SAN DIEGO--(BUSINESS WIRE)--June 13, 2005--The combination of Lisofylline (LSF) and Exendin-4, a glucagon-like peptide-1 (GLP-1), reversed diabetes in a type 1 mouse model, according to results of a study presented at the American Diabetes Association (ADA) annual meeting. The same study also showed that the two drugs, when administered concomitantly, enhanced islet cell function and reduced islet cell death.
"The results of this study are very encouraging and demonstrate that it may be possible to regenerate beta cells with the combination of an immune modulator, such as LSF, and a GLP-1 agonist. These results are also consistent with previous findings that indicate Lisofylline has positive effects on insulin production and islet cell health," said Jerry L. Nadler, M.D., Chief of Endocrinology and Metabolism at the University of Virginia whose group presented the results at the ADA's Session on Beta-Cell Preservation. "If results of human studies with the LSF/Exendin-4 combination prove as successful, the treatment of type 1 diabetes and latent autoimmune diabetes of adults could be altered significantly."
LSF is a synthetic small molecule with novel anti-inflammatory properties that block autoimmune damage to insulin producing cells. GLP-1s, such as Exendin-4, stimulate pancreatic beta cell growth. However, the autoimmune process in people with type 1 diabetes rapidly destroys the beta cells, preventing GLP-1 action. The addition of an immune modulator such as LSF should provide a novel approach to restore beta cell function without the use of toxic immunosuppressive medications.
In the study, non-obese diabetic (NOD) mice, a well established model of type 1 diabetes, were treated for 28 days with the combination of LSF/Exendin-4. The treatment completely reversed diabetes as evidenced by restored glucose homeostasis. Additionally, there was evidence of new cell growth in the area of the islet cells in the mice given the combined therapy. NOD mice treated similarly with saline or Exendin-4 alone experienced no improvement in the diabetic condition. As part of the same study, isolated mouse pancreatic islets exposed to inflammatory cytokines and treated with the LSF/Exendin-4 combination experienced a 2.5 fold increase in metabolism and a 40% decrease in apoptosis (cell death) than controls.
"The blood sugar levels remained normal even after withdrawal of both drugs, suggesting that the combination of LSF and Exendin-4 led to beta cell regeneration," said Zandong Yang, M.D., Associate Professor of Medicine at the University of Virginia.
The study was conducted by Jeffrey Carter, B.S.; Meng Chen, M.D., Ph.D.; Kellie Smith, B.S.; Jerry L. Nadler, M.D.; and, Zandong Yang, M.D. of the University of Virginia and funded by local donor support.
Lisofylline has demonstrated that it can effectively prevent type 1 diabetes in preclinical models. LSF has shown to improve cellular mitochondrial function and to block interleukin 12 (IL-12) signaling and STAT-4 activation in target cells and tissues. IL-12 and STAT 4 activation are important pathways linked to inflammation and autoimmune damage to insulin producing cells. Therefore LSF, and the next generation of orally bioavailable immune modulators with a similar spectrum of action, offer the promise of providing a new therapeutic approach to prevent or reverse type 1 diabetes.
GLP-1 is a hormone that has generated significant attention in the diabetes community because it has multiple gluco-regulatory effects in the body. Several GLP-1 agonists are currently in clinical development for the treatment of diabetes and one product was recently approved as an adjunctive therapy to improve glycemic control in the treatment of type 2 diabetes.
Lisofylline and related compounds are being commercialized into therapies for diabetes and related complications by DiaKine Therapeutics, Inc. Dr. Nadler is the co-founder and current Chairman and Chief Science Officer of DiaKine Therapeutics.
According to the ADA, more than 18 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease and amputations. It is the fifth leading cause of death by disease in the U.S.
Contacts
For DiaKine TherapeuticsBill Wells, 404-281-7490
Monday, June 13, 2005
Data Presented at ADA Showed that Basal Insulin Therapy with Lantus(R) Achieved Target Glycemic Control in Poorly Controlled Type 2 Diabetes
Two Studies Show Insulin Glargine Control of HbA(1C) in Poorly Controlled
Type 2 Diabetes Patients, with Comparable Rates of Hypoglycemia
BRIDGEWATER, N.J., June 13 /PRNewswire-FirstCall/ -- Data presented today
at the 65th Session of the American Diabetes Association (ADA), San Diego,
demonstrated that people with type 2 diabetes achieved significantly better
glycemic control, and also achieved it earlier, when treated with the 24-hour
basal insulin analog Lantus(R) (insulin glargine [rDNA origin] injection,
sanofi-aventis) and their usual oral antidiabetes therapies* compared with
patients receiving oral therapy alone, with comparable rates of hypoglycemia.
Further data at the ADA show that Lantus(R) can be safely and effectively
initiated in both primary and secondary care, to achieve their target glycemic
control.
"These studies re-affirm that Lantus can help more people with type 2
diabetes reach their target blood sugar levels, and reach them earlier, so
that introducing insulin glargine earlier in these patients may be beneficial.
This data also highlights that Lantus can be titrated confidently and safely
in both a primary and secondary care settings with comparable rates of
hypoglycemia," commented Hertzel Gerstein and one of the investigators in the
INSIGHT study.
The INSIGHT (Implementing New Strategies with Insulin Glargine for
Hyperglycemia Therapy) study of 405 patients with type 2 diabetes for at least
6 months, demonstrated that earlier addition of insulin glargine to current
diabetes therapy effectively reduced HbA(1C) levels significantly more than
optimization of oral agents, and with comparable rates of hypoglycemia.
During the study, patients received either addition of once daily insulin
glargine (with no increase in oral antidiabetic therapy [OAD]), or were
optimized on OAD therapy with no insulin.
There were no differences in hypoglycemia noted between those receiving
Lantus and those receiving oral agents.
The American Diabetes Association recommends that people with diabetes
achieve an HbA(1C) <7% for optimal diabetes control, although more stringent
glycemic goals (i.e. a normal HbA(1C), <6%) may further reduce complications
at the cost of increased risk of hypoglycemia. Other organizations, namely the
European Diabetes Policy Group (EDPG) and the American Association of Clinical
Endocrinologists (AACE), recommend a lower target of under 6.5%.
In clinical practice, however, the majority of patients with type 2
diabetes do not routinely reach treatment targets. According to the National
Health and Nutrition Examination Survey (NHANES IV) 1999-2000, only 37% of
participants with previously diagnosed diabetes achieved the target HbA(1C)
goal of less than 7.0%, and 37.2% of participants were above the "take action"
HbA(1C) level of greater than 8.0%. These figures did not change significantly
from those reported in NHANES III, which encompassed the years 1988 to 1994.
Another study, presented at the ADA, focusing on a sub-analysis of the
AT.LANTUS trial in UK patients, further confirmed that Lantus(R) can be safely
and effectively initiated in both primary and secondary care. The data
highlighted that severe and nocturnal hypoglycemia rates are comparable
between primary and secondary care managed patients (p=NS).
The UK sub-analysis data are part of one of the largest prospective
treatment trials of diabetes management ever undertaken -- AT.LANTUS, (A Trial
comparing Lantus(R) Algorithms to achieve Normal blood glucose Targets in
patients with Uncontrolled blood Sugar) -- published in the June 2005 issue of
the ADA's Diabetes Care journal. The global study of nearly 5,000 people from
59 countries with type 2 diabetes, demonstrated that a simple patient-
administered titration algorithm with Lantus(R) significantly improves
glycemic control with a low risk of severe hypoglycemia.
"We know from large, landmark studies that a reduction on HbA(1C) levels
reduces the risk of a diabetic patient from developing both the micro and
macrovascular complications of diabetes. With over half of the patients with
type 2 diabetes failing to reach their glycemic targets, the inclusion of
Lantus the first and only once-daily, insulin analog which may be used in
combination with oral antidiabetes agents, provides an important approach to
achieving better glycemic control," commented Dr. Melanie Davies, Consultant
in Diabetes at the University Hospitals of Leicester.
* 83.2% of patients received their usual OAD whereas 16.8% were treated
only with lifestyle intervention
About LANTUS(R) (insulin glargine [rDNA origin] injection)
Lantus(R) is indicated for once-daily subcutaneous administration, at the
same time each day, for the treatment of adult and pediatric patients (6 years
and older) with type 1 diabetes mellitus or adult patients with type 2
diabetes mellitus who require basal (long-acting) insulin for the control of
hyperglycemia.
LANTUS(R) MUST NOT BE DILUTED OR MIXED WITH ANY OTHER INSULIN OR SOLUTION.
If mixed or diluted, the solution may become cloudy, and the onset of
action/time to peak effect may be altered in an unpredictable manner.
Lantus(R) is contraindicated in patients hypersensitive to insulin
glargine or the excipients.
Hypoglycemia is the most common adverse effect of insulin, including
Lantus(R). As with all insulins, the timing of hypoglycemia may differ among
various insulin formulations. Glucose monitoring is recommended for all
patients with diabetes. Any change of insulin type and/or regimen should be
made cautiously and only under medical supervision. Concomitant oral
antidiabetes treatment may need to be adjusted.
Other adverse events commonly associated with Lantus(R) include the
following: lipodystrophy, skin reactions (such as injection-site reaction,
pruritus, rash) and allergic reactions.
For full prescribing information, please visit http://www.lantus.com.
About sanofi-aventis
The sanofi-aventis Group is the world's third largest pharmaceutical
company, ranking number one in Europe. Backed by a world-class R&D
organization, sanofi-aventis is developing leading positions in seven major
therapeutic areas: cardiovascular, thrombosis, oncology, metabolic diseases,
central nervous system, internal medicine, and vaccines. The sanofi-aventis
Group is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY)
The sanofi-aventis Group conducts its business in the United States
through its subsidiaries Sanofi-Synthelabo Inc., Aventis Pharmaceuticals Inc.
and Sanofi Pasteur Inc.
U.S. Contacts: Terri Pedone, +1-908-243-6578,
Terri.Pedone@sanofi-aventis.com
SOURCE sanofi-aventisWeb Site: http://www.sanofi-aventis.com http://www.lantus.comCompany News On Call: Company News On-Call: http://www.prnewswire.com/comp/232375.html
Type 2 Diabetes Patients, with Comparable Rates of Hypoglycemia
BRIDGEWATER, N.J., June 13 /PRNewswire-FirstCall/ -- Data presented today
at the 65th Session of the American Diabetes Association (ADA), San Diego,
demonstrated that people with type 2 diabetes achieved significantly better
glycemic control, and also achieved it earlier, when treated with the 24-hour
basal insulin analog Lantus(R) (insulin glargine [rDNA origin] injection,
sanofi-aventis) and their usual oral antidiabetes therapies* compared with
patients receiving oral therapy alone, with comparable rates of hypoglycemia.
Further data at the ADA show that Lantus(R) can be safely and effectively
initiated in both primary and secondary care, to achieve their target glycemic
control.
"These studies re-affirm that Lantus can help more people with type 2
diabetes reach their target blood sugar levels, and reach them earlier, so
that introducing insulin glargine earlier in these patients may be beneficial.
This data also highlights that Lantus can be titrated confidently and safely
in both a primary and secondary care settings with comparable rates of
hypoglycemia," commented Hertzel Gerstein and one of the investigators in the
INSIGHT study.
The INSIGHT (Implementing New Strategies with Insulin Glargine for
Hyperglycemia Therapy) study of 405 patients with type 2 diabetes for at least
6 months, demonstrated that earlier addition of insulin glargine to current
diabetes therapy effectively reduced HbA(1C) levels significantly more than
optimization of oral agents, and with comparable rates of hypoglycemia.
During the study, patients received either addition of once daily insulin
glargine (with no increase in oral antidiabetic therapy [OAD]), or were
optimized on OAD therapy with no insulin.
There were no differences in hypoglycemia noted between those receiving
Lantus and those receiving oral agents.
The American Diabetes Association recommends that people with diabetes
achieve an HbA(1C) <7% for optimal diabetes control, although more stringent
glycemic goals (i.e. a normal HbA(1C), <6%) may further reduce complications
at the cost of increased risk of hypoglycemia. Other organizations, namely the
European Diabetes Policy Group (EDPG) and the American Association of Clinical
Endocrinologists (AACE), recommend a lower target of under 6.5%.
In clinical practice, however, the majority of patients with type 2
diabetes do not routinely reach treatment targets. According to the National
Health and Nutrition Examination Survey (NHANES IV) 1999-2000, only 37% of
participants with previously diagnosed diabetes achieved the target HbA(1C)
goal of less than 7.0%, and 37.2% of participants were above the "take action"
HbA(1C) level of greater than 8.0%. These figures did not change significantly
from those reported in NHANES III, which encompassed the years 1988 to 1994.
Another study, presented at the ADA, focusing on a sub-analysis of the
AT.LANTUS trial in UK patients, further confirmed that Lantus(R) can be safely
and effectively initiated in both primary and secondary care. The data
highlighted that severe and nocturnal hypoglycemia rates are comparable
between primary and secondary care managed patients (p=NS).
The UK sub-analysis data are part of one of the largest prospective
treatment trials of diabetes management ever undertaken -- AT.LANTUS, (A Trial
comparing Lantus(R) Algorithms to achieve Normal blood glucose Targets in
patients with Uncontrolled blood Sugar) -- published in the June 2005 issue of
the ADA's Diabetes Care journal. The global study of nearly 5,000 people from
59 countries with type 2 diabetes, demonstrated that a simple patient-
administered titration algorithm with Lantus(R) significantly improves
glycemic control with a low risk of severe hypoglycemia.
"We know from large, landmark studies that a reduction on HbA(1C) levels
reduces the risk of a diabetic patient from developing both the micro and
macrovascular complications of diabetes. With over half of the patients with
type 2 diabetes failing to reach their glycemic targets, the inclusion of
Lantus the first and only once-daily, insulin analog which may be used in
combination with oral antidiabetes agents, provides an important approach to
achieving better glycemic control," commented Dr. Melanie Davies, Consultant
in Diabetes at the University Hospitals of Leicester.
* 83.2% of patients received their usual OAD whereas 16.8% were treated
only with lifestyle intervention
About LANTUS(R) (insulin glargine [rDNA origin] injection)
Lantus(R) is indicated for once-daily subcutaneous administration, at the
same time each day, for the treatment of adult and pediatric patients (6 years
and older) with type 1 diabetes mellitus or adult patients with type 2
diabetes mellitus who require basal (long-acting) insulin for the control of
hyperglycemia.
LANTUS(R) MUST NOT BE DILUTED OR MIXED WITH ANY OTHER INSULIN OR SOLUTION.
If mixed or diluted, the solution may become cloudy, and the onset of
action/time to peak effect may be altered in an unpredictable manner.
Lantus(R) is contraindicated in patients hypersensitive to insulin
glargine or the excipients.
Hypoglycemia is the most common adverse effect of insulin, including
Lantus(R). As with all insulins, the timing of hypoglycemia may differ among
various insulin formulations. Glucose monitoring is recommended for all
patients with diabetes. Any change of insulin type and/or regimen should be
made cautiously and only under medical supervision. Concomitant oral
antidiabetes treatment may need to be adjusted.
Other adverse events commonly associated with Lantus(R) include the
following: lipodystrophy, skin reactions (such as injection-site reaction,
pruritus, rash) and allergic reactions.
For full prescribing information, please visit http://www.lantus.com.
About sanofi-aventis
The sanofi-aventis Group is the world's third largest pharmaceutical
company, ranking number one in Europe. Backed by a world-class R&D
organization, sanofi-aventis is developing leading positions in seven major
therapeutic areas: cardiovascular, thrombosis, oncology, metabolic diseases,
central nervous system, internal medicine, and vaccines. The sanofi-aventis
Group is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY)
The sanofi-aventis Group conducts its business in the United States
through its subsidiaries Sanofi-Synthelabo Inc., Aventis Pharmaceuticals Inc.
and Sanofi Pasteur Inc.
U.S. Contacts: Terri Pedone, +1-908-243-6578,
Terri.Pedone@sanofi-aventis.com
SOURCE sanofi-aventisWeb Site: http://www.sanofi-aventis.com http://www.lantus.comCompany News On Call: Company News On-Call: http://www.prnewswire.com/comp/232375.html
Genasense(R) plus Rituximab Reported Active in Patients with Relapsed Non-Hodgkin's Lymphoma
BERKELEY HEIGHTS, N.J., June 13 /PRNewswire-FirstCall/ -- Genta
Incorporated (Nasdaq: GNTA) today announced the presentation of clinical data
reporting the safety and activity of Genasense(R) (oblimersen sodium)
Injection, the Company's lead anticancer drug, in combination with rituximab
(Rituxan(R); Genentech IDEC). The trial was conducted in patients with
relapsed and refractory non-Hodgkin's lymphoma (NHL) by investigators from the
M.D. Anderson Cancer Center, Houston, TX, McMaster University, Hamilton,
Ontario, and the Fox Chase Cancer Center, Philadelphia, PA. The data were
presented by the trial's principal investigator, Dr. Barbara Pro, on Saturday
at the International Conference on Malignant Lymphoma in Lugano, Switzerland.
In this study, Genasense was administered daily for 7 days on weeks 1, 3
and 5, and rituximab was administered weekly for 6 weeks. Thirty-five
patients who had failed a median of 2 prior chemotherapy regimens with or
without rituximab were entered into this ongoing trial. To date, 6 patients
have achieved a complete response, one of whom was refractory to prior
rituximab therapy. Nine other patients have achieved a partial response for
an overall response rate of 42%. Patients with the specific subset of
follicular lymphoma showed a response rate of 56%. Twelve other patients have
had stable disease. Side effects of the combination appeared qualitatively
similar to that for rituximab alone, including but not limited to neutropenia,
fever, infection, anemia and fatigue.
Prior studies have shown preclinical synergy of Genasense with rituximab
in NHL (1,2). The concurrent treatment schedule employed in this clinical
study closely follows the optimized dosing regimen that was recently described
for the use of this combination (3). This study - the first to report
clinical activity of Genasense plus rituximab without the use of cytotoxic
chemotherapy - was supported in part by the National Cancer Institute. Recent
clinical studies have also demonstrated safety and activity when using
Genasense and rituximab in combination with chemotherapy, such as CHOP-R in
patients with mantle cell lymphoma (4). Ongoing work is also assessing the
use of Genasense in combination with rituximab plus fludarabine in patients
with chronic lymphocytic leukemia (CLL).
"The Genasense-rituximab combination trials are high priorities for the
Company in both NHL and CLL", commented Dr. Loretta M. Itri, President,
Pharmaceutical Development and Chief Medical Officer. "We anticipate that
future registration trials in both of these indications will incorporate the
use of rituximab. These early demonstrations of safety and activity are key
to the translation of promising preclinical work into patients, as well as for
building the combination regimens for new trials in these diseases."
About Genasense
Genasense works by inhibiting the production of Bcl-2, a protein made by
cancer cells that is thought to block chemotherapy-induced cell death. By
reducing the amount of Bcl-2 in cancer cells, Genasense may enhance the
effectiveness of current anticancer treatments. Genasense is currently in
multiple, late-stage randomized and non-randomized clinical trials in multiple
indications including malignant melanoma, chronic lymphocytic leukemia (CLL),
acute myeloid leukemia and non-small cell lung cancer.
About Genta
Genta Incorporated is a biopharmaceutical company with a diversified
product portfolio that is focused on delivering innovative products for the
treatment of patients with cancer. The Company's research platform is anchored
by two major programs that center on oligonucleotides (RNA and DNA-based
medicines) and small molecules. Genasense(R) (oblimersen sodium) Injection,
the Company's lead compound from its oligonucleotide program is currently
undergoing late-stage, Phase 3 clinical testing. The leading drug in Genta's
small molecule program is Ganite(R) (gallium nitrate injection), which the
Company is exclusively marketing in the U.S. for treatment of patients with
cancer-related hypercalcemia that is resistant to hydration. For more
information about Genta, please visit our website at: http://www.genta.com/.
This press release contains forward-looking statements with respect to
business conducted by Genta Incorporated. By their nature, forward-looking
statements and forecasts involve risks and uncertainties because they relate
to events and depend on circumstances that will occur in the future. There are
a number of factors that could cause actual results and developments to differ
materially. For a discussion of those risks and uncertainties, please see the
Company's Annual Report/Form 10-K for 2004.
SOURCE Genta IncorporatedWeb Site: http://www.genta.com/
Incorporated (Nasdaq: GNTA) today announced the presentation of clinical data
reporting the safety and activity of Genasense(R) (oblimersen sodium)
Injection, the Company's lead anticancer drug, in combination with rituximab
(Rituxan(R); Genentech IDEC). The trial was conducted in patients with
relapsed and refractory non-Hodgkin's lymphoma (NHL) by investigators from the
M.D. Anderson Cancer Center, Houston, TX, McMaster University, Hamilton,
Ontario, and the Fox Chase Cancer Center, Philadelphia, PA. The data were
presented by the trial's principal investigator, Dr. Barbara Pro, on Saturday
at the International Conference on Malignant Lymphoma in Lugano, Switzerland.
In this study, Genasense was administered daily for 7 days on weeks 1, 3
and 5, and rituximab was administered weekly for 6 weeks. Thirty-five
patients who had failed a median of 2 prior chemotherapy regimens with or
without rituximab were entered into this ongoing trial. To date, 6 patients
have achieved a complete response, one of whom was refractory to prior
rituximab therapy. Nine other patients have achieved a partial response for
an overall response rate of 42%. Patients with the specific subset of
follicular lymphoma showed a response rate of 56%. Twelve other patients have
had stable disease. Side effects of the combination appeared qualitatively
similar to that for rituximab alone, including but not limited to neutropenia,
fever, infection, anemia and fatigue.
Prior studies have shown preclinical synergy of Genasense with rituximab
in NHL (1,2). The concurrent treatment schedule employed in this clinical
study closely follows the optimized dosing regimen that was recently described
for the use of this combination (3). This study - the first to report
clinical activity of Genasense plus rituximab without the use of cytotoxic
chemotherapy - was supported in part by the National Cancer Institute. Recent
clinical studies have also demonstrated safety and activity when using
Genasense and rituximab in combination with chemotherapy, such as CHOP-R in
patients with mantle cell lymphoma (4). Ongoing work is also assessing the
use of Genasense in combination with rituximab plus fludarabine in patients
with chronic lymphocytic leukemia (CLL).
"The Genasense-rituximab combination trials are high priorities for the
Company in both NHL and CLL", commented Dr. Loretta M. Itri, President,
Pharmaceutical Development and Chief Medical Officer. "We anticipate that
future registration trials in both of these indications will incorporate the
use of rituximab. These early demonstrations of safety and activity are key
to the translation of promising preclinical work into patients, as well as for
building the combination regimens for new trials in these diseases."
About Genasense
Genasense works by inhibiting the production of Bcl-2, a protein made by
cancer cells that is thought to block chemotherapy-induced cell death. By
reducing the amount of Bcl-2 in cancer cells, Genasense may enhance the
effectiveness of current anticancer treatments. Genasense is currently in
multiple, late-stage randomized and non-randomized clinical trials in multiple
indications including malignant melanoma, chronic lymphocytic leukemia (CLL),
acute myeloid leukemia and non-small cell lung cancer.
About Genta
Genta Incorporated is a biopharmaceutical company with a diversified
product portfolio that is focused on delivering innovative products for the
treatment of patients with cancer. The Company's research platform is anchored
by two major programs that center on oligonucleotides (RNA and DNA-based
medicines) and small molecules. Genasense(R) (oblimersen sodium) Injection,
the Company's lead compound from its oligonucleotide program is currently
undergoing late-stage, Phase 3 clinical testing. The leading drug in Genta's
small molecule program is Ganite(R) (gallium nitrate injection), which the
Company is exclusively marketing in the U.S. for treatment of patients with
cancer-related hypercalcemia that is resistant to hydration. For more
information about Genta, please visit our website at: http://www.genta.com/.
This press release contains forward-looking statements with respect to
business conducted by Genta Incorporated. By their nature, forward-looking
statements and forecasts involve risks and uncertainties because they relate
to events and depend on circumstances that will occur in the future. There are
a number of factors that could cause actual results and developments to differ
materially. For a discussion of those risks and uncertainties, please see the
Company's Annual Report/Form 10-K for 2004.
SOURCE Genta IncorporatedWeb Site: http://www.genta.com/
Teaming Up Against Malaria Morbidity, Mortality, and Disability
A Symposium Jointly sponsored by
North Carolina A&T State University & the Liberian History, Education Development, Inc. (LIHEDE), in collaboration with Bennett College of Greensboro, North Carolina,
and The Union of Associations of Liberian Organizations (UALO) in the Triad, North Carolina
"Theme of Symposium: Teaming up against malaria morbidity, mortality, and disability"
Date & Time of Symposium: July 29-30, 2005 from 8:00 A.M.-5:00 P.M. each day
Venue of Symposium: NC A&T State University’s Union SBR Foyer on July 29, 2005 and on July 30, 2005 in the Union Exhibit Hall.
The symposium organizing committee of the Liberian History, Education and Development, Inc. (LIHEDE) would like to invite you to attend this very important national symposium on Liberia, which is aimed at addressing the need for lasting, effective control and eventual eradication of malaria problems in Liberia - just as developed nations like the United States and Europe have done. At this symposium, we will explore cutting-edge technologies and treatments to end the suffering of the Liberian people and perhaps create a model for Africa to address this epidemic, which is destroying the lives of our children, the future of the African Continent. NC A&T State University Chancellor Dr. James Renick, Greensboro City Mayor, Mr. Keith Holiday are expected to formally welcome symposium participants and guests to the University's campus and to the City of Greensboro.
United States Senator Dr. William Frist, MD has been invited to deliver the keynote address at the opening program, while Dr. Joel Jones, Director of Malaria Program, Liberian Ministry of Health & Social Welfare, is expected to deliver the keynote address at the symposium banquet.
The symposium will also include panel discussions and presentations by mostly Liberian medical professionals, academicians, Liberian community leaders, religious leaders and former Liberian government officials on selected topics relevant to the theme of the symposium, including Malaria Control-Research and Reality, Harmful Effects of Malaria, Malaria Control Methodologies and Techniques, Agronomy and DDT Safety. Other topics include: Why Liberian Children Die from Malaria Before Access to Treatment, and The Role of Typhoid Fever and Its Effect on the Diagnosis and Effective Treatment of Malaria in Liberia.
Liberian community leaders, academicians, professionals, and former government officials, presenting papers or serving as panelists at the symposium include Dr. Delvin Walker, Ken Carter, MPH, Dr. Eugene Sawyer, Dr. E. Brumskine, Ms. Muna Wreh, Mr. Roger Bate, Dr. Abu Mansalay, Dr. Eugenia Cooper, Ms. Nicole William, Dr. Simukai Shamu, Mr. Peter Burgress, Mr. Sanie S. S. Sesay, Dr. Thomas Jaye, Dr. Simukai Shamu, Mr. Paul Driessen, Mr. Jeff Wildman, Dr. Lawrence A. Zumo, Dr. Francis Karteh, and Robert S. Desowitz, PhD, DSc., among others.
The symposium will climax with a soccer match between community teams, representing Liberia and Sierra Leone, within the spirit of the Mano River Union, and a dinner ball commemorating Liberia's Independence Day (July 26, 1847), sponsored by the Association of United Liberians in the Triad, North Carolina.
Thank you in advance for your interest and cooperation. We look forward to your participation and attendance.
Please confirm your participation by phone or email, by contacting one of the following LIHEDE members: Mr. Nat Galarea-Gbessagee
Secretary General – LIHEDE
E-mail: ngg06@yahoo.com
Telephone 240-447-7408
Mr. Sam Togba Slewion
The Secretariat, LIHEDE
E-mail: Samuel.slewion@phila.gov
Telephone 215- 964-3217Syrulwa Somah, Ph.D.
Executive Director – LIHEDE
E-mail: somah@ncat.edu
Telephone 336-334-7586/336-456-8075
Mr. Nya Flomo
E-mail: nyaflomo@bellsouth.net
Telephone 336-954-9084/641-3235
North Carolina A&T State University & the Liberian History, Education Development, Inc. (LIHEDE), in collaboration with Bennett College of Greensboro, North Carolina,
and The Union of Associations of Liberian Organizations (UALO) in the Triad, North Carolina
"Theme of Symposium: Teaming up against malaria morbidity, mortality, and disability"
Date & Time of Symposium: July 29-30, 2005 from 8:00 A.M.-5:00 P.M. each day
Venue of Symposium: NC A&T State University’s Union SBR Foyer on July 29, 2005 and on July 30, 2005 in the Union Exhibit Hall.
The symposium organizing committee of the Liberian History, Education and Development, Inc. (LIHEDE) would like to invite you to attend this very important national symposium on Liberia, which is aimed at addressing the need for lasting, effective control and eventual eradication of malaria problems in Liberia - just as developed nations like the United States and Europe have done. At this symposium, we will explore cutting-edge technologies and treatments to end the suffering of the Liberian people and perhaps create a model for Africa to address this epidemic, which is destroying the lives of our children, the future of the African Continent. NC A&T State University Chancellor Dr. James Renick, Greensboro City Mayor, Mr. Keith Holiday are expected to formally welcome symposium participants and guests to the University's campus and to the City of Greensboro.
United States Senator Dr. William Frist, MD has been invited to deliver the keynote address at the opening program, while Dr. Joel Jones, Director of Malaria Program, Liberian Ministry of Health & Social Welfare, is expected to deliver the keynote address at the symposium banquet.
The symposium will also include panel discussions and presentations by mostly Liberian medical professionals, academicians, Liberian community leaders, religious leaders and former Liberian government officials on selected topics relevant to the theme of the symposium, including Malaria Control-Research and Reality, Harmful Effects of Malaria, Malaria Control Methodologies and Techniques, Agronomy and DDT Safety. Other topics include: Why Liberian Children Die from Malaria Before Access to Treatment, and The Role of Typhoid Fever and Its Effect on the Diagnosis and Effective Treatment of Malaria in Liberia.
Liberian community leaders, academicians, professionals, and former government officials, presenting papers or serving as panelists at the symposium include Dr. Delvin Walker, Ken Carter, MPH, Dr. Eugene Sawyer, Dr. E. Brumskine, Ms. Muna Wreh, Mr. Roger Bate, Dr. Abu Mansalay, Dr. Eugenia Cooper, Ms. Nicole William, Dr. Simukai Shamu, Mr. Peter Burgress, Mr. Sanie S. S. Sesay, Dr. Thomas Jaye, Dr. Simukai Shamu, Mr. Paul Driessen, Mr. Jeff Wildman, Dr. Lawrence A. Zumo, Dr. Francis Karteh, and Robert S. Desowitz, PhD, DSc., among others.
The symposium will climax with a soccer match between community teams, representing Liberia and Sierra Leone, within the spirit of the Mano River Union, and a dinner ball commemorating Liberia's Independence Day (July 26, 1847), sponsored by the Association of United Liberians in the Triad, North Carolina.
Thank you in advance for your interest and cooperation. We look forward to your participation and attendance.
Please confirm your participation by phone or email, by contacting one of the following LIHEDE members: Mr. Nat Galarea-Gbessagee
Secretary General – LIHEDE
E-mail: ngg06@yahoo.com
Telephone 240-447-7408
Mr. Sam Togba Slewion
The Secretariat, LIHEDE
E-mail: Samuel.slewion@phila.gov
Telephone 215- 964-3217Syrulwa Somah, Ph.D.
Executive Director – LIHEDE
E-mail: somah@ncat.edu
Telephone 336-334-7586/336-456-8075
Mr. Nya Flomo
E-mail: nyaflomo@bellsouth.net
Telephone 336-954-9084/641-3235
Better living through microbes
from Nature Biotechnology
Monya Baker -San Francisco
Genetically engineered bacteria made biotech drugs possible. Now, they are becoming drugs in their own right, Monya Baker reports.
On April 30 this year, two Florida patients received a unique mouth rinse. Using a cotton swab, a dentist painted billions of genetically modified live bacteria of the species Streptococcus mutans onto their pearly whites. If all goes as planned, these bacteria, which lack the gene to make enamel-eroding lactic acid, will replace their naturally occurring, acid-making counterparts, which cause tooth decay.
Besides S. mutans, a number of strains of live bacteria are being developed as therapies. A Lactococcus Lactis strain, engineered to secrete a therapeutic protein, has already been tested in patients with Crohn disease at the University of Amsterdam; in April, trial results were submitted for publication. Also that month, Osel of Santa Clara, California, began phase 2 trials using a proprietary, naturally occurring strain of live Lactobacillus crispatus to treat recurrent urinary tract infection and recurrent bacterial vaginosis. Other academics and companies are exploring genetically modified bacteria against cancer and infectious diseases.
As drugs, bacteria offer several advantages: compared with therapeutic proteins, they are easier to grow, purify and store; although engineering them to express (or not express) a particular gene takes expertise, it needs to be done only once. But along with their convenience and versatility, bacteria reproduce and evolve, making them hard to predict. That creates tricky regulatory issues, and most investors are keeping their distance. But even without venture backing, the field is progressing steadily through the clinic.
Living therapies
The first dose of engineered S. mutans comes two years after the US Food and Drug Administration (FDA) placed Alachua, Florida-based Oragenics' clinical trial on hold for safety concerns. The current seven-day trial requires bacteria with additional engineering. The gene for alanine racemase is deleted, which makes the bacteria dependent on D-alanine for their growth. During the clinical trial, they are supplied with the nutrient in a mouth rinse applied twice-daily. And, just in case the bacteria must be eliminated quickly, all patients enrolled in the trial must wear dentures, which can be removed should problems arise. When the trial is over, patients will rinse their mouths with an antibiotic and be monitored, along with their spouses, for three months.
Oragenics hopes that eventually the bacteria will become a routine part of dentistry, a one-time treatment applied to children's teeth before they start getting cavities. CEO Chuck Soponis acknowledges no one has any specific idea what ill health effects the bacteria might cause. The strain does not make a recombinant protein or displace other species of bacteria living on the tongue and gums. Still, he says, the FDA is right to be cautious. “You're putting a genetically modified bacteria that's going to be in people's mouths for a lifetime, and that hasn't been done before.”
Using live bacteria, or probiotics, to promote health is already common in Japan and becoming increasingly so in Europe. In fact, about 30 probiotic prescription products are sold in Japan. Far more common are products sold without prescriptions as so-called functional foods. The Japanese company Yakult Honsha of Tokyo sells 25 million bottles a day of a fermented milk drink, each one boasting that it contains 8 billion live Lactobacillus casei strain Shirota, which allegedly make for a more healthful gut flora. However, the efficacy of these over-the-counter products is uncertain, and they can't command the high prices of prescription drugs.
Investors hang back
In general, companies seeking funding for live bacteria therapies will have an even harder time finding funding than other biotechnology startups, according to Irena Melnikova, research manager at consulting firm Life Sciences Insights of Framingham, Massachusetts. “This is something very novel,” she says, “and when you start talking about putting live bacteria in humans, there's a negative first reaction.”
In fact, neither Oragenics nor Osel are accessing traditional venture capital (VC) sources to fund their programs. Oragenics went straight to the public markets, listing the company on the Toronto Venture Exchange in June 2003, and moving it to the American Stock Exchange in May last year. Though Osel began in 1998 with money from the founders and has received funding from government agencies including the National Institutes of Health, it has relied mainly on private investors who are not venture capitalists, according to the company's president Ralph Levy. “The VC community does not have a model which our product fits into,” he says. “Small molecules and antibodies, they've seen that; live bacteria they don't understand.”
Oragenics is also pursuing an antibiotic and an over-the-counter probiotic, both stemming from research by the company's CSO and cofounder Jeff Hillman. The probiotic is a proprietary mixture of three naturally occurring bacteria expected to prevent periodontal disease when taken daily. Oragenics plans to partner with larger oral care companies and get the product on the market in Europe and Asia sometime next year and use revenues from probiotics sales to partly finance development of its genetically modified bacteria, which will be marketed as a prescription drug administered by dentists.
Osel's Levy is quick to distance himself from the nonprescription marketplace. He doesn't even like the term 'probiotic.' “The easy route is just manufacturing it and putting it in a store. My market is the physician who's going to write a script to treat a patient,” he says. Levy thinks venture capitalists will be more forthcoming with funding once phase 2 results are available. “When we have the data, they'll be where I need them to be.”
Producing drugs in situ
As an academic, Lothar Steidler, a molecular biologist at Cork University in Ireland, bypassed many corporate headaches while still moving a live bacteria therapy into clinical trials. The work began about ten years ago when Steidler, then at Belgium's Ghent University, was looking for an inexpensive source of cytokines—soluble protein regulators of the immune system. Steidler and his colleagues acquired all sorts of expression systems to make cytokines in-house, and routinely scanned the literature for more. “We bumped into Lactococcus because I met someone at a conference and he had a nice poster,” says Steidler, who eventually created Lactococcus that secreted human interleukins 2, 6 and 10 (IL-2, IL-6, IL-10) as well as trefoil factors. As a production system the bug was disappointing; its output was a hundredth to a thousandth that of Escherichia coli, says Steidler. “But what immediately struck our minds was that the product was soluble and was fully biologically active.” Most cytokines do not require glycosylation to be active, and so don't need to be made in eukaryotic cells. In Lactococcus cultures, soluble cytokines could be recovered from the supernatant with its secretion leader clipped off correctly. In other words, says Steidler, “The material you got for IL-10 was indistinguishable from the eukaryotic product.” Furthermore, people have safely eaten Lactococcus in cheese and yogurt for thousands of years. Perhaps, Steidler's team thought, patients could safely consume it as a drug.
The technology seemed especially applicable to inflammatory bowel disease, in which the immune system erroneously attacks the gut, causing chronic discomfort and frequent diarrhea. IL-10 tends to quiet the immune system, but administering the cytokine orally is problematic, as its activity is rapidly destroyed by acid in the stomach. Given intravenously, the cytokine spreads through the entire body, where it can actually rouse the immune system. But Lactococcus taken by mouth could travel through the stomach and secrete IL-10 exactly where it was needed, along the intestinal wall. “We're still surprised at the simplicity,” says Steidler. In two separate mouse models of colitis, treatment with the bacteria either prevented disease onset or dramatically reduced its severity1. The mice suffered no obvious adverse effects.
In an unusual move, the University of Amsterdam approached Steidler about putting the bacteria into clinical trials. But the therapy was not ready for people yet. “You can't just release genetically modified bacteria in the environment without precaution,” says Steidler. The research team needed a way to prevent the engineered bacteria from growing outside the body, so they decided to insert IL-10 into the locus normally occupied by the gene for thymidylate synthase2, which is essential for DNA synthesis, and hence required for growth.
The modified Lactococcus can readily absorb thymidine from the nutrient-rich gut, but quickly depletes any available in the environment; its viability decreases about a millionfold within 60 hours after the source of thymidine is removed.
To obtain permission to run trials in Holland, explains Steidler, researchers must publish trial plans in newspapers and the Royal National Library in The Hague. That way the general public can question trials before they start. However, no one raised concerns during that process, he says. Although that may seem surprising, given widespread objection to genetically modified food in Europe, attitudes toward transgenic plants do not predict attitudes toward transgenic therapies.
The technology is currently covered under 45 patents owned by Flanders Inter university Institute for Biotechnology (VIB) of Zwijnaarde, Belgium, which is working with Steidler to commercialize the technology. VIB director Rudy Dekeyser says the group is looking both at corporate partners to collaborate on clinical development, as well as venture capitalists to start a new company.
But even if the technology finds corporate backing, that doesn't mean that other companies developing live bacteria will necessarily have an easier time, says IDC's Melnikova, “It's always hard to be the first, but each individual therapy will be considered on its individual merits.”
Bacteria take on cancer
Several groups are looking for ways to use microbes against cancer, and in fact, the naturally occurring bacteria, bacillus Calmette-Guerin, is standard therapy for a type of bladder cancer. Still most work in this area uses viruses rather than bacteria. Viruses had a head start because they can target specific cells, according to David Bermudes, director of microbiology at Vion in New Haven, Connecticut. Still, he says, bacteria offer several practical advantages. “A virus depends on the cell to deliver its payload. Bacteria are self-contained factories.” Moreover, bacteria can carry more genetic material, be controlled with antibiotics and “are a joy to manufacture compared with viruses.”
Vion has already taken a cancer-fighting bacteria through three phase 1 trials. It chose bacteria for their ability to grow preferentially in tumors, an advantage that molecular biologists were slow to recognize, says Bermudes. The company's genetically modified Salmonella typhimurium makes cancer drugs potent at the site of the tumor, allowing a less toxic prodrug to be administered. As it grows in tumors, the engineered S. typhimurium expresses an E. coli enzyme for cytidine deaminase, which converts nontoxic 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU)3. In mouse studies, the treatment, called TAPET-CD, slowed tumor growth by as much as 95%.
In mice, the bacterium also has some ability to target tumor cells even without cytidine deaminase. Vion tested versions of S. typhimurium lacking the enzyme in phase 1 trials and found that although the bacteria found their way to tumors, the therapy had no antitumor activity. “It was a commercial failure, but a scientific success because you've shown that you can make a bacteria that's safe for systemic administration that targets tumors,” says Bermudes. Human trials with TAPET-CD showed conversion of 5-FC to 5-FU in two of three patients, but were stopped for what Bermudes calls “nonmedical reasons.” Vion is focusing efforts on a small molecule anticancer drug now in phase 2 trials.
Cerus of Concord, California, looked at both viral and bacterial vectors before deciding to engineer Listeria monocytogenes as a cancer vaccine. As one of the deadliest food-borne bacteria, it seems a surprising choice for a vaccine vector, but microbiologists have a long history of finding ways to attenuate pathogens, and L. monocytogenes had key advantages, according to Tom Dubensky, head of vaccine development at Cerus. The bacteria is easy to grow and elicits a potent immune response. Also, unlike many other microbes, it is not neutralized by antibodies, so repeated vaccinations are more likely to be effective. In fact, a clinical trial of 20 healthy volunteers showed that a genetically attenuated strain of L. monocytogenes could still prompt an immune response without serious side effects.
Wild-type L. monocytogenes enters liver cells and spreads from cell to cell by sending bacteria-filled protrusions into neighboring cells, thus avoiding the immune system. Cerus's engineered bacteria lack this ability, but they can still enter antigen-presenting cells and stimulate an immune response4. Although Cerus's first-generation L. monocytogenes works by boosting only innate immunity, researchers have also created a way to stimulate adaptive immunity. “We spent a lot of time learning how to program L. monocytogenes to secrete antigen from the bacterium within the antigen-presenting cell,” recalls Dubensky. The next-generation of L. monocytogenes vectors make mesothelin, a tumor marker present in many ovarian and prostate cancers; Cerus has a joint project with MedImmune of Gaithersburg, Maryland, using its proprietary EphsA2 antigen as well. Cerus hopes to file an investigational new drug application by the end of this year for its first-generation L. monocytogenes against colorectal cancer that has metastasized to the liver. Dubensky expects close scrutiny from the FDA but thinks that for cancer patients that have not benefited from other therapies, the risk-benefit calculations favor experimental therapies. “While there is risk to being the first use in man, these are people for whom there are no other options.”
Bert Vogelstein, an oncologist at Johns Hopkins University in Baltimore, uses a version of Clostridium novyi that lacks the gene to make -toxin. This spore-forming bacteria germinates in oxygen-poor tumors and turns them to mush within18 hours. Ruptured cells from the dying tumor prompt an immune response that trains the immune system to attack remaining cancer cells5. The therapy has been tried in mice, rats, and rabbits; in one in three animals the tumor is destroyed without additional drugs. Odds of vanquishing the tumor improve if anticancer drugs are given as well. Vogelstein thinks the therapy is promising, but is adamant that it is not ready to be tested in humans. Toxicities so far seem acceptable, he says, but the immune response elicited can be so strong that it harms the host.
Cautious yet optimistic
Whether liquifying tumors or pushing out harmful bacteria, live-bacteria therapies can exploit mechanisms impossible for small molecule and protein drugs, and can even be engineered to deliver drugs where the body needs them. But for all this, they present unpredictable and unquantifiable risks. As Vogelstein says, “The agent is new and it's self-replicating. The dose that we give and the dose that we get are not the same.” Vion's Bermudes says skepticism is warranted, but so is hope, particularly for patients who have no other options. “Ten years ago, everybody said antibody therapies don't work. Where are the products? Now there are almost twenty products on the market.”
References
Steidler, L. et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289, 1352–1355 (2000).
Steidler, L. et al. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat. Biotechnol. 21, 1785–1789 (2003).
Nemunaitis, J. et al. Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther. 10, 737–744 (2003).
Brockstedt, D.G. et al. L. monocytogenes-based cancer vaccines that segregate immunogenicity from toxicity. Proc. Natl. Acad. Sci. USA 101, 13832–13837 (2004).
Agrawal, N. et al. Bacteriolytic therapy can generate a potent immune response against experimental tumors. Proc. Natl. Acad. Sci. USA 101, 15172–15177 (2004).
Monya Baker -San Francisco
Genetically engineered bacteria made biotech drugs possible. Now, they are becoming drugs in their own right, Monya Baker reports.
On April 30 this year, two Florida patients received a unique mouth rinse. Using a cotton swab, a dentist painted billions of genetically modified live bacteria of the species Streptococcus mutans onto their pearly whites. If all goes as planned, these bacteria, which lack the gene to make enamel-eroding lactic acid, will replace their naturally occurring, acid-making counterparts, which cause tooth decay.
Besides S. mutans, a number of strains of live bacteria are being developed as therapies. A Lactococcus Lactis strain, engineered to secrete a therapeutic protein, has already been tested in patients with Crohn disease at the University of Amsterdam; in April, trial results were submitted for publication. Also that month, Osel of Santa Clara, California, began phase 2 trials using a proprietary, naturally occurring strain of live Lactobacillus crispatus to treat recurrent urinary tract infection and recurrent bacterial vaginosis. Other academics and companies are exploring genetically modified bacteria against cancer and infectious diseases.
As drugs, bacteria offer several advantages: compared with therapeutic proteins, they are easier to grow, purify and store; although engineering them to express (or not express) a particular gene takes expertise, it needs to be done only once. But along with their convenience and versatility, bacteria reproduce and evolve, making them hard to predict. That creates tricky regulatory issues, and most investors are keeping their distance. But even without venture backing, the field is progressing steadily through the clinic.
Living therapies
The first dose of engineered S. mutans comes two years after the US Food and Drug Administration (FDA) placed Alachua, Florida-based Oragenics' clinical trial on hold for safety concerns. The current seven-day trial requires bacteria with additional engineering. The gene for alanine racemase is deleted, which makes the bacteria dependent on D-alanine for their growth. During the clinical trial, they are supplied with the nutrient in a mouth rinse applied twice-daily. And, just in case the bacteria must be eliminated quickly, all patients enrolled in the trial must wear dentures, which can be removed should problems arise. When the trial is over, patients will rinse their mouths with an antibiotic and be monitored, along with their spouses, for three months.
Oragenics hopes that eventually the bacteria will become a routine part of dentistry, a one-time treatment applied to children's teeth before they start getting cavities. CEO Chuck Soponis acknowledges no one has any specific idea what ill health effects the bacteria might cause. The strain does not make a recombinant protein or displace other species of bacteria living on the tongue and gums. Still, he says, the FDA is right to be cautious. “You're putting a genetically modified bacteria that's going to be in people's mouths for a lifetime, and that hasn't been done before.”
Using live bacteria, or probiotics, to promote health is already common in Japan and becoming increasingly so in Europe. In fact, about 30 probiotic prescription products are sold in Japan. Far more common are products sold without prescriptions as so-called functional foods. The Japanese company Yakult Honsha of Tokyo sells 25 million bottles a day of a fermented milk drink, each one boasting that it contains 8 billion live Lactobacillus casei strain Shirota, which allegedly make for a more healthful gut flora. However, the efficacy of these over-the-counter products is uncertain, and they can't command the high prices of prescription drugs.
Investors hang back
In general, companies seeking funding for live bacteria therapies will have an even harder time finding funding than other biotechnology startups, according to Irena Melnikova, research manager at consulting firm Life Sciences Insights of Framingham, Massachusetts. “This is something very novel,” she says, “and when you start talking about putting live bacteria in humans, there's a negative first reaction.”
In fact, neither Oragenics nor Osel are accessing traditional venture capital (VC) sources to fund their programs. Oragenics went straight to the public markets, listing the company on the Toronto Venture Exchange in June 2003, and moving it to the American Stock Exchange in May last year. Though Osel began in 1998 with money from the founders and has received funding from government agencies including the National Institutes of Health, it has relied mainly on private investors who are not venture capitalists, according to the company's president Ralph Levy. “The VC community does not have a model which our product fits into,” he says. “Small molecules and antibodies, they've seen that; live bacteria they don't understand.”
Oragenics is also pursuing an antibiotic and an over-the-counter probiotic, both stemming from research by the company's CSO and cofounder Jeff Hillman. The probiotic is a proprietary mixture of three naturally occurring bacteria expected to prevent periodontal disease when taken daily. Oragenics plans to partner with larger oral care companies and get the product on the market in Europe and Asia sometime next year and use revenues from probiotics sales to partly finance development of its genetically modified bacteria, which will be marketed as a prescription drug administered by dentists.
Osel's Levy is quick to distance himself from the nonprescription marketplace. He doesn't even like the term 'probiotic.' “The easy route is just manufacturing it and putting it in a store. My market is the physician who's going to write a script to treat a patient,” he says. Levy thinks venture capitalists will be more forthcoming with funding once phase 2 results are available. “When we have the data, they'll be where I need them to be.”
Producing drugs in situ
As an academic, Lothar Steidler, a molecular biologist at Cork University in Ireland, bypassed many corporate headaches while still moving a live bacteria therapy into clinical trials. The work began about ten years ago when Steidler, then at Belgium's Ghent University, was looking for an inexpensive source of cytokines—soluble protein regulators of the immune system. Steidler and his colleagues acquired all sorts of expression systems to make cytokines in-house, and routinely scanned the literature for more. “We bumped into Lactococcus because I met someone at a conference and he had a nice poster,” says Steidler, who eventually created Lactococcus that secreted human interleukins 2, 6 and 10 (IL-2, IL-6, IL-10) as well as trefoil factors. As a production system the bug was disappointing; its output was a hundredth to a thousandth that of Escherichia coli, says Steidler. “But what immediately struck our minds was that the product was soluble and was fully biologically active.” Most cytokines do not require glycosylation to be active, and so don't need to be made in eukaryotic cells. In Lactococcus cultures, soluble cytokines could be recovered from the supernatant with its secretion leader clipped off correctly. In other words, says Steidler, “The material you got for IL-10 was indistinguishable from the eukaryotic product.” Furthermore, people have safely eaten Lactococcus in cheese and yogurt for thousands of years. Perhaps, Steidler's team thought, patients could safely consume it as a drug.
The technology seemed especially applicable to inflammatory bowel disease, in which the immune system erroneously attacks the gut, causing chronic discomfort and frequent diarrhea. IL-10 tends to quiet the immune system, but administering the cytokine orally is problematic, as its activity is rapidly destroyed by acid in the stomach. Given intravenously, the cytokine spreads through the entire body, where it can actually rouse the immune system. But Lactococcus taken by mouth could travel through the stomach and secrete IL-10 exactly where it was needed, along the intestinal wall. “We're still surprised at the simplicity,” says Steidler. In two separate mouse models of colitis, treatment with the bacteria either prevented disease onset or dramatically reduced its severity1. The mice suffered no obvious adverse effects.
In an unusual move, the University of Amsterdam approached Steidler about putting the bacteria into clinical trials. But the therapy was not ready for people yet. “You can't just release genetically modified bacteria in the environment without precaution,” says Steidler. The research team needed a way to prevent the engineered bacteria from growing outside the body, so they decided to insert IL-10 into the locus normally occupied by the gene for thymidylate synthase2, which is essential for DNA synthesis, and hence required for growth.
The modified Lactococcus can readily absorb thymidine from the nutrient-rich gut, but quickly depletes any available in the environment; its viability decreases about a millionfold within 60 hours after the source of thymidine is removed.
To obtain permission to run trials in Holland, explains Steidler, researchers must publish trial plans in newspapers and the Royal National Library in The Hague. That way the general public can question trials before they start. However, no one raised concerns during that process, he says. Although that may seem surprising, given widespread objection to genetically modified food in Europe, attitudes toward transgenic plants do not predict attitudes toward transgenic therapies.
The technology is currently covered under 45 patents owned by Flanders Inter university Institute for Biotechnology (VIB) of Zwijnaarde, Belgium, which is working with Steidler to commercialize the technology. VIB director Rudy Dekeyser says the group is looking both at corporate partners to collaborate on clinical development, as well as venture capitalists to start a new company.
But even if the technology finds corporate backing, that doesn't mean that other companies developing live bacteria will necessarily have an easier time, says IDC's Melnikova, “It's always hard to be the first, but each individual therapy will be considered on its individual merits.”
Bacteria take on cancer
Several groups are looking for ways to use microbes against cancer, and in fact, the naturally occurring bacteria, bacillus Calmette-Guerin, is standard therapy for a type of bladder cancer. Still most work in this area uses viruses rather than bacteria. Viruses had a head start because they can target specific cells, according to David Bermudes, director of microbiology at Vion in New Haven, Connecticut. Still, he says, bacteria offer several practical advantages. “A virus depends on the cell to deliver its payload. Bacteria are self-contained factories.” Moreover, bacteria can carry more genetic material, be controlled with antibiotics and “are a joy to manufacture compared with viruses.”
Vion has already taken a cancer-fighting bacteria through three phase 1 trials. It chose bacteria for their ability to grow preferentially in tumors, an advantage that molecular biologists were slow to recognize, says Bermudes. The company's genetically modified Salmonella typhimurium makes cancer drugs potent at the site of the tumor, allowing a less toxic prodrug to be administered. As it grows in tumors, the engineered S. typhimurium expresses an E. coli enzyme for cytidine deaminase, which converts nontoxic 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU)3. In mouse studies, the treatment, called TAPET-CD, slowed tumor growth by as much as 95%.
In mice, the bacterium also has some ability to target tumor cells even without cytidine deaminase. Vion tested versions of S. typhimurium lacking the enzyme in phase 1 trials and found that although the bacteria found their way to tumors, the therapy had no antitumor activity. “It was a commercial failure, but a scientific success because you've shown that you can make a bacteria that's safe for systemic administration that targets tumors,” says Bermudes. Human trials with TAPET-CD showed conversion of 5-FC to 5-FU in two of three patients, but were stopped for what Bermudes calls “nonmedical reasons.” Vion is focusing efforts on a small molecule anticancer drug now in phase 2 trials.
Cerus of Concord, California, looked at both viral and bacterial vectors before deciding to engineer Listeria monocytogenes as a cancer vaccine. As one of the deadliest food-borne bacteria, it seems a surprising choice for a vaccine vector, but microbiologists have a long history of finding ways to attenuate pathogens, and L. monocytogenes had key advantages, according to Tom Dubensky, head of vaccine development at Cerus. The bacteria is easy to grow and elicits a potent immune response. Also, unlike many other microbes, it is not neutralized by antibodies, so repeated vaccinations are more likely to be effective. In fact, a clinical trial of 20 healthy volunteers showed that a genetically attenuated strain of L. monocytogenes could still prompt an immune response without serious side effects.
Wild-type L. monocytogenes enters liver cells and spreads from cell to cell by sending bacteria-filled protrusions into neighboring cells, thus avoiding the immune system. Cerus's engineered bacteria lack this ability, but they can still enter antigen-presenting cells and stimulate an immune response4. Although Cerus's first-generation L. monocytogenes works by boosting only innate immunity, researchers have also created a way to stimulate adaptive immunity. “We spent a lot of time learning how to program L. monocytogenes to secrete antigen from the bacterium within the antigen-presenting cell,” recalls Dubensky. The next-generation of L. monocytogenes vectors make mesothelin, a tumor marker present in many ovarian and prostate cancers; Cerus has a joint project with MedImmune of Gaithersburg, Maryland, using its proprietary EphsA2 antigen as well. Cerus hopes to file an investigational new drug application by the end of this year for its first-generation L. monocytogenes against colorectal cancer that has metastasized to the liver. Dubensky expects close scrutiny from the FDA but thinks that for cancer patients that have not benefited from other therapies, the risk-benefit calculations favor experimental therapies. “While there is risk to being the first use in man, these are people for whom there are no other options.”
Bert Vogelstein, an oncologist at Johns Hopkins University in Baltimore, uses a version of Clostridium novyi that lacks the gene to make -toxin. This spore-forming bacteria germinates in oxygen-poor tumors and turns them to mush within18 hours. Ruptured cells from the dying tumor prompt an immune response that trains the immune system to attack remaining cancer cells5. The therapy has been tried in mice, rats, and rabbits; in one in three animals the tumor is destroyed without additional drugs. Odds of vanquishing the tumor improve if anticancer drugs are given as well. Vogelstein thinks the therapy is promising, but is adamant that it is not ready to be tested in humans. Toxicities so far seem acceptable, he says, but the immune response elicited can be so strong that it harms the host.
Cautious yet optimistic
Whether liquifying tumors or pushing out harmful bacteria, live-bacteria therapies can exploit mechanisms impossible for small molecule and protein drugs, and can even be engineered to deliver drugs where the body needs them. But for all this, they present unpredictable and unquantifiable risks. As Vogelstein says, “The agent is new and it's self-replicating. The dose that we give and the dose that we get are not the same.” Vion's Bermudes says skepticism is warranted, but so is hope, particularly for patients who have no other options. “Ten years ago, everybody said antibody therapies don't work. Where are the products? Now there are almost twenty products on the market.”
References
Steidler, L. et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289, 1352–1355 (2000).
Steidler, L. et al. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat. Biotechnol. 21, 1785–1789 (2003).
Nemunaitis, J. et al. Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther. 10, 737–744 (2003).
Brockstedt, D.G. et al. L. monocytogenes-based cancer vaccines that segregate immunogenicity from toxicity. Proc. Natl. Acad. Sci. USA 101, 13832–13837 (2004).
Agrawal, N. et al. Bacteriolytic therapy can generate a potent immune response against experimental tumors. Proc. Natl. Acad. Sci. USA 101, 15172–15177 (2004).
Metabasis to Present on CS-917 at the ADA Annual Meeting; Updates Status of CS-917 Development Program
SAN DIEGO, June 13 /PRNewswire-FirstCall/ -- Metabasis Therapeutics(Nasdaq: MBRX), will present at the American Diabetes Association's 65thAnnual Scientific Sessions held in San Diego, June 10-14, 2005. Dr. MarkErion, executive vice president of research and development for Metabasis,will participate in a symposium titled, "New Targets for Glycemic Control."Dr. Erion's presentation is titled, "MB06322 (CS-917): A Potent and SelectiveInhibitor of Fructose 1, 6-Bisphosphatase for Controlling Gluconeogenesis inType 2 Diabetes" and will take place on June 14, 2005. This presentation willdescribe Metabasis' efforts to identify an important new class of compoundswith potential for treating diabetes. Results from preclinical models will bepresented which show that selective gluconeogenesis inhibition has thepotential to be a well-tolerated and effective approach for the treatment ofelevated blood sugar levels that are characteristic of diabetes. The Companywill also present a poster during the meeting entitled, "MB06322, a PotentInhibitor of Gluconeogenesis, Attenuates Hyperglycemia without Causing WeightGain or Hypoglycemia in Female Zucker Diabetic Fatty Rats." Metabasis haslicensed CS-917 to Sankyo Co., Ltd. Sankyo is responsible for the globaldevelopment of the compound. Metabasis also announced an update on the review of CS-917 developmentthat began after two serious adverse events occurred in a drug-druginteraction study conducted in patients with diabetes that combinedadministration of CS-917 with metformin. Metabasis and Sankyo, together andseparately, have carefully reviewed the CS-917 development program. Theseefforts have included a thorough review of the safety and efficacy resultsfrom all studies completed with CS-917 and have involved discussions withmedical, clinical and regulatory experts. While the review at both companiesis continuing, Metabasis and Sankyo have concluded that CS-917 remains aninteresting and potentially important new approach for the treatment ofdiabetes and that further development should resume. Sankyo is responsiblefor conducting the development of CS-917. Decisions regarding the future ofthe product including details and timing of the future development program arestill being discussed and are subject to final approval of Sankyo management.Metabasis expects to provide a further update on the development status ofCS-917 after Sankyo management makes its determinations. Paul Laikind, Chairman, CEO and President of Metabasis stated, "Theconclusion that further development of CS-917 is warranted is a welcome onewith which we fully agree after a careful review of all the availableinformation and discussion with experts. The presentations at the ADA meetingwill highlight the strong potential of this approach. We look forward tocontinuing our fruitful collaboration with Sankyo and to seeing thedevelopment program for CS-917 resume." About Metabasis (http://www.mbasis.com): Metabasis Therapeutics is a biopharmaceutical company focused on thediscovery, development and commercialization of novel small molecule drugsprincipally to treat metabolic diseases, cancer and certain other diseaseslinked to pathways in the liver. Metabasis has established a pipeline thatincludes clinical and preclinical product candidates targeting large marketswith significant unmet medical needs. Metabasis has developed severalproprietary technologies for use in discovering and optimizing drugs,including the NuMimetic and HepDirect technologies. Metabasis is continuingto identify and develop new product candidates using its proprietarytechnologies and expertise. Forward-Looking Statements: Statements in this press release that are not strictly historical innature constitute "forward-looking statements." Such statements include, butare not limited to, references to the efficacy, safety and potential furtherdevelopment of CS-917, as well as the potential and progress of the Company'sother clinical and preclinical compounds. Such forward-looking statementsinvolve known and unknown risks, uncertainties and other factors which maycause Metabasis' actual results to be materially different from historicalresults or from any results expressed or implied by such forward-lookingstatements. These factors include, but are not limited to, risks anduncertainties related to Metabasis' dependence on Sankyo and its otherlicensees and collaborators for the clinical development and registration ofits product candidates, among other things; the progress and timing ofclinical trials for Metabasis' product candidates; serious adverse sideeffects of, or serious adverse events related to, Metabasis' productcandidates or proprietary technologies; difficulties or delays in development,testing, obtaining regulatory approval, producing and marketing Metabasis'product candidates; the potential and progress of preclinical compounds andprograms; and other factors discussed in the "Risk Factors" section ofMetabasis' Annual Report on Form 10-Q for the quarter ended March 31, 2005.All forward-looking statements are qualified in their entirety by thiscautionary statement. Metabasis is providing this information as of this dateof this release and does not undertake any obligation to update any forward-looking statements contained in this release as a result of new information,future events or otherwise.
SOURCE Metabasis Therapeutics, Inc.Web Site: http://www.mbasis.com
SOURCE Metabasis Therapeutics, Inc.Web Site: http://www.mbasis.com
Monsoon boost for ayurveda clinics in Kerala
THIRUVANANTHAPURAM: With the rains lashing Kerala, ayurveda clinics are having a boom time.
Be they big or small, tourist resorts across the state are getting Indian and foreign visitors seeking ayurvedic treatment in large numbers.
Ayurveda is India’s ancient medical science that claims to cure a wide variety of ailments, ranging from the simple cold to even mental diseases. Ayurvedic healing, it is said, is more effective during monsoon when the lack of perspiration helps the body absorb the medicinal oil.
The rains also help the body to relax, it is said.
Ayurveda clinics and resorts offer a simple rejuvenating body massage for as low as Rs250 and charge up to Rs350,000 for an intensive four-week package.
“We are expecting a much better monsoon season compared to previous years. Bookings are on at our six premium properties for ayurvedic packages,” said Jose Dominic, chief of CGH Earth, one of Kerala’s best-known resorts.
“We are getting innumerable inquires and we hope to have an extended monsoon season until August,” he said.
The ayurvedic package includes a simple body massage as well as treatment for the upkeep of the nose, mouth and throat.
The owner of country’s first floating resort at Poovar near Kovalam, M R Narayanan said that business was increasing every year and more and more women were flying in from Europe for rejuvenation, slimming and beauty care.
“Work is fast progressing at our Rs10mn ayurveda spa. We will open it in October,” he said.
The most sought after ayurveda healing system is the simple body massage, which is done by trained masseurs using a variety of herbal oils and powders.
Here too tourists can have a variety. Many go for a soothing massage in the moving ayurveda houseboat of Tomy Pulikattil, who owns a fleet of boats in the Alappuzha river.
“We have a one-day package and can cater to six people on the ayurveda houseboat. The price ranges from Rs750-Rs1,600 for a day depending on the treatment protocol,” said Pulikattil.
During treatment, vegetarian food is recommended. Most resorts have full-fledged ayurvedic kitchens.
While ayurveda is becoming popular, the government is doing its best to ensure that no one takes tourists for a ride. – Indo-Asian News Service
Be they big or small, tourist resorts across the state are getting Indian and foreign visitors seeking ayurvedic treatment in large numbers.
Ayurveda is India’s ancient medical science that claims to cure a wide variety of ailments, ranging from the simple cold to even mental diseases. Ayurvedic healing, it is said, is more effective during monsoon when the lack of perspiration helps the body absorb the medicinal oil.
The rains also help the body to relax, it is said.
Ayurveda clinics and resorts offer a simple rejuvenating body massage for as low as Rs250 and charge up to Rs350,000 for an intensive four-week package.
“We are expecting a much better monsoon season compared to previous years. Bookings are on at our six premium properties for ayurvedic packages,” said Jose Dominic, chief of CGH Earth, one of Kerala’s best-known resorts.
“We are getting innumerable inquires and we hope to have an extended monsoon season until August,” he said.
The ayurvedic package includes a simple body massage as well as treatment for the upkeep of the nose, mouth and throat.
The owner of country’s first floating resort at Poovar near Kovalam, M R Narayanan said that business was increasing every year and more and more women were flying in from Europe for rejuvenation, slimming and beauty care.
“Work is fast progressing at our Rs10mn ayurveda spa. We will open it in October,” he said.
The most sought after ayurveda healing system is the simple body massage, which is done by trained masseurs using a variety of herbal oils and powders.
Here too tourists can have a variety. Many go for a soothing massage in the moving ayurveda houseboat of Tomy Pulikattil, who owns a fleet of boats in the Alappuzha river.
“We have a one-day package and can cater to six people on the ayurveda houseboat. The price ranges from Rs750-Rs1,600 for a day depending on the treatment protocol,” said Pulikattil.
During treatment, vegetarian food is recommended. Most resorts have full-fledged ayurvedic kitchens.
While ayurveda is becoming popular, the government is doing its best to ensure that no one takes tourists for a ride. – Indo-Asian News Service
Exelixis and Helsinn Sign Agreement for XL119 (becatecarin)
SOUTH SAN FRANCISCO, and LUGANO, Switzerland, June 13 /PRNewswire/ -- Exelixis, Inc. (Nasdaq: EXEL - News) and Helsinn Healthcare S.A. reached an agreement for the development of XL119 (becatecarin). Under the terms of the agreement, Helsinn will pay Exelixis an upfront payment of $4 million and additional milestones up to $21 million. In addition, Helsinn will assume the cost of the Phase III program going forward. In return, Exelixis has granted to Helsinn a world-wide, royalty-bearing license to XL119. Exelixis has retained rights to reacquire commercial rights to XL119 for North America, and will receive milestones and royalties on sales in the rest of the world.
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"We are gratified that we have found an excellent partner for the development of XL119," said George A. Scangos, Ph.D., president and chief executive officer of Exelixis. "Helsinn is a high-quality company with experience in cancer drug development, as demonstrated by their successful development and licensing of Aloxi® to MGI Pharma. By combining our resources with those of an excellent European partner, we hope to make XL119 available to patients in need around the world. This agreement will free up substantial financial and product development resources, allowing Exelixis to focus on the Phase I and II trials for our internally developed pipeline. At the same time, we have structured this deal with rights to reacquire the commercial rights to XL119 for North America, which is our primary market. I believe that this is an excellent transaction and represents a win for both companies," said Dr. Scangos.
"Exelixis has a very strong scientific foundation and we are pleased to be in a partnership with such a company," said Enrico Braglia, Managing Director of Helsinn. "Through the development of XL119, we aim to create a new standard of care for patients with biliary tract cancers, a rare and aggressive form of cancer with a high medical need and very limited survival. While some existing therapies have been used off-label to treat this type of tumor, there is currently no drug therapy that has been approved by regulatory authorities for this indication. We believe that XL119 will offer a meaningful therapeutic benefit over currently used therapies and will become the therapy of reference for biliary tract cancer patients worldwide."
XL119 is currently in a multi-national Phase III clinical trial at approximately 50 centers in North America and Europe. The primary endpoint of the 600-patient trial is increased survival of patients with bile duct tumors treated with XL119 compared with the chemotherapy agents 5-fluorouracil (FU) and leucovorin. The trial is currently recruiting and enrolling patients as anticipated and is on track to be completed as planned. XL119 was granted the Orphan Drug designation in the USA on March 1, 2004.
Conference Call and Webcast
Exelixis' management will discuss this agreement and other business developments during a conference call beginning at 5:30 a.m. PDT / 8:30 a.m. EDT today, Monday, June 13, 2005. To listen to the discussion, please visit the Webcast section under Investor Information on the Exelixis website at http://www.exelixis.com or http://www.vcall.com/CEPage.asp?ID=92376 .
About Exelixis
Exelixis, Inc. is a leading genomics-based drug discovery company dedicated to the discovery and development of novel therapeutics across various disease areas. The company is leveraging its fully integrated gene-to-drug platform to fuel the growth of its proprietary drug pipeline. Exelixis' development pipeline covers cancer and metabolism and is comprised of the following compounds: XL784, initially an anticancer compound, which completed a Phase I clinical trial and is being developed as a treatment for renal disease; XL647, XL999 and XL880, anticancer compounds currently in Phase I clinical trials; XL820 and XL844, anticancer compounds for which INDs have been filed; XL184 a potential IND candidate for the treatment of cancer; and multiple compounds in preclinical development for diseases including cancer and various metabolic and cardiovascular disorders. Exelixis has established broad corporate alliances with major pharmaceutical and biotechnology companies including GlaxoSmithKline (GSK) and Bristol-Myers Squibb Company. Pursuant to a product development and commercialization agreement between Exelixis and GSK, GSK has the option, after completion of Phase IIa clinical trials, to elect to develop a certain number of compounds in Exelixis' product pipeline, which may include the cancer compounds identified in this press release (other than XL119), thus potentially triggering milestone payments and royalties from GSK and co-promotion rights by Exelixis. For more information, please visit the company's web site at http://www.exelixis.com.
About HELSINN HEALTHCARE
HELSINN HEALTHCARE SA is a privately owned pharmaceutical group with headquarters in Switzerland. Helsinn's core business is the licensing of pharmaceuticals in niche therapeutic areas. The company's business strategy is to in-license early-stage new chemical entities and complete their development from the performance of pre-clinical/clinical studies and CMC development to the attainment of market approvals in strategic markets (U.S. and Europe). HELSINN's products are eventually out-licensed to its marketing partners for distribution. The active pharmaceutical ingredients and the finished dosage forms are manufactured at HELSINN's cGMP facilities and supplied worldwide to its customers. For more information about HELSINN, please visit http://www.helsinn.com.
This press release contains forward-looking statements, including without limitation all statements related to Exelixis' potential to receive future payments related to the clinical development program for XL119, the potential success of the XL119 Phase III trial, the therapeutic and commercial potential of XL784, XL647, XL880, XL999, XL820, XL844 and XL184, other compounds in the Exelixis preclinical pipeline and its program in metabolic diseases. Words such as "believes," "anticipates," "plans," "expects," "intend," "will," "slated," "goal" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Exelixis' current expectations. Forward-looking statements involve risks and uncertainties. Exelixis' actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, the ability of the company to successfully conduct the clinical trials for XL784, XL647, XL880, XL999, XL820 and XL844; the ability of the company to advance additional preclinical compounds into clinical development; the uncertainty of the FDA approval process; and the therapeutic and commercial value of the company's compounds. These and other risk factors are discussed under "Risk Factors" and elsewhere in our quarterly report on Form 10-Q for the quarter ended March 31, 2005 and other filings with the Securities and Exchange Commission.. Exelixis expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in the company's expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.
Exelixis and the Exelixis logo are registered U.S. trademarks.
Source: Exelixis, Inc.
This guide can help you:Evaluate investment adviceUse advice to reach your goalsBe confident that the advice you get is in your best interest* We respect your privacy. By submitting your information,you consent to Schwab using the information you provide to communicate with you and provide more information about products and services.
"We are gratified that we have found an excellent partner for the development of XL119," said George A. Scangos, Ph.D., president and chief executive officer of Exelixis. "Helsinn is a high-quality company with experience in cancer drug development, as demonstrated by their successful development and licensing of Aloxi® to MGI Pharma. By combining our resources with those of an excellent European partner, we hope to make XL119 available to patients in need around the world. This agreement will free up substantial financial and product development resources, allowing Exelixis to focus on the Phase I and II trials for our internally developed pipeline. At the same time, we have structured this deal with rights to reacquire the commercial rights to XL119 for North America, which is our primary market. I believe that this is an excellent transaction and represents a win for both companies," said Dr. Scangos.
"Exelixis has a very strong scientific foundation and we are pleased to be in a partnership with such a company," said Enrico Braglia, Managing Director of Helsinn. "Through the development of XL119, we aim to create a new standard of care for patients with biliary tract cancers, a rare and aggressive form of cancer with a high medical need and very limited survival. While some existing therapies have been used off-label to treat this type of tumor, there is currently no drug therapy that has been approved by regulatory authorities for this indication. We believe that XL119 will offer a meaningful therapeutic benefit over currently used therapies and will become the therapy of reference for biliary tract cancer patients worldwide."
XL119 is currently in a multi-national Phase III clinical trial at approximately 50 centers in North America and Europe. The primary endpoint of the 600-patient trial is increased survival of patients with bile duct tumors treated with XL119 compared with the chemotherapy agents 5-fluorouracil (FU) and leucovorin. The trial is currently recruiting and enrolling patients as anticipated and is on track to be completed as planned. XL119 was granted the Orphan Drug designation in the USA on March 1, 2004.
Conference Call and Webcast
Exelixis' management will discuss this agreement and other business developments during a conference call beginning at 5:30 a.m. PDT / 8:30 a.m. EDT today, Monday, June 13, 2005. To listen to the discussion, please visit the Webcast section under Investor Information on the Exelixis website at http://www.exelixis.com or http://www.vcall.com/CEPage.asp?ID=92376 .
About Exelixis
Exelixis, Inc. is a leading genomics-based drug discovery company dedicated to the discovery and development of novel therapeutics across various disease areas. The company is leveraging its fully integrated gene-to-drug platform to fuel the growth of its proprietary drug pipeline. Exelixis' development pipeline covers cancer and metabolism and is comprised of the following compounds: XL784, initially an anticancer compound, which completed a Phase I clinical trial and is being developed as a treatment for renal disease; XL647, XL999 and XL880, anticancer compounds currently in Phase I clinical trials; XL820 and XL844, anticancer compounds for which INDs have been filed; XL184 a potential IND candidate for the treatment of cancer; and multiple compounds in preclinical development for diseases including cancer and various metabolic and cardiovascular disorders. Exelixis has established broad corporate alliances with major pharmaceutical and biotechnology companies including GlaxoSmithKline (GSK) and Bristol-Myers Squibb Company. Pursuant to a product development and commercialization agreement between Exelixis and GSK, GSK has the option, after completion of Phase IIa clinical trials, to elect to develop a certain number of compounds in Exelixis' product pipeline, which may include the cancer compounds identified in this press release (other than XL119), thus potentially triggering milestone payments and royalties from GSK and co-promotion rights by Exelixis. For more information, please visit the company's web site at http://www.exelixis.com.
About HELSINN HEALTHCARE
HELSINN HEALTHCARE SA is a privately owned pharmaceutical group with headquarters in Switzerland. Helsinn's core business is the licensing of pharmaceuticals in niche therapeutic areas. The company's business strategy is to in-license early-stage new chemical entities and complete their development from the performance of pre-clinical/clinical studies and CMC development to the attainment of market approvals in strategic markets (U.S. and Europe). HELSINN's products are eventually out-licensed to its marketing partners for distribution. The active pharmaceutical ingredients and the finished dosage forms are manufactured at HELSINN's cGMP facilities and supplied worldwide to its customers. For more information about HELSINN, please visit http://www.helsinn.com.
This press release contains forward-looking statements, including without limitation all statements related to Exelixis' potential to receive future payments related to the clinical development program for XL119, the potential success of the XL119 Phase III trial, the therapeutic and commercial potential of XL784, XL647, XL880, XL999, XL820, XL844 and XL184, other compounds in the Exelixis preclinical pipeline and its program in metabolic diseases. Words such as "believes," "anticipates," "plans," "expects," "intend," "will," "slated," "goal" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Exelixis' current expectations. Forward-looking statements involve risks and uncertainties. Exelixis' actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, the ability of the company to successfully conduct the clinical trials for XL784, XL647, XL880, XL999, XL820 and XL844; the ability of the company to advance additional preclinical compounds into clinical development; the uncertainty of the FDA approval process; and the therapeutic and commercial value of the company's compounds. These and other risk factors are discussed under "Risk Factors" and elsewhere in our quarterly report on Form 10-Q for the quarter ended March 31, 2005 and other filings with the Securities and Exchange Commission.. Exelixis expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in the company's expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.
Exelixis and the Exelixis logo are registered U.S. trademarks.
Source: Exelixis, Inc.
Multiple Second-Generation Antisense Drugs Show Potential as New Treatments for Diabetes and Metabolic Disease
Isis Pharmaceuticals and Partners Present Preclinical Research From Broad Antisense Drug Discovery Programs Targeting Metabolic Disease at ADA
CARLSBAD, Calif., June 13 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. (Nasdaq: ISIS - News) announced today results from fourteen preclinical studies demonstrating potent, selective antisense inhibitors of gene targets, directly associated with therapeutic potential in a variety of preclinical models of metabolic diseases, including diabetes, non-alcoholic fatty liver disease (NASH) and metabolic syndrome. Findings from the studies were presented by Isis and several collaborators this week during the American Diabetes Association's (ADA) 65th Scientific Sessions in San Diego.
"Data presented this week demonstrate the strong potential of second-generation antisense drugs for metabolic disease. The data show the specificity, efficiency and versatility of second-generation antisense oligonucleotides to rapidly validate novel targets in vivo. This unique advantage of antisense allows us to select the best targets and drugs for drug development. Furthermore, since several of these molecular targets (such as phosphatases and transcription factors) are difficult to inhibit selectively with small molecules, we have a unique drug development opportunity to advance antisense drugs as innovative treatments for metabolic disorders," said C. Frank Bennett, Ph.D., Vice President, Antisense Research at Isis Pharmaceuticals.
This sentiment was echoed by two internationally recognized diabetes experts and Isis collaborators, Dr. Gerald Shulman from Yale University and Dr. Luciano Rossetti from the Albert Einstein College of Medicine, Bronx, New York. "Using Isis' potent antisense inhibitors, we were able to investigate the role of several molecular targets in animal models of diabetes and we identified a critical target that results in the inability of insulin to inhibit excessive glucose release by the liver in obese and insulin resistant rodents," said Dr. Luciano Rossetti, M.D., Professor of Medicine and Molecular Pharmacology and Director, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY. "The Isis antisense inhibitors reduced the expression of this gene in the liver and completely restored normal hepatic insulin action."
"Over the past year, we have evaluated over a dozen of Isis' second-generation antisense oligonucleotides designed to target a variety of genes. Through these efforts we have identified several exciting targets, the inhibition of which prevents the development of fatty liver and fat induced insulin-resistance," said Dr. Gerald Shulman, M.D., Ph.D., Professor of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine. "Antisense inhibitors against these targets have great therapeutic potential for type 2 diabetes, obesity and fatty liver disease."
Key Presentations at the ADA:
Targeting Enzymes Involved in Intermediary Lipid Metabolism
In several presentations, optimized antisense inhibitors against key genes involved in intermediary lipid metabolism were evaluated in obese and diabetic animals that had a fatty liver and were insulin resistant. Inhibition of several genes, such as stearoyl-CoA desaturase 1 (SCD-1), acetyl-CoA carboxylases 1 (ACC1) and diacylglycerol acyltransferase 2 (DGAT2) resulted in decreased fat synthesis, increased fat oxidation (burning) and a clearing of fat in the liver. Since antisense oligonucleotides cause specific reduction of these enzymes in the liver and fat, side effects associated with antagonism of these enzymes in other key tissues such as the pancreas and brain were not observed. DGAT2, an enzyme involved in fat synthesis, emerged as one of the most promising targets for future antisense drug development.
Discovery of Novel Phosphatases as Drug Targets for Type 2 Diabetes
Using second-generation antisense oligonucleotides, Isis scientists evaluated more than twenty protein tyrosine phosphatases (PTPases) in animal models of diabetes and obesity. PTPases negatively regulate various cell signaling pathways, including pathways that mediate insulin action. However, traditional small molecule approaches to inhibit phosphatase targets are severely limited due to their lack of specificity. In contrast, specific targeting of phosphatases with antisense technology is a very effective approach to inhibit these targets very selectively. Data were presented demonstrating marked glucose lowering effects of specific antisense oligonucleotides that reduced hepatic expression of several novel phosphatases. Further, reduction of the expression of some of these phosphatases in the liver improved signaling via the insulin receptor and important post-receptor insulin-signaling enzymes. These phosphatases are distinct from protein tyrosine phosphatase-1 (PTP-1B), for which Isis has an antisense drug in Phase 2 clinical trials.
Additional presentations demonstrated glucose lowering effects and improvements in insulin sensitivity in animal models after reduction of hepatic expression of two transcription factors, Foxo1 (also known as Forkhead) and Carbohydrate Response Element Binding Protein (ChREBP), with antisense drugs. These exciting targets are also difficult to selectively inhibit with small molecules. The presentations further exemplify the versatility of the antisense approach for drug discovery and development.
Finally, Isis scientists presented data showing robust glucose lowering effects after reduction of the expression of renal sodium glucose transporter 2 (SGLT2) with an antisense drug optimized to target the kidney. The drug was extremely potent in inhibiting the target and caused greater than 80% reduction in SGLT2 expression at a dose less than 2 mg/kg/week, demonstrating about a 30-fold increase in potency compared to the standard phosphorothioate ASOs. This decrease in SGLT2 expression was accompanied by significant glucose lowering in several severely diabetic animal models including ob/ob and db/db mice.
ABOUT ISIS PHARMACEUTICALS, INC.
Isis Pharmaceuticals, Inc. is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 11 antisense drugs in development to treat metabolic, cardiovascular and inflammatory diseases, and cancer. In its Ibis division, Isis is developing and commercializing the TIGER biosensor system, a system that has the potential to revolutionize the identification of infectious organisms. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of more than 1,500 issued patents worldwide. Additional information about Isis is available at http://www.isispharm.com.
This press release includes forward-looking statements regarding the development, therapeutic potential and safety of Isis' antisense drugs and in the treatment of metabolic diseases. Any statement describing our goals, expectations, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement, including those statements that are described as Isis' goals. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing, and commercializing drugs that are safe and effective for use as human therapeutics and in the endeavor of building a business around such products. Our forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause our results to differ materially from those expressed or implied by such forward-looking statements. Although our forward-looking statements reflect the good faith judgment of our management, these statements are based only on facts and factors currently known by us. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' programs are described in additional detail on Form 10-K for the year ended December 31, 2004, and quarterly report on Form 10-Q for the quarter ended March 31, 2005, which are on file with the SEC. Copies of these and other documents are available from the Company.
Source: Isis Pharmaceuticals, Inc.
CARLSBAD, Calif., June 13 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. (Nasdaq: ISIS - News) announced today results from fourteen preclinical studies demonstrating potent, selective antisense inhibitors of gene targets, directly associated with therapeutic potential in a variety of preclinical models of metabolic diseases, including diabetes, non-alcoholic fatty liver disease (NASH) and metabolic syndrome. Findings from the studies were presented by Isis and several collaborators this week during the American Diabetes Association's (ADA) 65th Scientific Sessions in San Diego.
"Data presented this week demonstrate the strong potential of second-generation antisense drugs for metabolic disease. The data show the specificity, efficiency and versatility of second-generation antisense oligonucleotides to rapidly validate novel targets in vivo. This unique advantage of antisense allows us to select the best targets and drugs for drug development. Furthermore, since several of these molecular targets (such as phosphatases and transcription factors) are difficult to inhibit selectively with small molecules, we have a unique drug development opportunity to advance antisense drugs as innovative treatments for metabolic disorders," said C. Frank Bennett, Ph.D., Vice President, Antisense Research at Isis Pharmaceuticals.
This sentiment was echoed by two internationally recognized diabetes experts and Isis collaborators, Dr. Gerald Shulman from Yale University and Dr. Luciano Rossetti from the Albert Einstein College of Medicine, Bronx, New York. "Using Isis' potent antisense inhibitors, we were able to investigate the role of several molecular targets in animal models of diabetes and we identified a critical target that results in the inability of insulin to inhibit excessive glucose release by the liver in obese and insulin resistant rodents," said Dr. Luciano Rossetti, M.D., Professor of Medicine and Molecular Pharmacology and Director, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY. "The Isis antisense inhibitors reduced the expression of this gene in the liver and completely restored normal hepatic insulin action."
"Over the past year, we have evaluated over a dozen of Isis' second-generation antisense oligonucleotides designed to target a variety of genes. Through these efforts we have identified several exciting targets, the inhibition of which prevents the development of fatty liver and fat induced insulin-resistance," said Dr. Gerald Shulman, M.D., Ph.D., Professor of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine. "Antisense inhibitors against these targets have great therapeutic potential for type 2 diabetes, obesity and fatty liver disease."
Key Presentations at the ADA:
Targeting Enzymes Involved in Intermediary Lipid Metabolism
In several presentations, optimized antisense inhibitors against key genes involved in intermediary lipid metabolism were evaluated in obese and diabetic animals that had a fatty liver and were insulin resistant. Inhibition of several genes, such as stearoyl-CoA desaturase 1 (SCD-1), acetyl-CoA carboxylases 1 (ACC1) and diacylglycerol acyltransferase 2 (DGAT2) resulted in decreased fat synthesis, increased fat oxidation (burning) and a clearing of fat in the liver. Since antisense oligonucleotides cause specific reduction of these enzymes in the liver and fat, side effects associated with antagonism of these enzymes in other key tissues such as the pancreas and brain were not observed. DGAT2, an enzyme involved in fat synthesis, emerged as one of the most promising targets for future antisense drug development.
Discovery of Novel Phosphatases as Drug Targets for Type 2 Diabetes
Using second-generation antisense oligonucleotides, Isis scientists evaluated more than twenty protein tyrosine phosphatases (PTPases) in animal models of diabetes and obesity. PTPases negatively regulate various cell signaling pathways, including pathways that mediate insulin action. However, traditional small molecule approaches to inhibit phosphatase targets are severely limited due to their lack of specificity. In contrast, specific targeting of phosphatases with antisense technology is a very effective approach to inhibit these targets very selectively. Data were presented demonstrating marked glucose lowering effects of specific antisense oligonucleotides that reduced hepatic expression of several novel phosphatases. Further, reduction of the expression of some of these phosphatases in the liver improved signaling via the insulin receptor and important post-receptor insulin-signaling enzymes. These phosphatases are distinct from protein tyrosine phosphatase-1 (PTP-1B), for which Isis has an antisense drug in Phase 2 clinical trials.
Additional presentations demonstrated glucose lowering effects and improvements in insulin sensitivity in animal models after reduction of hepatic expression of two transcription factors, Foxo1 (also known as Forkhead) and Carbohydrate Response Element Binding Protein (ChREBP), with antisense drugs. These exciting targets are also difficult to selectively inhibit with small molecules. The presentations further exemplify the versatility of the antisense approach for drug discovery and development.
Finally, Isis scientists presented data showing robust glucose lowering effects after reduction of the expression of renal sodium glucose transporter 2 (SGLT2) with an antisense drug optimized to target the kidney. The drug was extremely potent in inhibiting the target and caused greater than 80% reduction in SGLT2 expression at a dose less than 2 mg/kg/week, demonstrating about a 30-fold increase in potency compared to the standard phosphorothioate ASOs. This decrease in SGLT2 expression was accompanied by significant glucose lowering in several severely diabetic animal models including ob/ob and db/db mice.
ABOUT ISIS PHARMACEUTICALS, INC.
Isis Pharmaceuticals, Inc. is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 11 antisense drugs in development to treat metabolic, cardiovascular and inflammatory diseases, and cancer. In its Ibis division, Isis is developing and commercializing the TIGER biosensor system, a system that has the potential to revolutionize the identification of infectious organisms. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of more than 1,500 issued patents worldwide. Additional information about Isis is available at http://www.isispharm.com.
This press release includes forward-looking statements regarding the development, therapeutic potential and safety of Isis' antisense drugs and in the treatment of metabolic diseases. Any statement describing our goals, expectations, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement, including those statements that are described as Isis' goals. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing, and commercializing drugs that are safe and effective for use as human therapeutics and in the endeavor of building a business around such products. Our forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause our results to differ materially from those expressed or implied by such forward-looking statements. Although our forward-looking statements reflect the good faith judgment of our management, these statements are based only on facts and factors currently known by us. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' programs are described in additional detail on Form 10-K for the year ended December 31, 2004, and quarterly report on Form 10-Q for the quarter ended March 31, 2005, which are on file with the SEC. Copies of these and other documents are available from the Company.
Source: Isis Pharmaceuticals, Inc.
Bentley Pharmaceuticals, Inc. Presents Results of Initial Phase II Intranasal Insulin
Study at the June 2005 ADA Meeting; Study Shows More Rapid Absorption and Higher Peak Levels Than Subcutaneous Insulin EXETER, N.H.--(BUSINESS WIRE)--June 13, 2005--Bentley Pharmaceuticals, Inc. (NYSE: BNT), a technology-based specialty pharmaceutical and drug delivery company with a growing branded and generic product line in Europe, today announced that it presented the results of its initial Phase II study in Type I diabetic patients entitled "Intranasal Insulin Administration in Type I Diabetic Patients Utilizing CPE-215 Technology" at a poster session of the American Diabetic Association meeting on June 11, 2005 in San Diego, California. Seven patients were studied at the Shandon Clinic and the Department of Clinical Pharmacology at the University of Cork, in Cork, Ireland.
Bentley's intranasal formulation demonstrated more rapid absorption and higher peak levels than subcutaneous insulin. It blunted post-prandial hyperglycemia for over two hours. Calculated relative bioavailability (amount of total dose absorbed) as compared to subcutaneous insulin was 15-20%, which is greater than that of most reported studies of inhaled insulin formulations. Further development work is planned.
Jim Murphy, President and CEO commented, "While we are still in the initial phases of our intranasal insulin studies, we believe that the demonstrated characteristics of rapid onset of action and greater than two hour suppression of post-prandial hyperglycemia are indications that our formulation may be useful in the treatment of diabetes. We believe that many diabetic patients would prefer an intranasal application of insulin, specifically those patients who are averse to multiple daily injections, and this would lead to increased compliance with treatment regimens."
Bentley Pharmaceuticals, Inc. is a specialty pharmaceutical company focused on advanced drug delivery technologies and pharmaceutical products. Bentley's proprietary drug technologies are designed to enhance or facilitate the absorption of pharmaceutical compounds across various membranes. Bentley also manufactures and markets a growing portfolio of generic and branded pharmaceuticals in Europe for the treatment of cardiovascular, gastrointestinal, infectious and neurological diseases through its subsidiaries, Laboratorios Belmac, Laboratorios Davur and Laboratorios Rimafar; and manufactures and markets active pharmaceutical ingredients through its subsidiary, Bentley API.
Copies of Bentley Pharmaceuticals' press releases and other information may be obtained through Bentley's web site at www.bentleypharm.com.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This press release contains forward looking statements, including without limitation, statements regarding the therapeutic potential of Bentley's intranasal insulin formulation. These forward-looking statements are subject to a number of risks and uncertainties that could cause actual results to differ materially from future results expressed or implied by such statements. Factors that may cause such differences include, but are not limited to risks associated with the timing and results of clinical trials, efficacy and safety of our products in development, competition from other manufacturers of generic and proprietary pharmaceuticals, technological changes, and other uncertainties detailed in Bentley's most recent Annual Report on Form 10-K and its other subsequent periodic reports filed with the Securities and Exchange Commission. Bentley cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this document, and Bentley undertakes no obligation to update or revise the statements, except as may be required by law.
Contacts
Bentley Pharmaceuticals, Inc. Michael D. Price, 603-658-6100www.bentleypharm.com or Porter, Le Vay & Rose, Inc.Investor Relations Contacts: Linda Decker, V.P. - Investor Relations Jeff Myhre, V.P. - Editorial 212-564-4700or Tom Gibson - Media Relations
Bentley's intranasal formulation demonstrated more rapid absorption and higher peak levels than subcutaneous insulin. It blunted post-prandial hyperglycemia for over two hours. Calculated relative bioavailability (amount of total dose absorbed) as compared to subcutaneous insulin was 15-20%, which is greater than that of most reported studies of inhaled insulin formulations. Further development work is planned.
Jim Murphy, President and CEO commented, "While we are still in the initial phases of our intranasal insulin studies, we believe that the demonstrated characteristics of rapid onset of action and greater than two hour suppression of post-prandial hyperglycemia are indications that our formulation may be useful in the treatment of diabetes. We believe that many diabetic patients would prefer an intranasal application of insulin, specifically those patients who are averse to multiple daily injections, and this would lead to increased compliance with treatment regimens."
Bentley Pharmaceuticals, Inc. is a specialty pharmaceutical company focused on advanced drug delivery technologies and pharmaceutical products. Bentley's proprietary drug technologies are designed to enhance or facilitate the absorption of pharmaceutical compounds across various membranes. Bentley also manufactures and markets a growing portfolio of generic and branded pharmaceuticals in Europe for the treatment of cardiovascular, gastrointestinal, infectious and neurological diseases through its subsidiaries, Laboratorios Belmac, Laboratorios Davur and Laboratorios Rimafar; and manufactures and markets active pharmaceutical ingredients through its subsidiary, Bentley API.
Copies of Bentley Pharmaceuticals' press releases and other information may be obtained through Bentley's web site at www.bentleypharm.com.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This press release contains forward looking statements, including without limitation, statements regarding the therapeutic potential of Bentley's intranasal insulin formulation. These forward-looking statements are subject to a number of risks and uncertainties that could cause actual results to differ materially from future results expressed or implied by such statements. Factors that may cause such differences include, but are not limited to risks associated with the timing and results of clinical trials, efficacy and safety of our products in development, competition from other manufacturers of generic and proprietary pharmaceuticals, technological changes, and other uncertainties detailed in Bentley's most recent Annual Report on Form 10-K and its other subsequent periodic reports filed with the Securities and Exchange Commission. Bentley cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this document, and Bentley undertakes no obligation to update or revise the statements, except as may be required by law.
Contacts
Bentley Pharmaceuticals, Inc. Michael D. Price, 603-658-6100www.bentleypharm.com or Porter, Le Vay & Rose, Inc.Investor Relations Contacts: Linda Decker, V.P. - Investor Relations Jeff Myhre, V.P. - Editorial 212-564-4700or Tom Gibson - Media Relations
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