Overview

Satiogen Pharmaceuticals has discovered a metabolic mechanism of action – termed “the bile acid brake” – that is a novel target for treating type 2 diabetes and obesity without intervention by systemically absorbed pharmaceuticals or invasive surgical methods.  Preclinical experiments testing several drugable concepts have demonstrated metabolic effects comparable to marketed drugs, and a clinical study has extended these findings to humans. Preclinical experiments are also underway with a non-surgical device designed to replicate the benefits of gastric bypass surgery.  Since starting in 2007 Satiogen has operated as a virtual company focused on demonstrating proof-of-concept and crafting a patent estate.  The company is aiming to out-license specific product concepts for commercial development, and the first of such licenses has been extended to Lumena Pharmaceuticals, which is focused on clinical development of a pill for treating diabetes and obesity.

The bile acid brake is a metabolic regulatory mechanism which potently suppresses food intake and plasma glucose when excessive amounts of bile acids arrive in the colon and rectum.  These bile acids are ligands for intralumenal G-protein coupled bile acid receptors on colorectal L-cells which secrete multiple metabolic hormones that regulate satiety and glucose homeostasis via mechanisms predicted to be cardioprotective.  This intralumenal, nonsystemic mechanism of action offers important safety advantages for therapeutic products:  non-absorbed drugs are intrinsically safer than drugs which must be systemically bioavailable, and a device for diverting biliary secretions could be inserted using a non-surgical medical procedure.

Satiogen has focused its efforts on two activities: research on three product concepts, including two drugable ideas and a medical device, and crafting a patent portfolio that will control freedom to operate in these product areas.  Judging from recent publication trends, many researchers are now beginning to understand key parts of Satiogen’s therapeutic concepts, and the company’s presentations were warmly received at the 2010 meetings of the American Diabetes Association and the European Association for the Study of Diabetes.  Having found a home for its leading drug candidate, Satiogen is now focused on finding a development partner for its device concept.


OVERVIEW OF SATIOGEN’S PRODUCT OPPORTUNITIES

The markets for devices and drugs to treat T2D and obesity (“diabesity”) are large and growing around the globe, but they have been graveyards for numerous, expensive product failures.  Satiogen believes new product ideas must be judged against four key factors for success, and that its discovery of the bile acid brake meets these criteria as an attractive therapeutic target:

         Long-term efficacy:  To permanently intervene in the pathophysiology of diabesity, products need to alter the set points of multiple metabolic hormone signals that control eating behavior and glucose homeostasis.  The bile acid brake activates circulating levels of three hormones known to exert powerful satiagenic and incretin effects.

         Squeaky clean safety:  To achieve regulatory approval, diabesity products must clear a high bar of safety.  The bile acid brake can be activated by non-systemic intervention strategies, and the resulting hormonal response can be expected to lower CV risk without introducing the risk of hypoglycemia.

         Acceptable tolerability:  To enjoy market acceptance among caregivers and patients, diabesity products must be easy to use and their benefits must clearly outweigh side effects in the minds of patients and prescribers.  Satiogen’s top priority for pharmacological intervention would be an orally active pill, and the company’s proposed device would be inserted without invasive surgery.

      Competitive cost-effectiveness:  To receive reimbursement in an increasingly tight financial landscape, diabesity products will need to offer quantifiable cost-benefit advantages over alternative modalities.  The product designs for targeting the bile acid brake present no cost-of-goods challenges, and for certain strategies the R&D investment could be modest relative to other therapeutic targets.


The bile acid brake is an important physiological regulator of body weight and glucose homeostasis intrinsic to the gastrointestinal system:

         L-cells are important metabolic regulators:  This population of cells, ubiquitous throughout the body, secretes three metabolic hormones that are known to have satiagenic and incretin effects:  GLP-1, PYY, and oxyntomodulin, which are independently the subject of clinical research and development aimed at intervening in diabesity.

         Bile acids are stimulators of L-cell activity:  Bile acids are ligands for TGR5 receptors which activate L-cell secretion.  This discovery in 2003 expanded the role of bile acids from being viewed as just digestive surfactants to being studied as hormonal signaling mechanisms for regulating blood glucose and body weight.

         Lumenal L-cells are most prevalent in the colon-rectum:  Gastrointestinal L-cells receive bile acid signaling from within the lumen of the gut, and the tissue concentration of these L-cells increases 100-fold from the duodenum to the rectum.
 
         Elevations in colorectal bile acids activate satiagenic and incretin hormones:  To prevent fecal excretion of bile acids, their arrival in the colon-rectum exerts a strong secretory effect on luminal L-cells.  This activation raises blood concentrations of the satiagenic and incretin hormones which slow down nutrient transit and amplify insulin response.


Satiogen believes that this “bile acid brake” is an important feedback loop which minimizes fecal excretion of bile acids not reabsorbed into systemic circulation before entering the large intestine.  When fecal bile acids are detected, multiple hormonal signals shut down the urge to eat, slow nutrient passage through the gut, and enhance insulin response to rising blood glucose.

Satiogen has confirmed this effect in preclinical animal models by using rectal administration of bile acids and by blocking bile acid transport from the ileum.  In a small study of obese T2D patients, rectal instillation of taurocholic acid stimulated release of GLP-1 and PYY in sufficient quantities to reduce food intake, and the release of GLP-1 was sufficient to stimulate insulin secretion and reduce circulating glucose concentrations.

To harness the bile acid brake for treating diabesity, Satiogen has defined six product strategies:

      Non-absorbed ASBT inhibitor:  Block active bile acid transport out of the ileum with an oral drug that is not absorbed.

      Non-surgical biliary shunt:  Install a device to divert a therapeutically effective amount of bile acid into the colon.

      Rectal satiagen:  Deliver bile acid to the rectum via suppository or gel.

      Non-absorbed TGR5 ligand:  Activate colorectal L-cells with an oral drug that is not absorbed.

      Labile bile acid sequestrant:  Use an orally administered polymer that binds bile acid more strongly in the low pH conditions of the small intestine.

      Encapsulate TGR5 ligand for colonic release:  Utilize encapsulation technology designed to deliver orally administered drugs to the colon.


Satiogen has focused on two of these product ideas which it believes are most attractive for commercialization:  the non-absorbed ASBT inhibitor and non-surgical biliary shunt.  Satiogen is also aiming to demonstrate proof-of-principle of rectal satiagens as possible low cost therapies for certain non-US markets.


NON-ABSORBED ASBT INHIBITOR

The first line drug for treating T2D is metformin:  it is a reasonably effective oral drug for lowering blood glucose, does not cause weight gain and sometimes promotes weight loss, has a respectable safety record (except for rare cases of lactic acidosis), and is cheap because of its generic status.  It is also used in combinations with most modern T2D drugs.  While the effects of metformin have been studied since it was introduced about 50 years ago, its molecular mechanism of action has remained elusive.

Satiogen believes that one property of metformin can explain most of its efficacy:  metformin weakly blocks bile acid transport out of the ileum, thereby increasing fecal bile acids and triggering the bile acid brake.  The resulting increase in circulating GLP-1 suppresses glucagon secretion, which reduces hepatic glucose production, the hallmark of metformin’s acute effects.  For the first time since its introduction there is now a rationale for developing “second generation” metformin-like molecules that are more potent and safer:  for example, dosing could be reduced from about two grams twice daily to milligrams once daily, and the boxed warning about lactic acidosis could be avoided.  New ASBTi molecules could be designed to better integrate with the effects of other glucose and/or weight lowering drugs.

During the 1990s pharmaceutical research focused on discovering compounds that inhibit the apical sodium-dependent bile acid transporter in the ileum.  The goal was to cause a deficit of bile acids in enterohepatic circulation which would force the breakdown of circulating cholesterol.  Numerous clinical studies examined the cholesterol lowering effects of ASBT inhibitors, but people with diabetes and obesity were specifically excluded from these studies.  When the lipid lowering effects were found to be inferior to those of the statins, these programs (and many composition patents) were abandoned.  Industry lost interest in ASBTi compounds until Satiogen realized they could be useful for activating the bile acid brake and demonstrated this effect in animal models.

Satiogen believes there is good precedence for method-of-use patent claims for using ASBTi compounds (except metformin) to lower glucose and body weight.  In the early 1990s inhibitors of dipeptidyl peptidase 4 were studied in vivo to understand the role of this enzyme in immune responses.  Then in 2001 a German company, Probiodrug AG, was issued a patent which claims, “a method for lowering elevated blood glucose levels in mammals resulting from food intake comprising administering at least one oral administration of a therapeutically effective amount of at least one inhibitor of Dipeptidyl Peptidase 4 or of DPP4-like activity.” 

The DPP4i patent estate was owned by OSI Pharmaceuticals (now part of Astellas), who reported in their 2009 annual report: “As of February 15, 2010, twelve pharmaceutical companies have non-exclusive licenses to these patents, which provide us with upfront payments as well as potential milestones and royalties. As of December 31, 2009, this patent estate has generated approximately $178 million in upfront license fees, milestones and royalties.”

Satiogen is working to expedite issuance of patent claims covering ASBT inhibition for lowering blood glucose and body weight.  The company plans to carry a candidate compound through Phase 2 testing and to offer one or more licenses to this intellectual property in a manner similar to the DPP4i licenses.


NON-SURGICAL BILIARY SHUNT

Bariatric surgery is now recognized as the gold standard for inducing weight loss and correcting T2D.  The most effective procedure is Roux-en-y gastric bypass, which results in an average excess weight loss of over 60% and resolves T2D in over 80% of patients.  However, insurance companies are reluctant to cover the cost of RYGB, and patients prefer the cheaper and reversible, but less effective laparoscopic adjustable gastric band procedure.

The efficacy difference between RYGB and LAGB can be attributed to their different impacts on satiagenic and incretin hormones:  RYGB causes increased L-cell secretions, whereas LAGB does not.  The reason is that LAGB only affects the capacity of the stomach to accept food, whereas RYGB also re-routes food and bile past a portion of the small intestine.  By disrupting digestive physiology in the duodenum, RYGB causes L-cells to amplify their satiagenic and incretin signaling.  The effect of RYGB is equivalent to activating the bile acid brake.

Satiogen proposes to mimic the endocrine effects of RYGB by shunting bile acids beyond the duodenum to disrupt bile acid physiology.  The procedure would be a variation of endoscopic biliary stenting, which is the most common palliative treatment for patients suffering from obstructive jaundice associated with malignant hepatobiliary tumors or benign strictures.  The stent would be modified to have a catheter extending down the small intestine that would carry bile acids past some portion of the duodenum and, perhaps, jejunum.  This shunt would mimic the effects on bile transport and function induced by RYGB, but without the laparoscopic surgery.

Assuming that a biliary shunt could be designed to induce a therapeutically effective reduction in body weight and blood glucose, it would be positioned as a simpler (cheaper) non-surgical, reversible alternative to LAGB and perhaps RYGB.  To this end Satiogen has been sponsoring experiments in rats and pigs to refine the shunt design.  In the most recent experiments the current design was quickly and easily inserted in the bile duct, and the two treated pigs behaved normally for six weeks following insertion.


RECTAL SATIOGEN

Satiogen’s first experimental administration of a rectal satiagen in patients with T2D produced clear effects predicted by the bile acid brake concept.  The company intends to pursue further development of this concept:  (1) bile salts are “generally regarded as safe” by the FDA, (2) suppository and gel delivery systems are widely available, and (3) rectal administration of drugs is acceptable in many countries.

To this end, Satiogen is assisting in two clinical research programs:

      University of South Australia Medical School, Prof. Michael Horowitz:  Beginning in June 2010 three Phase I-IIb studies of taurocholic acid in suppositories were begun:  (1) dose finding in eight healthy volunteers; (2) lowering postprandial glycemia in twelve T2D patients; and (3) effect on appetite and food intake in twelve lean, obese or T2D subjects.  In the second half of 2011 a 16-week Phase IIa,b efficacy and tolerability study of glucose lowering and weight loss will be started, which will be followed by a Phase III, 26-week double-blind, parallel-group study of safety, dose tolerance, weight loss, body composition, fasting glucose, HbA1c, and lipids profile.  This study is now complete, and the data is being analyzed.

      United Arab Emirates University, Prof. Tom Adrian:  The overall objectives of the study are to establish that stimulation of the release of GLP-1 and PYY from L-cells in twenty obese T2D subjects results in enhanced insulin secretion, reduced blood glucose concentrations, improvements in peripheral insulin sensitivity and marked weight loss that is sustained over a period of ten weeks. The local relevance of these studies is high, because no other region worldwide has a larger prevalence problem with T2D. These studies could potentially lead to a simple, efficacious and cost-effective treatment for obesity and T2D.


Satiogen has received encouragement from experts with perspective on therapeutic needs outside the US to pursue the idea of a rectal satiagen for treating diabesity, since conceptually a suppository could be a cheap, easy to develop product for receptive but economically challenged markets.  To this end Satiogen is exploring whether companies experienced in rectal delivery outside the US would be interested in collaborating.


CORPORATE OVERVIEW

Satiogen was founded in late 2007 and has been operating as a virtual company by outsourcing all activities required to validate the bile acid brake concept.  The initial focus has been on experiments to support proof-of-concept and assembling an intellectual property portfolio.  To this end the company has assembled the following talent pool:

      Patent filings:  Satiogen’s patent counsel, Wilson Sonsini Goodrich & Rosati (San Diego), has filed a series of patent applications in the US and certain foreign countries.  Three US patents have published to date.

      Founders and project managers:  Satiogen’s projects have been managed by a team that includes individuals experienced in discovery and development of diabetes and obesity therapeutics (see Chapter VII for details):

-     Andrew Young is co-founder of Satiogen and principal discoverer of the bile acid brake.  Andrew was head of physiology research at Amylin Pharmaceuticals and played a leading role in research leading to the launch of BYETTA and SYMLIN.  Andrew is now head of Enteroendocrine Biology at GSK in North Carolina.

-     Bronislava Gedulin is co-founder of Satiogen and named inventor on all patent applications.  Working with Andrew at Amylin, Slava was a key scientist who using preclinical models deciphered the mechanisms of action of the hormone amylin and of the GLP-1 agonist exenatide.  Slava performed the preclinical experiments that underlie the bile acid brake concept, and she is participating in the biliary shunt project.

-     Ted Greene is chairman and named inventor on several patent applications.  Ted was the founding CEO of Amylin and has been involved in a series of biotech ventures as CEO, investor, and board member.

-     Rob Ayling is managing the biliary shunt project and is coordinating funding of the rectal satiogen clinical program.  Rob co-founded Finistere Partners originally as an agbio focused consulting business which now manages a small strategic investment fund.

      Scientific Advisors:  Satiogen has enlisted the advisory help of several senior researchers in relevant fields (complete CVs are in Chapter VII):

-     Tom Adrian is focused on the biology of pancreatic cancer, growth pathways, novel therapeutics, mechanisms of cachexia and metabolic disturbance, and diabetes mellitus.  Tom discovered the escalating concentration of L-cell hormones in the distal gut, and confirmed the bile acid brake concept in humans.

-     Steve Bloom is a pioneer in the field of gastrointestinal hormones and led research that has defined the physiology of satiagenic and incretin hormones.  Steve co-founded the spin out company Thiakis Ltd. to commercialize his discovery of the antiobesity effects of the L-cell hormone oxyntomodulin.

-     Michael Horowitz is engaged in clinical research related primarily to gastrointestinal motor, sensory, and hormonal function, particularly in the context of appetite regulation, diabetes mellitus, glycemic control, critical illness and aging.

-     Jay Skyler is a scientific advisor to the pharmaceutical and medical equipment industries, and he has chaired advisory committees for Alinea, Amylin, Aventis, Bristol-Myers-Squibb, Eli Lilly, Glaxo-SmithKline, Kos, Lipha, MannKind, MiniMed, Novartis, Novo-Nordisk, Pfizer, Roche, Sanofi-Aventis, and Wyeth. He was a Founder of Mega Technologies, Inc., was on the Board of Directors of MiniMed Inc. and is on the Boards of Amylin Pharmaceuticals, Inc. and DexCom, Inc.

      Investors:  Satiogen’s cumulative funding of less than $2 million has come principally from three sources:

-     Andrew Young funded early preclinical experiments and patent filings out of his own pocket.

-     Mesa Verde Venture Partners, a life sciences venture capital fund founded in San Diego in 2006, has invested about $1 million.  General Partner Dan Wood is serving as CEO of Satiogen, and Senior Associate Carey Ng is serving as corporate and R&D advisor.

-     Ted Greene and Rob Ayling have provided the rest of the equity funding.


Satiogen’s strategy going forward has four elements:  (1) continue sufficient funding to support issuance of the intellectual property portfolio and ongoing project management, (2) move a non-absorbed ASBTi candidate through Phase 2 trials under Lumena’s leadership, (3) scale up development of the biliary shunt by organizing a separately funded medical device startup venture or collaboration with an existing device company, and (4) seek non-equity funding of additional research into the bile acid brake, in particular for clinical studies of rectal satiagens.

In summary, Satiogen believes the bile acid brake is a new target for treating diabetes and obesity that offers an attractive profile of efficacy, safety, tolerability, and cost.