NEUROTECHNOLOGY

Neuromodulation sends electrical pulses to the brain or central nervous system. Illustration by David Dunston, Zygote Media Group.

Traditional drug therapy failed them. Pat,
whose doctors initially prescribed 10 mg a
day of a painkiller for her chronic back pain
still suffers three years later, even at 300 mg a
day. Bob found relief from his depression for a
time—until the medication could no longer hold back the
feelings of hopelessness and anxiety.

For Ruth, it isn't medication, but physical therapy that has
proved ineffective. After a stroke, Ruth is paralyzed on the
left side of her body. She may regain some movement with
physical therapy, but she can recover only
minimal function. Like most stroke
victims, she will have to adapt to her
disabilities.

For Pat, Bob, and Ruth, hope
may come from technology. A
handful of neurotechnology companies
have been quietly working
to change the lives of these patients.
New therapies—in particular,
neuromodulation—are being
developed, reaping the results of
years of research that has provided
a better understanding
of the brain and the central
nervous system.

In 2006, neurotechnology
products generated
more than
$120 billion in
revenue, with the
market seeing 10%
growth over the previous
year. Despite its already large size, the neurotechnology
sector is poised for large growth with several factors
driving this demand, says Zack Lynch. Lynch is executive
director of the Neurotechnology Industry Organization
(NIO). Primary among these, he says, is that neurotechnology
companies address brain-related injuries
and illnesses, the largest unmet medical market.

In 2007, neuromodulation is estimated to be a $1.8 billion
market, adds Mona Patel, vice president of marketing
for the pain management division of Boston Scientific.
This market includes spinal cord stimulators, cochlear implants,
deep-brain stimulators, drug pumps, and vagus
nerve stimulators. “These devices have helped more than
300,000 people regain some level of normalcy in their
lives,” she says.

Neurotechnology is a pretty broad category, notes John
Bowers, CEO of Northstar Neuroscience. “There are great
diagnostic and imaging tools that have been developed over
recent years, and there are pharmacologic therapies,” he
says. Then there are implantable, electrical therapies that
are themselves inherent to the therapy. “That's what's most
exciting: when a device can actually be the therapy or be
integral to the therapy itself. When you're able to accomplish
that, that's the Holy Grail of medical technology.
That's why we're interested in that area,” he
says.

As early as 10 years ago, devices were beginning
to be approved for the treatment of epilepsy,
and a host of devices are now in pivotal trials
and feasibility studies for drug- resistant
depression, stroke recovery, and tinnitus,
just to name a few.

One of the earliest uses of neurotechnology was for the development of cochlear implants. Image courtesy of Advanced Bionics (Valencia, CA), a Boston Scientific company.

An Electrical Approach

“The central nervous system is a miraculous
symphony of chemistry and electricity
that is in almost perfect balance in
healthy individuals,” says Christopher
Chavez, president of St. Jude Medical's
neuromodulation division.
When the central nervous system is
out of balance because of trauma,
disease, aging, or other causes, people
can experience hard-to-manage
chronic pain and diseases including
chronic depression, Parkinson's,
Alzheimer's, and many others, he
says.

The Genesis neurostimulation system is being tested in clinical research as a therapy for helping patients with chronic migraine headache. Genesis is an investigational system that sends mild electrical pulses to the occipital nerves in the back of the head from a device implanted in the buttock or chest. Illustration at bottom of facing page and at left provided by Advanced Neuromodulation Systems (Plano, TX), the neuromodulation business of St. Jude Medical.

Advances in technologies such as
neuromodulation are for the first time
making it possible to address these conditions. “I think about the millions
and millions of people who suffer from

some type of neurological disorder or disease that really is
not adequately treated today,” says Bowers. “If you look at
the medical technology industry and all of the advances
we've made over the last 40 years for cardiovascular therapies,
for example, there are still huge opportunities for developing
effective therapies for neurological disorders.”

Those in this business are passionate about its future.
Patel notes that although relatively unknown,
the science of neuromodulation has
been around for decades. Recent advances in
the underlying science and in technology
are making it possible for neurotechnology
devices to change the practice of
medicine today.

“This science has already allowed deaf
people to hear. Tomorrow brings the
promise of making the blind able to see,”
she says. “Scientists and engineers around
the world are exploring how to modulate
the nervous system to address such common
ailments as migraines, depression, obesity,
Parkinson's, and epilepsy. Therefore, if you look
across the field of medicine, there are only a few
areas that hold as much promise in the next
decade as neuromodulation.”

The Eon spinal cord stimulation system is approved for the treatment of chronic pain of the trunk and limbs and failed back surgery syndrome. A device implanted in the buttock sends mild electrical pulses to leads located near the spinal cord. Illustration courtesy of Advanced Neuromodulation Systems (Plano, TX), the neuromodulation business of St. Jude Medical.

Throughout history, humanity has explored
multiple modalities to treat chronic
diseases, says Chavez. “Recently, modern
medicine has significantly advanced
the use of systemic drugs and surgery
to treat such conditions,” he says, “and
more advances are on the horizon.” Even
so, many chronic diseases remain undertreated
because they are refractory, or resistant,
to existing therapies. The new therapeutic
strategies now being developed
are needed to address these diseases,
especially those related
to neurological disorders
and an aging population.

“It's already happening
in some areas,” says Dan
Moore, CEO of Cyberonics. Several devices, including the
company's vagus nerve stimulation (VNS) device, are enjoying
broad adoption and acceptance by physicians. In
most cases, Moore says, neurotechnology is requiring physicians
to change the way they treat patients.

(click to enlarge) The VNS Therapy System uses a surgically implanted medical device that delivers electrical pulsed signals to the vagus nerve in the left side of the neck. Illustration courtesy of Cyberonics (Houston).

“Most neurological disorders are
treated with pharmaceuticals, but
the brain is an electrical organ,
so it's logical to apply an electrical
approach to treating
neurological disorders.”

According to Chavez, advances
in microelectronics and in
the understanding of neurophysiology
have created an opportunity to treat
the central nervous system's electrical-chemical system
using neuromodulation. He says that the delivery of microdoses
of electricity or drugs to specific neural targets offers
tremendous potential to address a significant and
expanding list of clinical applications.

The Gold Standard

Neuromodulation is one of the fastest-growing emerging
technologies and is one of the most promising, says Patel.
The market for neuromodulation devices, she says, is estimated
to grow 20% a year and will likely maintain that
growth for well over a decade. “The fact that neuromodulation
can address a variety of disease states that have very
few—or often, much more invasive—options makes this an
ideal way to treat these conditions.”

Chavez also credits advances in technology and an increased
understanding of the central nervous system for the
growth of the industry. “These advances will accelerate innovative
and entrepreneurial activity in the neuromodulation
field,” he says. “The market for neuromodulation is approaching
$2 billion worldwide and is likely to grow as
more indications for the modality are developed. Neuromodulation
is already helping thousands of people and
promises to help millions more in the future.”

“Neuromodulation is likely to become the gold standard of treating many chronic diseases.” — Christopher Chavez

In terms of specific clinical indications, Bowers says the
biggest advances are being seen in spinal cord stimulation for pain, deep-brain stimulation for movement disorders,
and VNS for epilepsy. “No single therapy will solve all
chronic medical problems,” says Chavez. “We must explore
multiple strategies and modalities to address the many
difficult-to-treat conditions that destroy the lives of so many
people.”

In a world where change and innovation have become
predictable constants, says Chavez, those who work in neuromodulation
will embrace new knowledge and technology
to make products smaller, smarter, and more affordable.
“An important strategy for the future will be to invest in
clinical studies that demonstrate the safety, efficacy, and
value of such products, then to make sure that patients, insurers,
and physicians have information to select the right
technology at the right time for each patient. Neuromodulation
is likely to become an important therapeutic option
or even the gold standard for treating many chronic diseases,”
says Chavez.

Moore agrees. “Neurostimulation devices are the next
frontier in medicine,” he says. “Much like cardiac pacemakers
some decades back, the neurostimulation market is
burgeoning as it addresses huge patient populations in epilepsy,
depression, stroke, anxiety disorders, Parkinson's and
others with tremendous unmet needs.”

Understanding the Science

A better understanding of the underlying science has been
key to the advances in neuromodulation, says Bowers, noting
that just 20 years ago, the idea that the brain could
change was not widely discussed or accepted. “If you had a
brain injury or some type of neurological disorder, it was
thought of as irreversible.

“Over the years, scientists have learned that the brain is
plastic. Through neuroplasticity, the brain changes over time.
For example, it changes in response to an injury such as a
stroke or a traumatic brain injury,” he says. “Although the
cells in the area of the brain that was destroyed by a stroke
aren't coming back, the brain forms alternate neural connections
that attempt to take over the function for the area
that was destroyed.” That concept wasn't widely understood
20 years ago. Today it is, so the idea that you can take
a targeted device therapy through electrical stimulation and
help enhance that process—that's what's new, says Bowers.

The neurotechnology industry has also taken some base
technologies that have proven effective in other areas—such
as cardiac applications—to find novel ways to deliver therapies
elsewhere in the body. The result has been devices that
provide electrical stimulation of various areas to the cerebral
cortex.

The Eon spinal cord stimulation system. Illustration courtesy of Advanced Neuromodulation Systems (Plano, TX), the neuromodulation business of St. Jude Medical.

Certainly for spinal cord stimulation, the push for improved
patient outcomes has been a major driver for the
market, notes Patel. She also points to significant advances
in technology such as the introduction of rechargeable devices,
which have allowed newer devices to offer a greater
range of parameters. Devices now have pulse widths as well
as leads that can deliver an electric drug to the target site with
greater precision. “Clinicians can now treat patients that
just three years ago would not have been deemed candidates
for spinal cord stimulation, or SCS, devices.”

“There are few areas that hold as much promise in the next decade as neuromodulation.” — Mona Patel

Advanced Bionics, which was purchased by Boston
Scientific in 2004, introduced a system that uses multiple
independent current sources to relieve pain, a key advance
in this field. This system is the equivalent of having
16 implantable pulse generators or batteries of the
older systems, explains Patel. “This allows it to better
target nerves and maintain therapy over time.”

The demographics are favorable for neuromodulation
therapy. “The population is aging, and many of the disease
states that neuromodulation can address occur later
in life. And baby boomers have higher expectations of the
quality of life in later years,” says Patel. “The average
age for someone to receive an SCS implant is 55. Therefore,
many people are in their prime when they are
severely disabled. Just like other areas of medicine, the
prospect of the Internet as a way to educate patients is
promising, and notably, 70% of Advanced Bionics customers
use the Internet regularly. The fact that this target
population is Internet savvy, and will become even more so
in the future, only further supports growth of this therapy.”

Although neuromodulation is just hitting its stride now,
it has already made some significant inroads as a therapy of choice for some disorders. This July marks the 10th anniversary
of FDA approval of Cyberonics's VNS Therapy for
pharmacoresistant epilepsy, says Moore. “More than
45,000 patients worldwide have been implanted with VNS
Therapy for both epilepsy and treatment-resistant depression
combined. One of the biggest drivers in the adoption
of neurotechnology therapies is the growing body of data
and the adoption rate among physicians,” he says. “There
is a greater understanding of the types of patients for whom
nonpharmacological options are appropriate.”

A study of depression found that one-third of patients
with depression are not helped by antidepressant medications.
The study, “Results for Sequenced Treatment Alternatives
to Relieve Depression, or STAR*D,” was funded
by the National Institute of Mental Health. The researchers
noted that other options, including VNS Therapy, should be
evaluated for those patients.

Within many of the disease states targeted by neuromodulation,
a significant market opportunity is for those patients
that are drug refractory, says Patel. She says that addressing
these patients will be the priority for clinicians.
“There are thousands of patients who don't have any solutions
today. The one clear area of differentiation is the fact
that drugs have a systemic effect on the patient, whereas
neuromodulation has the ability to target the specific neural
networks or organ.”

“There are still huge opportunities for developing effective therapies for neurological disorders.” — John Bowers

In most cases, says Moore, neuromodulation devices
have been approved as adjunctive therapies or to treat patients
who have tried many pharmaceuticals without getting
relief. Many patients are treated appropriately and
successfully with pharmaceutical therapy. The patients
who could most benefit from devices like VNS Therapy are
those for whom medications do not help to reduce symptoms
or for whom the side effects of those medications become
intolerable.

Neuromodulation has been effective in its ability to apply
targeted stimulation to yield a clinical benefit, says Bowers.
Rather than taking a drug systemically, it provides direct
stimulation. “For the stroke indication, currently there are
no effective therapies. There are no pharmacology therapies
that help motor recovery or motor function.”

(click to enlarge) Stimulation is delivered to the appropriate site of the brain depending on the disorder being treated. Northstar Neuroscience is investigating the safety and efficacy of cortical stimulation for patients with post-stroke speech and motor deficits, major depression disorder, and tinnitus. Image courtesy of Northstar Neuro science (Seattle).

Northstar Neuroscience has a feasibility study under way
designed to treat depression. Bowers says the existing therapies,
of which there are many, do not adequately meet the
needs of millions of people. “Physicians, patients, and families
are really looking for results. Tinnitus is another disorder
for which we have a feasibility study. No effective
therapies exist for chronic sufferers of that condition.”

The Regulatory and Reimbursement Landscape

“Adoption of neurotechnology devices takes time,” says
Moore. “Just as the treating physicians are required to
change the way they practice medicine, the regulatory
bodies are adapting in order to be able to evaluate these
new technologies and new approaches to treating neurological
disorders,” he says. FDA has approved VNS Therapy
for two indications. In addition, the agency is reviewing
deep-brain stimulation devices for a variety of
indications. “This shows that FDA recognizes the progress
being made in neurotechnology,” explains Moore.
“Nonetheless, more progress is needed in establishing the
standards for evaluating the safety and effectiveness of
these new approaches to treating illness, because the clinical
evaluation of neurotechnology devices provides some
unique challenges.” As an illustration, he says, determining
the appropriate dose of the treatment may be more
complex when using a device than it is when using a drug.
“For example, with VNS Therapy, there are five different
parameters that a physician can alter when adjusting the
dose of stimulation a patient will receive. This in turn results
in an enormous number of different potential combinations
of dose settings.”

Bowers notes that implantable device therapies take
about a year to move through FDA's approval process. “If
you're doing a premarket approval (PMA) supplement, it
can go faster, but if you look at something that truly is a
new therapy, a year is about right.” He adds, “When therapies
are new, you are breaking new ground in terms of
what are appropriate outcome measures and making sure
that any safety data are captured and reviewed appropriately.
It's really important for the agency as well as for all
of us who are in the business of developing new therapies
to have really good communication with FDA. Communication
is important not just as you go through review of
your PMA, but also during the months or, in our case,
years of work leading up to filing the original investigational
device exemption (IDE) for the trial. This is essential so that you have a common understanding of outcome
measures and data analysis.”

CMS recently denied coverage of Cyberonics's VNS Therapy
for treatment-resistant depression (TRD), despite overwhelmingly
favorable comments. But, in general, CMS has
been fairly receptive to providing coverage for neuromodulation
therapies.

“Several studies are under way to help us learn more about
VNS Therapy for TRD, and we will share the growing body
of evidence with CMS and other insurers as it becomes available,”
says Moore. “Since [FDA] approval of VNS Therapy
for TRD, more than 300 payers have provided coverage for
more than 3000 patients on a case-by-case basis.”

Bowers say that CMS is sending an important message that
coverage is about data. “It's about having well-run clinical trials
that have a meaningful clinical outcome—one that can be
understood and that shows a consistent and clear benefit for
an appropriate group of patients,” he says. For example, he
says, CMS routinely provides coverage for VNS for epilepsy.
“We have watched and learned from [CMS's denial of VNS
for depression] as we design our trials. As we put together the
data and information package with the healthcare providers,
we'll be able to move forward. If you look at reimbursement
broadly for neurostimulation, it's a positive. In general, there
are codes that exist today so manufacturers don't have to go
through the time-consuming steps of getting codes.”

Patel points to CMS's recognition of the advances of having
a rechargeable system and allowed for a pass-through
code in 2006. “This additional reimbursement for rechargeable
SCS systems was a key factor in the market taking
off,” says Patel.

(click to enlarge) Northstar's Renova-ST Cortical Stimulation System is an investigational device designed to enhance recovery of stroke patients who suffer from Broca's aphasia. Image courtesy of Northstar Neuroscience (Seattle).

Bowers adds that the payments under the codes available
are at least reasonable enough so that there is not a dis -
incentive for institutions to offer the therapies. And then, he
stresses, any other new therapy must get coverage under
those codes. “To do that, you have to have a really strong,
robust clinical data set,” he says.

Neurotechnology in Practice

Clinicians have been responsive to advances that allow
them to offer a solution for a patient who has been suffering
for years, says Patel. With advances in technology resulting
in improved outcomes, she says that more clinicians
are interested in becoming experts with neuromodulation
devices. “We have had more than 1000 physicians trained in
cadaver courses since the introduction of the Advanced Bionics
system. More and more physicians want to be able to have
this therapy among those that they can offer their patients,”
she says.

“Neuromodulation is changing the practice of medicine,”
notes Bowers. “Clinicians are very hopeful and interested in
these therapies because they have patients whose ailments
aren't being adequately addressed today, and they'd like to
have solutions to offer them.” For example, he points to the
millions of people in the United States who have had a
stroke and have some level of paralysis of their hand and
arm. Right now, nothing has proven to be effective for
motor recovery in the years following a stroke. “So that's
one example where there are certainly a lot of physicians,
clinicians, and therapists who would like to be able to offer
hope to those patients via an effective therapy. So they're
very interested in what we're doing,” he says.

As they are with any therapy, though, physicians want
clinical data, says Bowers. “They want you to be able to
show to them validated outcome measures that you're having
an effect with a well-run study and that the effect really
makes a difference in that patient's life.”

Physicians are excited about the potential of neurostimulation,
says Moore. “We see this in the adoption of VNS
Therapy for approved indications such as epilepsy and TRD,
as well as in the interest in research in other potential therapeutic
indications. At a recent meeting of the American Psychiatric
Association in San Diego, Moore says the consensus
among psychiatrists prescribing VNS Therapy was that
it provides measurable and effective relief to their patients.

Conclusion

Brain-related illnesses generate more healthcare costs than
any other therapeutic area—$1.1 trillion annually in the
United States, says NIO's Lynch. With new tools to better
understand the brain, though, neurotechnology companies
are making great strides to develop products to address
these illnesses. In many cases, advances in technologies such
as neuromodulation are for the first time making it possible
to address conditions that are drug resistant.

With market growth moving into double digits, neurotechnology
devices have the potential to change the practice
of medicine for a number of serious age-related diseases
and conditions, including Parkinson's, Alzheimer's,
and stroke.