Updates
Winter 2012

from the Faustman Laboratory at Massachusetts General Hospital

Pursuing New Treatments for
Advanced Type 1 Diabetes
A Note from Dr. Faustman

It is hard to believe another year
is already coming to a close at
the Faustman Lab! I hope 2012
has been as good to you and yourfamily as it has been to us. With
your support, we have maderemarkable progress toward ourgoal of reversing type 1 diabetes.
We were delighted to publish
some very important findings
this year. First was the discovery
that people with type 1 diabetes
may continue making their owninsulin for decades after disease
onset, challenging long-heldassumptions that pancreaticfunction drops off abruptly afterdiagnosis.
Next was the publication of thefindings from our Phase I trial.
Our Phase I data demonstrated
early signs of the potential of
bacillus Calmette-Guérin (BCG),
a tuberculosis vaccine with ademonstrated safety record,
to reverse type 1 diabetes.
Our testing showed that BCG
stimulated production of aprotein that killed the insulinattacking cells, temporarilyrestoring some pancreaticfunction in individuals withlongstanding type 1 diabetes.
This discovery is a potential gamechanger for the future of type 1
diabetes treatment.
Together, these findings
validate our belief that it isindeed worthwhile to pursue newtreatments for patients who have fund the next stage of clinical
had type 1 diabetes for many
testing, and we are more thanyears.
half way there with $13.5
million raised to date. I can’t
In 2013, we will continue
thank enough each person
to work to bring forward a
who has supported our efforts
safe, inexpensive, generic
medication—the BCG vaccine— for all of the dedication andgenerosity that has helped
through clinical testing for typeus reach this stage. You are
1 diabetes. Our hope is that weintegral to the work thatcan show that this well-known
we do every day and to thevaccine has the potential to be
groundbreaking results that wean affordable and long-lastingsee. With continued support,
treatment for type 1 diabetes.
we will see this trial through to
Based on our Phase I results,
shape the next era of diabetes
we are currently designing andresearch and treatment.
planning the Phase II humanHappy Holidays!
clinical trial. We anticipate that
we will begin enrolling patients in Sincerely,
the study later in 2013.
With your help, we also
continue our efforts to raise
the full $25.2 million needed toDenise L. Faustman, MD, PhD

UpdateWinter 2012

Phase I Study Results
Publishedplacebo, spaced four weeks apart.
Blood samples from these patientswere also compared with samples
Generic drug shows benefits in from six non-diabetic control
participants and with samples
advanced type 1 diabetes
from 75 additional individuals with
The results of our Phase I human diabetes and 15 without. Frequentclinical trial were published inblood tests measured participants’
PLoS ONE, a peer-reviewed,
blood levels of insulin-autoreactive
scientific journal, this August
T cells (“bad” T cells), GAD
under the title “Proof-of-Concept, autoantibodies (a marker ofRandomized, Controlled Clinicalpancreatic function), regulatory
Trial of Bacillus Calmette-Guérin
T cells (cells that help control thefor Treatment of Long-Term
immune response), and C-peptide
Type 1 Diabetes.” In the trial,(a marker of insulin secretion).
we saw early evidence that theDuring the 20-week study period,
bacillus Calmette-Guérin (BCG)
we saw that BCG vaccination killed
vaccine can not only kill the “bad” the “bad” T cells in two of theT cells that attack the insulinthree BCG-treated participants.
secreting cells of the pancreas,
These patients also had increases
but can also temporarily restore
in the number of their protective
insulin production in people with regulatory T cells. In addition,
longstanding type 1 diabetes. ABCG-treated patients also hadgeneric drug with over 90 years
a temporary but statisticallyof clinical use, BCG is currently
significant elevation in C-peptide
approved by the Food and Druglevels, suggesting restoration ofAdministration for vaccination
insulin production. These sameagainst tuberculosis and for theresponses were seen in one of thetreatment of bladder cancer.
placebo-treated patients who, after
Our lab first reported in 2001
enrolling in the study, coincidently
that temporarily elevating levels
developed infection with theof tumor necrosis factor (TNF,
Epstein-Barr virus (EBV, which,an immune regulator) helped
like BCG, is known to elevate TNF
to reverse type 1 diabetes inlevels). There were no significant
mice by eliminating the “bad” T
adverse events in any patient.
cells that destroy the pancreaticWith this Phase I study, weislets, permitting these islets
believe we have validated in
to regenerate. In our researchhumans the treatment pathway weprogram, we are using BCG
originally reported in mice—that
to safely elevate TNF levels inis, that elevating TNF levels canhumans.
eliminate the “bad” T cells, giving
Our recent Phase I trial enrolled the pancreas the opportunity tosix type 1 diabetes patients who
begin to regenerate its insulinhad been living with the diseaseproducing cells—and arefor an average of 15 years. Patients seeing early evidence of BCG’s
were randomly assigned to receive effectiveness. Our findings show
two doses of either BCG or athat a simple, inexpensive vaccine

modifies the autoimmunity
underlying type 1 diabetes andappears to briefly restore pancreaticbeta-cell function, even in those
who have had type 1 diabetes formany years.
Our Phase I findings werecovered by media outlets including
Bloomberg, US News & World
Report, FOX News Boston, WebMD,and Reuters, as well as international
news organizations. Please visit
www.faustmanlab.org and click on“News” to read these articles.
In the Phase II human clinical
trial, which is currently being
planned, we will seek to identify
the right dose and frequency ofvaccination needed to sustaina therapeutic response. For
long-term restoration of insulin
secretion, we expect that more
frequent or higher BCG dosing will
be needed compared to that usedin the Phase I study.

Over Half Way to Full
Phase II Funding$13.5 million raisedWith $13.5 million raisedfor the Phase II BCG humanclinical trial, we are morethan half way to our goal of$25.2 million. Thank you toeveryone who has given theirsupport, from the individuals
and families affected by thisdevastating disease to theIacocca Foundation and othermajors donors who have beenso critical to our efforts to movethis research forward.

www.faustmanlab.org

Frequently Asked
Questions
Could you briefly summarize themost important outcomes of thePhase I trial?

The major findings from thePhase I study were that:• The BCG vaccine with multidosing was safe in advanced
type 1 diabetes.
• Although the drug was given in
relatively small doses, we saw
targeted death of the “bad” Tcells that attack the insulinsecreting islets, an early signthat BCG has the potential tostop the autoimmune attack andsuccessfully reverse disease.

What is the design of thePhase II study?

Will BCG will be a one-time
vaccination?

We are currently planning
the study and do not yet knowwhat the final design will be. In
general, the trial will include
a larger number of patients tofurther validate our preliminary
Phase I efficacy findings. The study
will look at what dose of BCG isneeded, along with how frequently
it would need to be given, to makethis a sustained type 1 diabetes
therapy.

Because this human clinical trial
program translates only one partof the two-part intervention weused to permanently reverse type 1
diabetes in mice, we envision thatBCG vaccination would have tobe repeated over time. In Phase II,
we will be looking for the optimal
dosing and timing of administration
so that patients can have asustained response with infrequent
dosing.

Are you enrolling patients?
How do I participate?

How might BCG benefit people
with type 1 diabetes?

We are currently reviewing
our patient database so that when
the patient eligibility criteria isfinalized, we can quickly enroll theneeded participants. If you wish
• In people living with diabetes
for an average of 15 years, there to learn more about participating,please visit www.faustmanlab.org,
was a transient increase in/restoration of pancreatic insulin email diabetestrial@partners.org,
secretion after BCG vaccination. or call 617-726-4084.

We hope that BCG treatment
will put type 1 diabetes
into remission, sparing people
with this disease the need to sofrequently monitor blood glucose
levels or administer insulin—andalso better protecting them against
the fluctuations in blood sugar thatlead to diabetes complications.

Insulin Production Declines More Slowly Than We Thought
Many with type 1 diabetes continue to make insulin decades after diagnosis
For over 20 years, scientists have thought that the ability of the pancreas to produce insulin declines very abruptly—
within one to two years of diagnosis—in people who develop type 1 diabetes. These findings, based on standard
C-peptide tests (C-peptide is an indicator that the pancreas is secreting insulin), have meant that most clinical trials
testing treatments to stop or reverse type 1 diabetes have focused only on newly diagnosed patients, who were thought
to have the best chances of recovering insulin secretion.
We now see that the decline of insulin-production occurs much more slowly than scientists have traditionally thought.
Using an ultrasensitive blood test, we found that C-peptide production can persist for decades after type 1 diabetes
onset and remain responsive to blood sugar levels. Although C-peptide levels were lower among those who had lived
longer with the disease, they did not abruptly decline, but rather decreased gradually over time. What’s more, C-peptide
was detected in 10% of patients in our study who had been living with the disease for 31-40 years.
Our findings suggest that people with advanced disease may benefit from treatments that retain or enhance beta cellfunction—and that we should focus more clinical trials on this population. In other words, there may be a longer
period in which we may be able to intervene in type 1 diabetes, even in people diagnosed decades ago—for instance, bystopping the disease from progressing or reversing type 1 diabetes by regenerating the insulin-producing cells.
“Persistence of Prolonged C-peptide Production in Type 1 Diabetes as Measured with an Ultrasensitive C-peptide
Assay” was published in the February 2012 issue of Diabetes Care. We also presented these findings at the American
Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) annual scientific meetings.

UpdateWinter 2012

The BCG Vaccine and Multiple Sclerosis
Italian trials show vaccine efficacy in a second
autoimmune disease
Recent human trials in Italy, led by Dr. Giovanni Ristori of theUniversity of Rome, show that BCG vaccination can decrease
symptoms and prevent the progression of brain lesions inadvanced multiple sclerosis. Like type 1 diabetes, multiple
sclerosis is an autoimmune disease that is caused by autoreactive(“bad”) T cells vulnerable to TNF-triggered cell death. In type1 diabetes, these cells attack the insulin-secreting cells of thepancreas. In multiple sclerosis, they attack the protective coveringthat surrounds the nerve cells.
The work of Dr. Ristori and his colleagues is exciting. Like ourPhase I study in humans with type 1 diabetes, their human studies
in multiple sclerosis show that the inexpensive BCG vaccine may
benefit patients affected by these autoimmune diseases.

About the Type 1 Diabetes Reversal Trials at MGH
Led by Dr. Denise Faustman at Massachusetts General
Hospital (MGH), the BCG Human Clinical Trial Program istesting Bacillus Calmette-Guérin (BCG), an inexpensive genericdrug, as a treatment for advanced type 1 diabetes. In therecently completed Phase I study, BCG was administered toadults who had been living with type 1 diabetes for an averageof 15 years. This treatment not only helped eliminate thedefective T cells that mistakenly attack and destroy the insulinproducing cells of the pancreas, it also temporarily restored theability of the pancreas to produce small amounts of insulin.
The next step, a Phase II study, is currently being planned, withthe goal of identifying the drug dose and schedule that will put
advanced type 1 diabetes into remission.

Looking for more information about this type 1 diabetes research?
Please visit www.faustmanlab.org.
Have questions about participating in future studies?
Please email: DiabetesTrial@partners.org.

How You Can Help
Please consider making a taxdeductible donation today tosustain the momentum of this type1 diabetes research program. Every
gift makes a difference for patients… today and tomorrow.
1. To make a secure online
donation, please visit
www.faustmanlab.org andclick on “Support.”
2. You may make a gift by check(**payable to “Massachusetts
General Hospital”**) and mailyour check to:
Diabetes Clinical Trial
c/o Dr. Denise Faustman
Immunobiology Laboratory
Massachusetts General
Hospital-East
Building 149, 13th Street, CNY-3601
Charlestown, MA 02129

On the memo line of your check,please write: “Type 1 diabetesresearch.”Thank you for joining us in thefight against diabetes!

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