Spring 2008

Updates
Clinical Trial for Promising
Diabetes Drug is UnderwayT

he long-awaited launch of our Phase I
clinical trial evaluating the effects of Bacillus
Calmette-Guérin (BCG) in type 1 diabetes has begun!
The trial will be conducted here at Massachusetts
General Hospital. This Phase I trial is predicted to takeapproximately 18 months to complete.

Trials testing new drugs typically occur in Phase I-IV andtake 10 or more years, but we are fortunate in thiscase to be “recycling” a drug that is already available.
This should enable the study to move forward at a more
rapid pace, which has always been one of our goals.
BCG is a generic drug with an excellent safety
profile in humans and is already being used for otherdiseases, such as tuberculosis (TB) and cancer. BCG
causes the body to make a natural substance called
TNF, which helps regulate the immune system bykilling the rogue T cells that cause diabetes. We hopethat the administration of BCG will lead to TNF
selectively destroying the disease-causing T cells
that are present in diabetes. This trial is an important
step in testing this hypothesis.
We and others have already proven that this treatment
can work in mice with end-stage diabetes. If the BCG
studies show that BCG can help patients with type 1
diabetes, and if we can introduce this inexpensive drug
to the market, it will be a tremendous achievement.
All of your generous gifts have paid off, as we now
have the necessary blood tests and machinery built tomonitor this trial. With these tools, we can begin tosee what dose of the drug, if any, works best by
precisely counting white blood cells from blood
samples taken before and after BCG treatment.
If we see a reduced number of the rogue cells, then
we know that the therapy is working. Conducting
this clinical trial will be the only way to know if BCG
works against type 1 diabetes.

Spring 2008

Updatesfrom Dr. Faustman’s Lab at the Massachusetts General Hospital

The Safety of Bacillus Calmette-Guérin (BCG)
Bacillus Calmette-Guérin (BCG) has an impeccable safety
profile in humans. In fact, it has been labeled by somemedical experts as the “safest vaccine” ever developed.
BCG has been used for over 80 years worldwide as a vaccine
for tuberculosis (TB) and is also used for the treatment ofbladder cancer at high doses. In many countries, receiving
BCG to prevent TB is mandatory. Although it is approved
for use in the United States to prevent TB, BCG is not given
as a routine vaccine because the incidence of TB is low here.
The BCG vaccine carries an attenuated (weakened)strain of the bacteria Mycobacterium bovis, a live
bacteria that causes TB in cattle. It was first usedfollowing human clinical trials in 1921 thataffirmed the safety and efficacy of this vaccine.
Administering BCG is a relatively painless processwith few side effects. Typically, BCG is given as aneedle injection in the upper arm, just into the skin.
This may cause a slight reaction for about a week
followed by a small, flat scar for approximately aweek. Side effects may include headache, fever,swollen lymph nodes and skin scaling at the siteof injection. For some people, there is a small chanceof allergic reaction to BCG, in which case thosepatients may develop rashes or infections. People
with AIDS or other patients with compromised
immune systems should not be given BCG.
We have started our clinical trial by administering
small doses of BCG. As we learn more about thesafety and efficacy of BCG in type 1 diabetes, wewill be able to graduate to the next phase of thetrial, in which we will test increased doses or more
frequent doses.
Phase II Trials
We are very excited about the launch of our humanPhase I clinical trial. With this launch, we are finallywitnessing our basic research efforts bear fruit as
we progress from mice to human trials. Unfortunately,
finding a cure for type 1 diabetes does not stop here.
As the results of Phase I are accumulated and wecan show this drug is safe and effective in type 1
diabetes, we will move into Phase II clinical trials.

Phase II trials are larger-scale studies that evaluate
whether a drug works in a wide variety of people
and look at what doses are most effective. The Phase IIinvestigation, a critical part of the drug-testing process,will likely be our next step – and one that we are alreadygearing up for. Your continued support will help us expedite
this process of preparation and prevent a gap in funding(and thereby prevent a time delay) between Phase I
and Phase II testing, which we predict will begin inapproximately 18 months.

Spring 2008

Dr. Faustman Speaks: Toward Better Therapies for type 1 Diabetes
In what ways is this trial promisingand unprecedented?
This trial is very unique in the field oftype 1 diabetes research. Currently, thereis great emphasis on new treatments

involving blood-glucose monitoringdevices for type 1 diabetes, but there
is almost no emphasis on disease
reversal or cures for this disease. Our
goal is to reverse established type 1
diabetes, not simply temporarily halt
it or treat its symptoms. What also
makes this approach unique is that it
does not involve unknown risks – neither
large monetary risk nor the risk ofunknown toxicity to patients – typicalof new drug development. In addition,
the BCG trial does not require the useof immuno-suppressants or requirecell transplant. Instead, our approachis designed to target only the defective
white blood cells in type 1 diabetes,
sparing healthy cells. That should
translate into much less toxicity thanother treatments and makes thepossible long-term safety of the drug
remarkable.
What is involved in the process of
the Phase I clinical trial?
In this human clinical trial, we areenrolling diabetic volunteers andhealthy, non-diabetic volunteers who
serve as a control population. Many ofour volunteers are taken from a
database we have established at
MGH that includes type 1 diabetics
and healthy subjects who haveexpressed interest in participating intype 1 diabetes trials at MGH’s
Diabetes Research Center. After
patients are screened and enrolled,
the diabetic patients are randomly
assigned to receive a placebo (saline)
or BCG vaccination in the arm. Boththe diabetic placebo group and thehealthy subjects serve as control groups
whose results will be compared todiabetics who will receive a BCG
vaccination. We will monitor the
response of the white blood cells to themedication and look at islet function
during the study period, making useof automated cell separation methods
and the bioassay (a specialized bloodtest) created by our lab to monitor trial
results and measure drug efficacy.

If BCG works, what does the future
look like for type I diabetics? Howsoon will that future be realized?
In the short term, if we see in thePhase I trial that BCG is successful andis having the effect that we expect –which is to stimulate the immune
system to eliminate one population of
defective cells in type 1 diabetes – thenwe will move into Phase II and Phase
III trials to test the efficacy in larger
groups of patients. In the long term, if
this approach can be proven in clinical
trials, we think it would mean being able
to bring new, inexpensive treatments,
or even a cure, to diabetics.
Why is the MGH the right place tobe conducting this research?
MGH has one of the leading diabetes
centers in the world, and is home to
many of the world’s top diabetes experts.
In addition, the MGH is known forsuccessfully bringing many innovative
therapies from the research laboratory
to patients who are treated here. Thatis one of the hallmarks of MGH.
How can philanthropy help?
We would not have been able to get
this far without the generosity ofdonors. In fact, this trial would not havebeen possible at all were it not for thesupport we have received both fromprivate foundations like the Iacocca
Foundation – which provided thefunding for much of the basic researchleading up to the trial and Phase I of
the trial – and from countless individuals
and families. That philanthropic support,
and support from others, has beenabsolutely pivotal.

Spring 2008

from Dr. Faustman’s Lab at the Massachusetts General Hospital

Racing Toward a Cure: The Story Behind Brendan’s BrigadeW

hen the Iacocca Foundation, a charity benefiting
diabetes research founded by former Chrysler
chief executive Lee Iacocca, issued a challenge
to “Join Lee Now” and raise $10 million to support theBacillus Calmette-Guérin clinical trial, families from all overthe country responded.

Diana Buono, whose son Brendan, 16, has juvenile diabetes,
read about the developments in a Boston Globe article.
She and her husband Joe had beenlong-time donors to other organizations
funding research on the disease eversince Brendan was diagnosed at
17 months of age. After reading thearticle, Mrs. Buono tracked down
Dr. Faustman’s phone number andcalled her office to ask what her family
could do to help her efforts. That’s
when Brendan began giving regularblood samples to contribute toDr. Faustman’s development of a new
blood assay test that promised to beinstrumental in the planned clinical trial.
“When I read about the Iacocca
challenge and I began to learn about
how promising Dr. Faustman’s research
was, I felt we had to get involved,”says Mrs. Buono. “Ever since Brendanwas diagnosed, we had been hearing how a cure is rightaround the corner, and we felt like those promises weregoing nowhere. But it was obvious to us that Dr. Faustman’s
research was different – that she is on the path to findinga real cure, and soon.”
The Buonos were encouraged by Dr. Faustman’s success incuring type 1 diabetes in mice and also recognized that
this trial is unique in that its goal is to reverse diabetes inpeople who have the disease, not just reverse symptoms.
“We saw how committed Dr. Faustman is for finding acure for this disease, and how she and her group added
such a personal touch to their work,” says Mrs. Buono.

As a result, the Buonos transferred all their philanthropy
for diabetes to Dr. Faustman’s lab, and, in addition,
brainstormed to come up with a fund-raising event thatwould be meaningful – and fun – for Brendan.
Brendan loves biking, so in 2004 the family – including
Timothy, 13, and Maria, 7 – decided to hold an annual
bike ride on the 28-mile-long East Bay Bike Path near
Providence, Rhode Island.

Now entering its fourth year, “Brendan’s Brigade”
attracts about two dozen friends and family members
every year and has raised a total of approximately$18,700 for Dr. Faustman’s lab. Much of that money israised from sponsors and non-riders responding to the
Buono family’s letter campaign leading up to the event.
“The bike ride is small act of gratitude and assistance forthe tremendous amount of work that Dr. Faustman is so
passionate about in finding a cure,” says Brendan Buono.
“She’s a hope for all families living with type 1 diabetes.
She certainly is for us.”Spring 2008

Please Support Our Work
Please support the ongoing research of our lab with a tax-deductible
donation. Every gift makes a difference for patients ... today andtomorrow.
1) To make a secure online donation, please visit:www.mgh.harvard.edu/diabetes/diabetes_support.htm
and click on “Type 1 Research.”2) You may make a gift by check (payable to “Massachusetts
General Hospital”). Send your check to:
The Massachusetts General Hospital
Development Office
Attn: Jocelyn Hoey
165 Cambridge Street, Suite 600
Boston, MA 02114
On the memo line of your check, please write:“Type 1 diabetes research” or “Autoimmune research.”3) More information is available on line at:www.fautsmanlab.org
Thank you for joining us in the fight against diabetes.
Warmly,Denise L. Faustman, MD, PhD

How can I learn more about
this clinical trial?
Please log onto our web site:www.faustmanlab.org. If you would liketo schedule an appointment for theinitial blood work, pleasee-mail Ana Souza, MD, atasouza1@partners.org or callDr. Faustman’s office at617-726-4084.

Spring 2008

Updatesfrom Dr. Faustman’s Lab at the Massachusetts General Hospital

A History of Trying to Reverse Established Diabetes inAnimals Translation into Humans
In 2001, the Faustman lab reversed established type 1 diabetes in end-stage mice. In the non-obese
diabetic mouse model of autoimmune diabetes, Dr. Denise Faustman’s brief, two-part, non-toxic treatment
1,2,3
achieved a permanent cure of established diabetes. The intervention involved a regimen of immunomodulation
lasting six weeks, combined with control of hyperglycemia. After termination of all therapy, normal
glycemia was restored permanently in more than 75 percent of treated mice and the autoimmune state
reverted to normal. The lab successfully achieved targeted disease-removal of only the disease-causing
white blood cells in these long-term diabetic animals. In addition, the intervention not only removed thedisease, but allowed the animals to regenerate their pancreases. Long-term normoglycemia was restored
without any other intervention for their entire lives. Based on this finding, a proof-of-concept, Phase I
clinical trial using BCG began in January, 2008.
A drug named Complete Freund’s Adjuvant (CFA) was one part of the Faustman lab’s two-part therapy
and specifically eliminated the disease-causing cells in the mice. The human equivalent of this drug thatis manufactured for human use is called Bacillus Calmette-Guérin (BCG). BCG is a generic drug already
FDA-approved for prevention of tuberculosis and treatment of bladder cancer, which has been usedworldwide. Both drugs stimulate the production of TNF-alpha, which the lab staff believes will eliminate
a population of defective cells (pathogenic memory T cells) in type 1 diabetes.
Today, based on this research, an FDA-approved Phase I trial is being conducted at Massachusetts General
Hospital to evaluate whether treatment with BCG vaccination can eliminate the abnormal white blood cells
in patients with type 1 diabetes. Overall, this trial is part of the program of research aimed at developing acurative therapy for human type 1 diabetes.
Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function.
J Clin Invest. 2001 Jul; 108(1):63-72.
Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science.
2003 Nov 14; 302(5648):1223-7.
Faustman D, Tran S, Kodama S, Lodde B, Szalayova I, Key S, Toth Z, Mezey E. Comment on Papers by Chong et al, Nishio et al and Suri et al on
Diabetes Reversal in NOD Mice. Science 2006 314:1243-4.

Massachusetts General Hospital
Development Office
165 Cambridge Street, Suite 600
Boston, MA 02114