells also require

somewhat invasive biopsy strategies and significant

waiting times to sufficiently expand the cells to a

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sufficient level to produce a therapeutic dose. Alloge-

neic cells are sourced from young, healthy donors that

undergo rigorous screening following strict eligibility

criteria defined by the FDA. The cells are expanded

in culture, typically by dedicated manufacturers with

expertise in cellular products. These younger cells

have the advantage of producing vigorous therapeutic

impact, and are available in high doses ‘off the shelf’.

Allogeneic cells have an obvious advantage in that they

do not require a biopsy from the recipient. While the

autologous versus allogeneic debate has raged on for

nearly 20 years, there is an increasing push toward

allogeneic approaches driven by manufacturing safety.

Most autologous cell products are produced by stem

cell clinics, which typically have neither the training nor

the resources to pursue Good Manufacturing Practices

(GMPs). While it is easy to self-proclaim an adherence to

GMPs, the simple reality is that specialized manufacturers

have higher safety standards than small clinics, and

tend to produce safer products. In the same way that few

parents would expect the pediatrician to produce a dose of

penicillin for a sick child, most patients gravitate toward

allogeneic cells produced by dedicated manufacturing

facilities. At Novastem, we use cells produced by the

most experienced cellular manufacturers in the world.

SafetyVery clearly, the most important consideration in any

stem cell trial is safety. Above all else, at Novastem we

prioritize safety and engage all of our patients in an open

and transparent risk-benefit analysis. We understand

that the decision to seek treatment is deeply personal

and often emotional, and we work to set realistic expec-

tations. Moreover, we work diligently to minimize the

risk to our patients. Our absolute commitment to safety

falls into three basic components- Protocol Design, Cell

Sourcing, and Personnel.

Protocol design There is no question that stem cell treatments are still on

the cutting edge of science, and for every credible clinical

trial design, there are ten studies driven by enthusiasm

and hope. Unfortunately, for most patients, it is difficult

to distinguish between the two. At Novastem, our

commitment to safety starts with designing safe, ethical

protocols. All of our clinical procedures sit under clinical

trial protocols regulated by the Mexican FDA (COFEPRIS).

Each one requires approval from independent committees

With annual reviews of study data by independent data safety monitoring boards, Novastem has a unparalleled commitment to patient safety.

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that review the protocol design from both ethical and

clinical perspectives. The protocols are further reviewed

by COFEPRIS to ensure overall safety. A common thread

that unites both review processes is a commitment to

data monitoring to capture and report adverse events.

With annual reviews of study data by independent data

safety monitoring boards, Novastem has an unparalleled

commitment to patient safety.

Cell sourcingAs noted above, it is difficult to predict which cell

sourcing strategy will generate the best clinical results.

Irrespective of harvest and sourcing strategy, we believe

that the most significant risk associated with any stem

cell therapy is the manufacturing technique. Because

stem cells are living products, they cannot be sterilized

before injection in the same way that many medical

devices are. Rather, they must be handled in a special-

ized cleanroom environment using aseptic techniques.

Human error can introduce dangerous contaminants

into the growth media, which can unintentionally be

administered to the eventual recipient. Indeed, the most

prevalent and dangerous risk associated with stem cell

therapy is a blood infection (sepsis) introduced by a

contaminated cell preparation. Biologics and implantable

medical device manufacturers, in partnership with

regulatory agencies like the FDA, have developed

exhaustive quality assurance protocols to ensure that

implantable products meet stringent lot release criteria.

At Novastem, we not only utilize cGMP certified

manufacturers to provide our stem cells, but we also

perform regular QA audits to make sure that all

products are safe for injection.

PersonnelNovastem’s commitment to safety and unassailable

scientific credibility starts with our team. Our medical

staff is comprised of world-class physicians and scientists

with decades of experience in regenerative medicine.

Beyond this core leadership team, we recognize that the

commitment to safety ultimately resides with a highly

trained team of technicians that prepare the cellular in-

jections. From ‘vial to vein,’ our team and our processes

are driven by strict SOPs. The SOPs are reviewed on an

annual basis, and in addition to independent audits and

ongoing education, technicians are recertified on an

annual basis.

While these small details are mostly invisible to the patient, they form the backbone of Novastem’s unparalleled commitment to safety and are an important differentiator from other stem cell clinics.

At Novastem, we not only utilize cGMP-certified manufacturers to provide our stem cells, but we also perform regular QA audits to make sure that all products are safe for injection.

Our medical staff is comprised of world class physicians and scientists with decades of experience in regenerative medicine.

Novastem is focused on therapeutic targets where there is significant clinical data demonstrating both safety and efficacy. Moreover, we limit our enrollment to treatments where we can consistently reach back to the patient and their family to assess efficacy.

Conditions we treat with stem cells

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With these guidelines in place, we treat a variety of conditions that fall within three general categories:

Orthopedic Applications

Osteoarthritis

Rotator Cuff Repair

Cartilage damage or degeneration

Joint pain and/or joint replacement

candidates

Neurological and

Neurodegenerative Applications

Cerebral palsy

Stroke

Select cases of Parkinsons, ALS, and

Alzheimers (early onset of symptoms)

Respiratory Conditions

COPD

ARS

Cystic Fibrosis

Do stem cell therapeutics work?

Contact our staff for more details on specific enrollment criteria, and protocol details.

The most frequent question we get is, understandably, some version of “what are the chances that we will see significant improvement?”

Sadly, regenerative medicine is a field that has been

fueled by hope. An enthusiastic media often portrays

‘miracle cures,’ and many stem cell clinics feed on this

hype to engage desperate patients with few options

from traditional medicine. At Novastem, our commitment

to the ethical use of stem cells begins with realistic

expectations and open dialogue about potential risks

and benefits.

It is very difficult to generalize the likelihood of success

for any individual patient, but the literature can establish

realistic expectations. Unquestionably, stem cells work

very well for most orthopedic applications. With tears

to muscle or tendon (rotator cuff, for example), we and

others demonstrate meaningful improvement in the

overwhelming majority of the patients (~60-80%).

For degradative or degenerative damage to joints and

cartilage, the results are still favorable but slip to ~20-

40%. For patients with advanced damage (bone on

bone joint replacement candidates), the success rates

drop to ~5-10%.

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Neurological damage is, in general, much more difficult

to repair, and very difficult to predict. Outcomes for

stroke are generally the most favorable, and significant

improvement can probably be expected in 20-40% of

the patients. Cerebral Palsy studies are notoriously diffi-

cult to interpret, but modest improvements are typically

seen in 10-30% of the patients. It is rare for profound

improvements, but we encourage a strong commitment

to rehabilitative medicine and a commitment to multiple

dosing regimens to maximize the therapeutic benefit of

the cells.

Stem cells have not been shown to reverse the damage

from neurodegenerative diseases like Alzheimer’s

significantly. We believe that we can, however, slow the

onset of symptoms. We, therefore, enroll select patients

at relatively early stages of disease in a program of serial

dosing.

There is an increasing body of evidence demonstrating

that stem cells can benefit certain lung conditions. That

said, this is still an emerging field, and we have not treat-

ed enough patients to make meaningful predictions. We

anticipate that for chronic diseases like COPD or Cystic

Fibrosis, the best-case scenario is to slow the onset rate.

For acute damage from COVID or other ARDS, the data

appears to be much more impactful (>60% response).

It is unclear, however, if this early data will withstand

further scrutiny in expanded clinical use.

Stem cell therapeutics work very well for most orthopedic applications, and degradative or degenerative damage to joints and cartilage.

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Led by a team of world-class physicians and scientists, Novastem has created a unique stem cell clinic. With access to best in class manufacturers and personalized cell sourcing strategies, we will provide your best option for effective therapies. With a commitment to patient safety and a realistic risk-benefit analysis, we will be your trusted partner in difficult healthcare decisions.

The Novastem difference

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Your journey with Novastem begins with a detailed

review of your medical records and a consultation with

our clinical director to map out a personalized treatment

plan and determine whether or not stem cells are an

appropriate therapeutic pathway for you and your family.

This consultation can be scheduled with one of our

enrollment coordinators (email/phone contact info) and

generally requires at least 14 days to collect and review

appropriate records. There is a nominal charge for this

service of USD $400. If, after discussing the treatment

plan with your local healthcare provider and your family,

you elect to receive stem cells at Novastem, you will

work with the enrollment coordinator to complete

prescreening activities and schedule your visit. Patients

typically fly into and stay in downtown San Diego. On

the day of your treatment, you will be driven across the

border and will be back to your hotel in time for dinner

in most cases. We encourage patients to remain in San

Diego for at least one day for observation before

returning home. You will have 7/24 access to our

medical team, and a follow-up visit at your hotel. Each

protocol requires intermittent follow up to collect data

on outcomes, adverse events, etc.

Next steps and the patient journey

Our message to prospective patients:

1) We believe that our treatment protocols are extremely safe.

2) We will work to educate you to make an informed decision based on a personalized risk-benefit assessment.

3) While we work diligently to develop the best treatment protocols in the world, ‘miracle cures’ are few and far

between, and for most non-orthopedic indications, significant response rates are seen in less than 40% of

the patients.

4) The early intervention combined with serial dosing maximizes the likelihood for success- with the exception of

some orthopedic indications and some stroke indications, “one and done” injection strategies are unlikely to

repair damage to billions of cells.

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Other FAQs

Why is your treatment cost higher compared to other clinics?

Our mission is to make these types of treatments affordable and available to everyone, however, at this point in time,

being that is personalized medicine and tailored to everyone’s needs, the manufacturing and safety profiling process

and storage of these products have an increased cost due to low demand. Once this is scalable and automated, the cost

can only be expected to decrease.

Are your stem cells safe?

We have delivered over 700 treatments and have ran our due diligence on each type of stem cell. We believe that the

manufacturing process is an important contributor to the overall safety of the product, so we make sure that the

certificate of analysis of each lot is compliant with our safety standards for each patient. Controlling the manufacturing

and the delivery reduces the risk of unwanted adverse events.

What are the risks and side effects from a stem cell therapy?

Stem cell treatment is not right for everyone. It is important to evaluate each patient and see if they might have any

chronic or acute medical condition not necessarily aware of, that could elevate the risk of an unwanted adverse event.

We have seen after the treatment, cold-like symptoms such as body ache, slight fever, mild headache and low energy.

This usually takes from 1-4 days. For direct injections, there is soreness and pain on treatment region and limited

mobility for 1-5 days.

Is Novastem licensed for this type of treatments?

Absolutely. We have all of the necessary licenses from our Mexican government. We also have a robust IRB and internal

committees that oversee all activities related to stem cell treatments.

How do you determine the dose or how many stem cells I will receive?

Stem cells are an approximation to what we determine to be the dose. Usually we calculate based on a patient’s weight

or sites to be treated.

Do I need to stay overnight or is there any down time?

Our treatments are outpatient procedures where patients are not required to stay overnight in our clinic, even though

we are fully equipped to do so if necessary. The average appointment and treatment time takes an average of 5 hours,

the last hour is dedicated to a monitoring and observation period to ensure you are discharged safely.

How many patients have you treated?

We have safely treated over XX patients in the course of six years.

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How long after the therapy can I expect too se results?

Each case and each patient is different, we usually expect to see results within 3 months after the therapy.

How are stem cells administered?

Depending on the condition to be treated, the application can vary between Intravenous, Intrathecal and local

application to affected area. For example, Osteoarthritis applications are usually a combination between intravenous

and direct injections.

How long do I have to remain in your facility to receive treatment?

A patient, on average, spends 5 hours upon arrival to discharge. It is very importer to us that we observe and monitor

each patient after each application to ensure a safe discharge.

Do I have to prepare for stem cell therapy?

We have some general recommendations depending on the type of application you will be administer. You will also

receive personalized instructions by our physicians prior to your appointment.

How many stem cell treatments do I need to see results?

After your first intravenous delivery, MSCs will continue to proliferate and carry on their work of repairing tissue. Some

patients choose to receive treatment more than once to expedite the healing process. That decision is yours. If you

decide to repeat the treatment, a waiting period of 6 months is recommended.

How do I schedule an appointment?

You can call us at +1(619)863-1368. A Novastem patient coordinator will then assist you through the whole process.

Once we have received your detailed medical history, a physician will review the records, discuss treatment options

with you and schedule the earliest available appointment. This process takes 1 to 3 weeks.

References:

1. Advanced Therapies Manufacturing Guidelines http://cellmanufacturingusa.org/road-map

2. Komaki M, Numata Y, Morioka C, et al. Exosomes of human placenta-derived mesenchymal stem cells stimulate

angiogenesis. Stem Cell Res Ther. 2017;8(1):219. doi:10.1186/s13287-017-0660-9

3. Levy M., Crawford JR., Dib N., Verkh L., Tankovich N., et al. Phase I/II Study of Safety and Preliminary Efficacy of Intravenous

Allogeneic Mesenchymal Stem Cells in Chronic Stroke, Stroke 2019; 50:2835-2841. doi.org/10.1161/STROKEAHA.119.026318

4. Petrenko, Y., Vackova, I., Kekulova, K. et al. A Comparative Analysis of Multipotent Mesenchymal Stromal Cells derived from

Different Sources, with a Focus on Neuroregenerative Potential. Sci Rep, 2020;10:4290. doi.org/10.1038/s41598-020-61167-z

5. Rivière, Isabelle et al. Perspectives on Manufacturing of High-Quality Cell Therapies. Molecular Therapy, 2017;25(5):

1067-1068. doi.org/10.1016/j.ymthe.2017.04.010

6. Song Yancheng, Zhang Junhui, Xu Hualiang, Lin Zhujian, Chang Hong, Liu Wei, Kong Ling, Mesenchymal stem cells in knee

osteoarthritis treatment: A systematic review and meta-analysis. Journal of Orthopaedic Translation, 2020. doi.org/10.1016/j.

jot.2020.03.015

7. Wu M, Zhang R, Zou Q, et al. Comparison of the Biological Characteristics of Mesenchymal Stem Cells Derived from the

Human Placenta and Umbilical Cord. Sci Rep. 2018;8(1):5014. doi:10.1038/s41598-018-23396-1

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Contact:

NovastemAv. Juan Sarabia 8452Zona Centro, 22000 Tijuana B.C.

Telephone: (619) 863-1368 Fax. (619)512-4341Email: info@novastem.mx