Updates
Summer/Fall 2009

from the Faustman Laboratory at Massachusetts General Hospital

The Diabetes Reversal Challenge
The Unique Clinical Trial at the Faustman LabT

he Faustman Lab atMassachusetts General
Hospital, run by Denise L.
Faustman, MD, PhD, is moving
rapidly through the clinical trial
challenge to test and possibly
establish a vaccine using a genericdrug, Bacillus Calmette-Guérin(BCG) to reverse type 1 diabetes.
The experiments have moved frommice to a clinical trial in humans,
and the testing has passed every
research milestone ahead ofschedule — an astonishing feat for
any clinical research project.
The Phase I safety trial inpeople with type 1 diabetes isnear completion. The next stepis to find, in a Phase II study, thepossible dose and frequencyof administration of BCG
vaccinations that will benefit
patients with type 1 diabetes.
What makes these trials
unique? First, unlike otherimmunosuppressive therapies forautoimmune diseases that harm
both healthy and disease-causing
T-cells, this treatment appears toprovide a way to achieve “targetedremoval” of only autoimmune
disease-causing cells.
BCG works by causing therelease of a natural protein in thebody called tumor necrosis factor,or TNF. In mice, temporarilyelevating TNF levels destroys theautoreactive T-cells, allowing
the insulin-producing cells of
the pancreas to regenerate andproduce insulin. TNF in mice also
elevates a good population ofT-cells, thus restoring the immune
system to near normal. In otherwords, the treatment literallyreverses type 1 diabetes, at leastin a mouse model of diabetes. In
laboratory experiments, TNF also
destroys the autoreactive cells inhuman blood samples. TNF does
not harm the normal, healthy
T-cells that help fight infection,leaving the immune system intact.
The human clinical trials we areconducting seek to expand thesefindings in human subjects.
The BCG trial is also uniquesince BCG is a generic drugthat has been used widely as a
vaccine for more than 80 years inhumans. Currently, BCG is usedin small doses as a vaccine against
tuberculosis, and it is used inlarger doses as a bladder cancer
therapy. Because it has beenused for so long and in so many
humans, the safety of this vaccine
is well-established. This fact allows
us to move more quickly throughsafety studies compared to clinical
trials that test new drugs.
With a generic drug, we canmove BCG to the public rapidly
if the drug is indeed found to besafe and effective in patients with
type 1 diabetes. Our Phase I safety
study is following our enrolled
patients over months looking forchanges in the T-cells and also
testing the reliability of our blood
tests for tracking disease-causing
T-cells.
The BCG trial is one of the few
translational studies in humantesting where the animal data
showed disease reversal in diabetic
mice that had hyperglycemia, notjust in mice with normal blood
sugars and with a predisposition
to diabetes. Therefore, this humantrial at Mass General is designed
to treat people with establishedtype 1 diabetes unlike most humantesting that focuses only on not
yet diabetic patients at risk forthe disease or newly diagnosed
diabetics with a short time periodof high blood sugars.

Updates

Summer/Fall 2009

Ben Rosenthal
At 17, a mature understanding of the importance of a cureB

en Rosenthal’s mother, Susan
Benford, learned her son
had diabetes when he was 13
months old. He had lost a quarterof his body weight, was urinating
frequently and was hungry andirritable. “Until then, he wasan easy child, and suddenly
everything turned on its head,”recalls Susan. “I was able to detectthat something was wrong mostly
because I already had anotherchild, who was healthy. I knew that
Ben’s behavior and his symptoms
were totally abnormal.”

The diagnosis, she says, was“shocking, terrifying”. Though she
knew it was a treatable disease,
she worried constantly when hefell asleep, in particular, because
she didn’t know if he was simply
tired or if his insulin levels weredangerously low, which could
lead, potentially, to a coma or evendeath.
“He was too young to speak, so
I was doing a lot of guesswork,”
Susan recalls.
By the age of eight, Ben wasable to monitor himself. Today,

Faustman Lab in the News!
U.S. News and World Report has included Dr. Faustman ina recent feature entitled, “Pioneers of Medical Progress”(August 2009). Dr. Faustman is honored to be included
among the 14 research-scientists described in the article
as “cutting-edge researchers”.

at age 17, he says that keeping on
top of his condition is just “partof life”. But when Susan, Ben
and his step-father, Ted, learned
about Dr. Denise Faustman’s
research towards a cure of type1 diabetes at Mass General, they
immediately took notice — andhave been following the trial for
BCG closely ever since. “There is somuch research on diabetes goingon. What’s so attractive about Dr.
Faustman’s trial, however, is thatit addresses the source of type 1
diabetes by eliminating the cells
that cause the disease,” says Susan,who met Dr. Faustman when Susan
served on the board of the Juvenile
Diabetes Research Foundation.
Ben recently returned froman internship in Dar es Salaam,
Tanzania, where he worked ina diabetes clinic, assisting aphysician who treats adults andchildren with type 1 diabetes.
There, the patients “get a fractionof the insulin and monitoring
supplies they need to keep theirdiabetes under control — it is somuch less than what I get as apatient in the U.S.,” he says. As aresult, average life expectancy fordiabetics in Africa is far lower than
it is in America.
The experience made Ben feel
lucky to have received the care hehas, he says, but it also convinced
him how important a cure — of thekind Dr. Faustman is pursuing —would be, especially in developing
countries like Tanzania where thelack of access to insulin makes thedisease more immediately lifethreatening.

Updates

Summer/Fall 2009

The Nuts and Bolts of Phase II ofthe Cure Diabetes Now Clinical Trial
The Cure Diabetes Now Phase I results are likely to be published in early 2010.
Our goal is to initiate the three-year, Phase II program without delay. We want to sharewith you some of the steps we will take to begin the next, exciting phase of testing
the BCG therapy when we have funding.
Step 1: Set Up theFDA Regulatory TeamA critical aspect of Phase II will
be to hire experts in vaccine drug
development to ensure that thetrial complies with Federal Drug
Administration (FDA) procedures.
The team of experts will design

a trial that fits with regulatory
constraints specifically dictatedby the FDA branch that regulates
vaccines. In addition, the teamwill help to do all the necessary
paperwork from the viewpoint of
the FDA proposals highly regulated
process. Therefore, we will needto assemble a highly specialized
team of professionals who have had
success with vaccine development
and the complex regulatory
processes. They will assist Mass
General in making presentations tothe FDA and will serve to maintaindata integrity in reporting and follow

Updates

Summer/Fall 2009

regulatory and manufacturing
processes to proceed in unison andin time-efficient ways.
Step 2: Set Up
Manufacturing of BCG
For Phase II, we will need to repackage or manufacture BCG so it
comes to the clinic in small vials
that represent one easy dose pervial. Currently for Phase I, Mass
General pharmacists take large
bottles of high-dose BCG and thendilute the drug to create one doseand load that dose into a syringe.
Due to the increased number ofpatients who will be enrolled inPhase II, we will need to manage
the dosing in a more formalized
process. In addition, the FDA
will likely require that the drug bepackaged and manufactured in thesame way it would potentially be
distributed to the public. We will
also need to establish state-of-theart manufacturing processes thatmeet the highest standards. BCG
has been around for so many years
that the current manufacturing
process will not be approved by theFDA for a new indication. Setting up
BCG manufacturing is a critical stepin making every piece of data weobtain from human experimentation
with BCG count in Phase II.
Step 3: Set Up
Manufacturing Oversight
The FDA will have strict
requirements for the manufacturing
process that include rigorous
documentation of thatprocess. Once the contracts for
manufacturing and packaging BCG
for the new purpose of treating type1 diabetes are established, we willhire our own personnel to performdaily to weekly inspections of the
manufacturing process. These
inspections will ensure that the
product manufacturing process istightly controlled and meets
FDA standards.
Step 4: Hire Director ofRegulatory Operations
The director of regulatory
operations will oversee theregulatory details of the trial. This
person will make sure the clinicaldocumentation of the trial meets therecordkeeping standards that arenecessary for submission to the FDA
at all stages of clinical testing.
Step 5: Design Phase IIClinical Trial
For Phase II, we will design a trialthat is able to detect BCG’s effect onestablished diabetic patients — inparticular, the best dose and timingof drug administration. How wedesign Phase II will be dictated inpart by the data in Phase I and also
by input from the FDA, our advisors
and the clinical trial teams at MGH.
The FDA will likely request that alarger number of patients (knownas “sample size”) be enrolled in thetrial and that we perform long-term
follow-up with trial participants.
Enrolling/testing large numbers ofpatients and then following theirstatus for a long time can make trials
very costly. Therefore, we will workwith biostatisticians to design a trialthat is as streamlined as possible
so that we enroll enough patientsto achieve FDA standards while
ensuring that our sample size has

the possibility to show meaningful
results in terms of the effects BCG
has on diabetes.
Step 6: Establish a Data
Safety Monitoring Board
For Phase II testing, we willassemble a Data Safety Monitoring
Board (DSMB). This group will haveaccess to data from the clinicaloperations manager and will
analyze the data for both positive
and negative side effects that might
require early clinical reporting. TheDSMB will need to have expertisein vaccine trial design and vaccine
therapies seeking regulatory
approval.
Step 7: Establish Large-Scale,
Automated Blood Handling Process
The Phase II trial will include
many more patients than the Phase
I trial. Therefore, the Faustman
Immunobiology Laboratory willneed to have the capability tohandle more blood specimens andwill need to expand its engineering
efforts and platforms to be readyto process the increased numberof patient blood samples. Our staffof engineers and bench scientists
will require at least six months oftraining prior to the arrival of thefirst clinical samples in Phase II. The
automated blood handling process
yields highly pure T-cells fromhuman blood. Some of these pureT-cells are the autoreactive T-cells
that cause diabetes. The automatedblood-handling process allows us
to monitor, in an individual patient,
the burden of autoreactive T-cells
that are predicted to decrease with
optimized BCG therapy.

www.faustmanlab.org

BCG Therapy At WorkM

any people have asked us
how the BCG therapy works
to eliminate type 1 diabetes. Below
is an explanation of how the BCG
therapy finds the “bad” diseasecausing cells and eliminates themin type 1 diabetic blood.
How are autoreactiveT-cells detected?
There are many different
technologies to detect the “bad”
T-cells of autoimmunity. Thediabetes research community
can, under certain circumstances,
identify individual “bad” T-cellswith a technology that uses proteins
called “tetramers”. These protein
structures, which can be made toglow, bind to the “bad” T-cells andcan then be detected using a device
called a “flow cytometer,” whichallows us to visualize and count theglowing particles.
How does BCG or TNF
kill only the “bad” T-cells?
The process of eliminating only
the “bad” T-cells has evolved overtwo decades and is based on basic
science work performed in theFaustman Lab and elsewhere.
About 20 years ago, Drs. Faustman
and David Nathan, director of theMGH Diabetes Center, set up oneof the first clinical trials on theU.S. east coast at Mass General
to transplant islets. During thistransplantation work, the data
revealed that the transplanted islet
cells were killed by a recurrence ofthe disease. This suggested the type1 disease was still active years after
the diagnosis.

Therefore, we designed aresearch program to not only
identify “bad” T-cells in humans
with diabetes but to devise ways
to specifically kill those cells. One
sub-population of these cells hasa cellular defect that makes thesecells susceptible to death in thepresence of elevated levels of TNF.
This discovery, first in mice andthen in humans, set the stage for
us to design targeted ways to kill
the disease-causing cells whilesparing the healthy cells. The goal
was to find a treatment that wouldinterfere with the protein pathwaysof the disease-causing T-cells, but
not the normal T-cells. Identifying
differences in the proteins between
the “bad” T-cells and the normal
T-cells of people with type 1

diabetes allowed us to design anintervention to kill the cells thatcause disease.
Cure Diabetes Now is a rapid
clinical translation program
designed to safely test thistherapeutic concept in humans
with type 1 diabetes. We areusing BCG, a generic drug that is
inexpensive to produce and has aproven safety record, to cause thepatient’s own body to temporarily
produce elevated amounts of TNF
in the hopes that this will eliminate
one population of disease-causing
cells in type 1 diabetes. In Phase
II of the clinical trial, we will start
the important process of testing
the dose and frequency of drugadministration to eliminate thedisease in diabetic patients.

Updates

Summer/Fall 2009

Tom Hewson
After living with type 1
diabetes for 73 years,
Tom is ready for a cure.

Two Ways YouCan Help

At age 11, while attending
summer camp on the Jersey
Shore, Tom recalls developing
an unquenchable thirst, atelltale sign something waswrong. Shortly thereafter he wasdiagnosed as a type 1 diabetic
and has been insulin-dependent
since 1936.
He recalls how scary it wasat age 11 to learn that his life
depended on daily injections
and urine tests, a strict dietand management of all theencumbrances that came with
the new life regimen. There
were no disposable syringes orinsulin pens in those days. It
was necessary to sterilize a glass
syringe and needle in boilingwater before each use. Drops ofurine were put in a test tube withwater and a reagent, then heated
to develop a color indicative of
its sugar content.
Since Tom began taking insulin
73 years ago, he has benefited
greatly from the many new
device developments, delivery
systems and new types of insulin.
Glucose monitors have enabled
patients to self-manage theirdiabetes more effectively. Now in
his mid-80’s, Tom is still active,swims almost daily, and follows
a rigorous intensive therapy
for his diabetes. He estimates
he has had about 40,000 finger
sticks (blood samples) and about
85,000 insulin injections over

Please support the ongoing
research of our lab with atax-deductible donation.
Every gift makes a difference
for patients … today andtomorrow.

the years. In spite of his vigilanceand diligence, however, he has
had eye and heart complications
and, from time to time, has
suffered with temporarily
disabling hypoglycemia.
“Diabetes has a bright side
and a dark side,” he says. “Youcan live a nearly normal lifestyle.
However, not mastering theintricacies of your own selftreatment can be fatal. You must
pay attention every hour of every
day, but simultaneously thinkpositive thoughts and live life tothe fullest.”
Tom adds, “Over the years,
medical scientists have brought
new understanding about thecause, care and possible curefor diabetes. Many researchgroups are active today pursuing
different, promising approaches
to a cure. As the possibilityof a cure appears closer thanever at the Faustman Lab, I
encourage everyone to support
this important and promisingresearch. Its success could
bring enormous benefits to theAmerican healthcare system andto millions of diabetics aroundthe world.”

1. To make a secure online
donation, please visit
www.faustmanlab.org andclick on “Support”
2. You may make a giftby check (payable to“Massachusetts General
Hospital – Cure DiabetesNow”) and mail yourcheck to:
MGH Development Office
Attn: Jocelyn Hoey
165 Cambridge St., Suite 600
Boston, MA 02114
On the memo line of you
check, please write: “Type 1diabetes research”.
How can I learn more
about this research?
1. Please log onto our web
site: www.faustmanlab.org
2. E-mail us at diabetestrial@
partners.org
3. Call us at 617-726-4084
Thank you for joining us in
the fight against diabetes.
Warmly,Denise L. Faustman,
MD, PhD