New Diamyd Medical-licensed patent issued


Diamyd Medical (Nasdaq Stockholm First North, Ticker: DMYD B) announced today
that the University of California, Los Angeles, UCLA, has been granted a key
patent for a combo treatment for type 1 diabetes with GABA and preproinsulin or
an immunogenic fragment thereof. Immunogenic fragments include c-peptide,
proinsulin and other insulin molecules. This adds to Diamyd Medical’s patent
estate of exclusively licensed intellectual property using GABA for treatment
and interception of type 1 diabetes and inflammatory diseases including type 2
diabetes, metabolic syndrome and rheumatoid arthritis. The Company also
exclusively licenses UCLA patents for GAD65 (a major autoantigen in type 1
diabetes) for which the last patent expires 2032.
“This new patent may very well bring substantial value to Diamyd Medical since
various preproinsulin derived compounds are being developed by others as Antigen
Based Therapies (ABTs) in parallel with Diamyd Medical’s development of the GAD
-based ABT, Diamyd®, says Anders Essen-Möller, President and CEO of Diamyd
Medical. “The diabetes vaccine Diamyd® is clearly today’s leading candidate ABT
for type 1 diabetes but any synergistic reinforcement of its efficacy is
important. Like in cancer therapy, incremental improvements by combining
compounds that hit the disease from different angles, is likely the winning path
forward in the forthcoming battle for this multibillion USD market.”

Diamyd Medical is collaborating with Professor Kenneth McCormick, the University
of Alabama at Birmingham, in a GABA/Diamyd® combo trial in 75 recent onset type
1 diabetes patients, ages 4-18 years. Recruitment has been ongoing since March
this year.

Gamma-Amino Butyric Acid (GABA) is a major neurotransmitter. GABA taken orally
is widely considered safe with few side effects (Tian, 2011), and is available
over the counter in the US. Diamyd® has been used in clinical studies with more
than 1,000 patients and has shown a good safety profile. In a European Phase III
study Diamyd® showed good clinical effect in several subgroups, and a limited
overall 16% efficacy (p=0.10) in preserving endogenous insulin secretion.
Diamyd® is easy to administer in any clinical setting.

Tian, Kaufman, et al showed that combining GABA with GAD-alum (Diamyd®),
synergistically prolongs transplanted beta cell survival in an animal model for
type 1 diabetes (PLoS One, (http://www.ncbi.nlm.nih.gov/pubmed/21966502) 2011).
More recently the same authors, (Tian, Kaufman et al, Diabetes, 2014), reported
that combined treatment with GABA plus proinsulin synergistically restored
normoglycemia and promoted beta cell replication in newly diabetic mice. In
conclusion, GABA in combination with antigen based therapy (ABT) holds promise
for type 1 diabetes intervention leading to restored or improved endogenous
insulin production.

Evidence is accumulating that GABA is an important compound for treatment and
prevention for diabetes and other inflammatory diseases. GABA lowers the
production of pro-inflammatory cytokines and stimulates beta cell proliferation
while it inhibits apoptosis. (Ligon, Diabetologia, 2007; Soltani, Proc
 (http://www.ncbi.nlm.nih.gov/pubmed/21709230)Natl Acad Sci USA, 2011; Birnir,
Amino Acids 2013; Wan, 2015).

Tian, Dang, Chen, Guan, Jin, Atkinson and Kaufman also showed that GABA
regulates both the survival and replication of human beta cells. (Diabetes,
2013).

Abstracts from related scientific articles are included in this press release as
appendix further below.

Ongoing studies with GABA and/or Diamyd® include:

  · GABA/ DIAMYD® – COMBINING GABA WITH DIAMYD®

A placebo-controlled study, where Diamyd® is being tested in combination with
GABA. The study comprises 75 patients between the ages of 4 and 18 recently
diagnosed with type 1 diabetes, and will continue for a total of 12 months. The
aim of the combination treatment is to preserve the body’s residual capacity to
produce insulin. The study is led by Professor Kenneth McCormick at the
University of Alabama at Birmingham, USA. The first patient was included in the
study in March 2015.

  · DIABGAD-1 – COMBINING DIAMYD® WITH IBUPROFEN AND VITAMIN D

A placebo-controlled study, where Diamyd® is being tested in combination with
ibuprofen and vitamin D. The study comprises a total of 64 patients between the
ages of 10 and 18 recently diagnosed with type 1 diabetes, and will continue for
a total of 30 months. The aim of the combination treatment is to preserve the
body’s residual capacity to produce insulin. The study runs at nine clinics in
Sweden and is led by Professor Johnny Ludvigsson at Linköping University,
Sweden. 15 month results from the study are due in the fourth quarter of 2015.

  · DIAGNODE – DIAMYD® IN LYMPH GLANDS IN COMBINATION WITH VITAMIN D

An open label study, where Diamyd® is administered directly into lymph nodes in
combination with treatment with vitamin D. The study comprises five patients
between the ages of 18 and 30 newly diagnosed with type 1 diabetes, and will
continue for a total of 30 months. The aim of the study is to evaluate the
safety of the combination treatment and the effect on the immune system and the
patients’ insulin producing capacity. The study is led by Professor Johnny
Ludvigsson at Linköping University, Sweden. The first patient was included in
the study in February 2015.

  · EDCR IIa – COMBINING DIAMYD® WITH ETANERCEPT AND VITAMIN D

An open label study, where Diamyd® is combined with etanercept and vitamin D.
The study comprises 20 patients between the ages of 8 and 18 who have been newly
diagnosed with type 1 diabetes, and will continue for a total of 30 months. The
aim of the study is to evaluate the safety of the combination treatment and the
effect on the immune system and the patients’ insulin producing capacity. The
study is led by Professor Johnny Ludvigsson at Linköping University, Sweden. The
first patient was included in May 2015.

  · DiAPREV-IT 1 – DIAMYD®

A placebo-controlled study, where Diamyd® is being tested in children at high
risk of developing type 1 diabetes, meaning that they have been found to have an
ongoing autoimmune process but do not yet have any clinical symptoms of
diabetes. A total of 50 participants from the age of four have been enrolled in
the study, which will last for five years. The aim of the study is to evaluate
whether Diamyd® can delay or prevent the participants from presenting with type
1 diabetes. The study is led by Dr. Helena Elding Larsson at Lund University,
Sweden. Five year results are expected at the end of 2016.

  · DiAPREV-IT 2 – COMBINING DIAMYD® WITH VITAMIN D

A placebo-controlled study, where Diamyd® is being tested in combination with
vitamin D in children at high risk of developing type 1 diabetes, meaning that
they have been found to have an ongoing autoimmune process but do not yet have
any clinical symptoms of diabetes. A total of 80 participants between the ages
of 4 and 18 will be enrolled in the study, which will last for five years. The
aim of the study is to evaluate whether Diamyd® can delay or prevent the
participants from presenting with type 1 diabetes. The study is led by Dr.
Helena Elding Larsson at Lund University, Sweden. The first patient was included
in March 2015.

About Diamyd Medical
Diamyd Medical is dedicated to working toward a cure for type 1 diabetes and
LADA. The Company’s projects include development of combination regimens with
the GAD-based diabetes vaccine Diamyd® for arresting the destruction of insulin
-producing beta cells. The Company exclusively licenses UCLA-rights to GAD65,
the active ingredient in the vaccine, for which the last patent expires in 2032.
Additionally, the Company exclusively licenses UCLA patents for using GABA for
the treatment of diabetes and other inflammation-related conditions.

Diamyd Medical is one of the major shareholders in the stem cell company
Cellaviva AB, which is establishing a Swedish commercial bank for private family
saving of stem cells in umbilical cord blood and other sources of stem cells.
Stem cells can be expected to be used in Personalized Regenerative Medicine
(PRM), for example, to restore beta cell mass in diabetes patients where
autoimmunity has been arrested.

Remium Nordic AB is the Company’s Certified Adviser.

APPENDIX

Diabetes Metab Syndr Obes. 2015 Feb 3;8:79-87. doi: 10.2147/DMSO.S50642.
eCollection 2015.

GABAergic system in the endocrine pancreas: a new target for diabetes treatment.

Wan Y, Wang Q, Prud'homme GJ.

Excessive loss of functional pancreatic β-cell mass, mainly due to apoptosis, is
a major factor in the development of hyperglycemia in both type 1 and type
2 diabetes (T1D and T2D). In T1D, β-cells are destroyed by immunological
mechanisms. In T2D, while metabolic factors are known to contribute to β-cell
failure and subsequent apoptosis, mounting evidence suggests that islet
inflammation also plays an important role in the loss of β-cell mass. Therefore,
it is of great importance for clinical intervention to develop new therapies. γ
-Aminobutyric acid (GABA), a major neurotransmitter, is also produced by islet β
-cells, where it functions as an important intraislet transmitter in regulating
islet-cell secretion and function. Importantly, recent studies performed in
rodents, including in vivo studies of xenotransplanted human islets, reveal
that GABA exerts β-cell regenerative effects. Moreover, it protects β-cells
against apoptosis induced by cytokines, drugs, and other stresses, and has anti
-inflammatory and immunoregulatory activities. It ameliorates the manifestations
of diabetes in preclinical models, suggesting potential applications for the
treatment of diabetic patients. This review outlines the actions
of GABA relevant to β-cell regeneration, including its signaling mechanisms and
potential interactions with other mediators. These studies increase our
understanding of the regenerative processes of pancreatic β-cells, and help pave
the way for the development of regenerative medicine for diabetes.

Diabetes. (http://www.ncbi.nlm.nih.gov/pubmed/25146474) 2014 Sep;63(9):3128-34.
doi: 10.2337/db13-1385.

Combined therapy with GABA and proinsulin/alum acts synergistically to restore
long-term normoglycemia by modulating T-cell autoimmunity and promoting β-cell
replication in newly diabetic NOD mice.

Tian J, Dang H, Nguyen AV, Chen Z, Kaufman DL.

Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic
NOD mice, perhaps because too few β-cells remain by the time that ABT-induced
regulatory responses arise and spread. We hypothesized that combining a fast
-acting anti-inflammatory agent with an ABT could limit pathogenic responses
while ABT-induced regulatory responses arose and spread. γ-Aminobutyric acid
(GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg)
responses, and promote β-cell replication in mice. We examined the effect of
combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly
diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia,
while GABA monotherapy restored normoglycemia for a short period. Combined
treatment restored normoglycemia in the long term with apparent permanent
remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4-
and IL-10-secreting T-cell responses that spread to other β-cell autoantigens.
GABA monotherapy induced moderate IL-10 (but not IL-4) responses to β-cell
autoantigens. Combined treatment synergistically reduced spontaneous type 1 T
-helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses,
and insulitis, but enhanced IL-10 and Treg responses and promoted β-cell
replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic
T-cell responses, induce Treg responses, promote β-cell replication, and
effectively restore normoglycemia in newly diabetic NOD mice. Since these
treatments appear safe for humans, they hold promise for type 1 diabetes
intervention.

Amino Acids. 2013 Jul;45(1):87-94. doi: 10.1007/s00726-011-1193-7. Epub 2011 Dec
13.

GABA is an effective immunomodulatory molecule.

Jin Z, Mendu SK, Birnir B.

In recent years, it has become clear that there is an extensive cross-talk
between the nervous and the immune system. Somewhat surprisingly, the immune
cells themselves do express components of the neuronal neurotransmitters
systems. What role the neurotransmitters, their ion channels, receptors and
transporters have in immune function and regulation is an emerging field of
study. Several recent studies have shown that the immune system is capable of
synthesizing and releasing the classical neurotransmitter GABA (γ
-aminobutyric acid). GABA has a number of effects on the immune cells such as
activation or suppression of cytokine secretion, modification of cell
proliferation and GABA can even affect migration of the cells. The immune cells
encounter GABA when released by the immune cells themselves or when the immune
cells enter the brain. In addition, GABA can also be found in tissues like the
lymph nodes, the islets of Langerhans and GABA is in high enough concentration
in blood to activate, e.g., GABA-A channels. GABA appears to have a role in
autoimmune diseases like multiple sclerosis, type 1 diabetes, and rheumatoid
arthritis and may modulate the immune response to infections. In the near
future, it will be important to work out what specific effects GABA has on the
function of the different types of immune cells and determine the underlying
mechanisms. In this review, we discuss some of the recent findings revealing the
role of GABA as an immunomodulator.

Diabetes. 2013, 62:3760-5.

γ-Aminobutyric acid regulates both the survival and replication of human β
-cells.

Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA, Kaufman DL.

γ-Aminobutyric acid (GABA) has been shown to inhibit apoptosis of rodent β-cells
in vitro. In this study, we show that activation of GABAA receptors (GABAA-Rs)
or GABAB-Rs significantly inhibits oxidative stress-related β-cell apoptosis and
preserves pancreatic β-cells in streptozotocin-rendered hyperglycemic mice.
Moreover, treatment with GABA, or a GABAA-R- or GABAB-R-specific agonist,
inhibited human β-cell apoptosis following islet transplantation into NOD/scid
mice. Accordingly, activation of GABAA-Rs and/or GABAB-Rs may be a useful
adjunct therapy for human islet transplantation. GABA-R agonists also promoted β
-cell replication in hyperglycemic mice. While a number of agents can promote
rodent β-cell replication, most fail to provide similar activities with human β
-cells. In this study, we show that GABA administration promotes β-cell
replication and functional recovery in human islets following implantation into
NOD/scid mice. Human β-cell replication was induced by both GABAA-R and GABAB-R
activation. Hence, GABA regulates both the survival and replication of human β
-cells. These actions, together with the anti-inflammatory properties of GABA,
suggest that modulation of peripheral GABA-Rs may represent a promising new
therapeutic strategy for improving β-cell survival following human islet
transplantation and increasing β-cells in patients with diabetes.

Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11692-7. doi:
10.1073/pnas.1102715108.

GABA exerts protective and regenerative effects on islet beta cells and reverses
diabetes.

Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti
R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q.

Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and
islet β-cell loss. Thus, an effective therapy may require β-cell restoration and
immune suppression. Currently, there is no treatment that can achieve both goals
efficiently. We report here that GABA exerts antidiabetic effects by acting on
both the islet β-cells and immune system. Unlike in adult brain or islet α-cells
in which GABA exerts hyperpolarizing effects, in islet β-cells, GABA produces
membrane depolarization and Ca(2+) influx, leading to the activation of PI3
-K/Akt-dependent growth and survival pathways. This provides a potential
mechanism underlying our in vivo findings that GABA therapy preserves β-cell
mass and prevents the development of T1D. Remarkably, in severely diabetic mice,
GABA restores β-cell mass and reverses the disease. Furthermore, GABA suppresses
insulitis and systemic inflammatory cytokine production. The β-cell regenerative
and immunoinhibitory effects of GABA provide insights into the role of GABA in
regulating islet cell function and glucose homeostasis, which may find clinical
application.

PLoS One. (http://www.ncbi.nlm.nih.gov/pubmed/21966502) 2011;6(9):e25337. doi:
10.1371/journal.pone.0025337. Epub 2011 Sep 22.

Combining antigen-based therapy with GABA treatment synergistically prolongs
survival of transplanted ß-cells in diabetic NOD mice.

Tian J, Dang H, Kaufman DL.

Antigen-based therapies (ABTs) very effectively prevent the development of type
1 diabetes (T1D) when given to young nonobese diabetic (NOD) mice, however, they
have little or no ability to reverse hyperglycemia in newly diabetic NOD mice.
More importantly, ABTs have not yet demonstrated an ability to effectively
preserve residual ß-cells in individuals newly diagnosed with type 1 diabetes
(T1D). Accordingly, there is great interest in identifying new treatments that
can be combined with ABTs to safely protect ß-cells in diabetic animals. The
activation of γ-aminobutyric acid (GABA) receptors (GABA-Rs) on immune cells has
been shown to prevent T1D, experimental autoimmune encephalomyelitis (EAE) and
rheumatoid arthritis in mouse models. Based on GABA's ability to inhibit
different autoimmune diseases and its safety profile, we tested whether the
combination of ABT with GABA treatment could prolong the survival of
transplanted ß-cells in newly diabetic NOD mice. Newly diabetic NOD mice were
untreated, or given GAD/alum (20 or 100 µg) and placed on plain drinking water,
or water containing GABA (2 or 6 mg/ml). Twenty-eight days later, they received
syngenic pancreas grafts and were monitored for the recurrence of hyperglycemia.
Hyperglycemia reoccurred in the recipients given plain water, GAD monotherapy,
GABA monotherapy, GAD (20 µg)+GABA (2 mg/ml), GAD (20 µg)+GABA (6 mg/ml) and GAD
(100 µg)+GABA (6 mg/ml) about 1, 2-3, 3, 2-3, 3-8 and 10-11 weeks post
-transplantation, respectively. Thus, combined GABA and ABT treatment had a
synergistic effect in a dose-dependent fashion. These findings suggest that co
-treatment with GABA (or other GABA-R agonists) may provide a new strategy to
safely enhance the efficacy of other therapeutics designed to prevent or reverse
T1D, as well as other T cell-mediated autoimmune diseases.

[image]

Fig 1. Synergistic effects of combined GAD/alum+GABA treatment to prolong
transplanted syngenic ß-cell survival in diabetic NOD mice (Tian 2011 e25338)

Diabetologia. (http://www.ncbi.nlm.nih.gov/pubmed/17318626) 2007 Apr;50(4):764
-73. Epub 2007 Feb 22.

Regulation of pancreatic islet cell survival and replication by gamma
-aminobutyric acid.

Ligon B, Yang J, Morin SB, Ruberti MF, Steer ML.

AIMS/HYPOTHESIS:

Pancreatic islets have evolved remarkable, though poorly understood mechanisms
to modify beta cell mass when nutrient intake fluctuates or cells are damaged.
We hypothesised that appropriate and timely adjustments in cell number occur
because beta cells release proliferative signals to surrounding cells when
stimulated by nutrients and 'bleed' these growth factors upon injury.

MATERIALS AND METHODS:

In rat pancreatic islets, we measured DNA content, insulin content, insulin
secretion after treatment, immunoblots of apoptotic proteins and the uptake of
nucleoside analogues to assess the ability of gamma-aminobutyric acid (GABA),
which is highly concentrated in beta cells, to act as a growth and survival
factor. This focus is supported by work from others demonstrating
that GABA increases cell proliferation in the developing nervous system, acts as
a survival factor for differentiated neurons and, interestingly, protects plants
under stress.

RESULTS:

Our results show that DNA, insulin content and insulin secretion are higher in
freshly isolated islets treated with GABA or GABA B receptor agonists. Exposure
to GABA upregulated the anti-apoptotic protein B-cell chronic lymphocytic
leukaemia XL and limited activation of caspase 3 in islets. The cellular
proliferation rate in GABA-treated islets was twice that of untreated controls.

CONCLUSIONS/INTERPRETATION:

We conclude that GABA serves diverse purposes in the islet, meeting a number of
functional criteria to act as an endogenous co-regulator of beta cell mass.
For further information, please contact:
Anders Essen-Möller, President and CEO
Phone: +46 70 55 10 679. E-mail: anders.essen-moller@diamyd.com
Diamyd Medical AB (publ)
Kungsgatan 29, SE-111 56 Stockholm, Sweden. Phone: +46 8 661 00 26, Fax: +46 8
661 63 68
E-mail: info@diamyd.com. Reg. no.: 556242-3797. Website: www.diamyd.com.

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