ADA Meeting 2009: Novel Diabetes Therapies Presented

By Jeffrey Martini, PhD., Vice President of MD Becker Partners LLC

Approximately 250 million people worldwide have been diagnosed with diabetes mellitus and that number is growing with the increasing obesity population. Broadly, patients with diabetes are characterized by elevated blood glucose levels that result from either insufficient insulin secretion (type-1 diabetes) or ineffective insulin action (type-2 diabetes). The market for treating patients with diabetes is large and complex and is valued at over $90 billion (Ref 1).

In addition, secondary diseases such as cardiovascular disease and neuropathy are the results prolonged insulin deficiencies and will significantly add to the current heath economic burden.

As highlighted at the recent American Diabetes Association (ADA) meeting June 5-9, 2009, pharmaceutical and biotechnology companies are actively seeking new medications to treat the growing demand for innovative and cost-effective therapies.

In healthy patients, insulin is released from pancreatic B cells in response to elevated glucose which causes depolarization through the closing of ion gated K+ channels and opening of Ca2+ channels. The increased intracellular Ca2+ levels results in insulin release from the B cells entering the circulation. The primary target of insulin is the insulin receptor found in many tissues including the liver, brain, and muscle. Activation of this receptor initiates a complex signaling network resulting in energy storage, cell growth, and metabolism. Circulating insulin is cleared through the liver (60%) and the kidneys (40%).

Diabetes is a chronic, long-term disease with treatments focusing on disease management. This includes drugs and devices that alter and monitor insulin levels. Patients with abnormal insulin levels or who are insulin resistant may develop a series of complications as a result of metabolic derangements such as cardiovascular disease, stroke, nephropathy, retinopathy, peripheral neuropathy, renal failure, and amputations of the extremities. Therefore, new medications that allow for tighter control of insulin levels are needed.

There are a number of drugs available for patients with type-2 diabetes mellitus. The oral anti-diabetic agents are categorized in four classes based on the mechanism of action: biguanides (reduced gluconeogenesis) thiazolidinediones (PPAR-g ligands), insulin secretagogues (closure of K+ channels on B cells), and a-glucosidase inhibitors (inhibitors of a-glucosidases). Many of these drug classes have more established profiles such as the insulin secretagogues and biguanides and are the first line of therapy for early stage type-2 diabetes. In addition, several of these drugs are available in generic forms.

Many patients with type-2 diabetes unable to make lifestyle modifications are unable to achieve normal glucose levels and require a combination of oral anti-diabetic medicines and insulin analogs.

Several different insulin analogs are available for type-1 and advanced type-2 diabetic patients. The injected insulin types differ in their onset and duration. The main players in this area are many of the larger pharmaceutical companies including Lilly (LLY), Sanofi-Aventis (SNY), Novo Nordisk (NVO) and Pfizer (PFE). Total sales of insulin analogs in 2006 were greater than $4 billion.

Current strategies for physicians treating diabetics are through the drug classes mentioned above resulting primarily in diabetes management. Many new insulin altering drugs have entered the market in the past 10 years, but there is mixed evidence that these new drugs are superior to more established therapies (Ref 2-5) probably because many of these drugs are active on the same molecular sights as previously approved drugs. Importantly, as the number of patients with diabetes increases, developing new medicines that reduce the cost of long-term treatment for this chronic disease will become a necessity.

PPAR and GLP-1 receptor agonists

As discussed at the recent ADA meeting, new technology and approaches for treating these patients is changing and the competition to secure the growing market is fierce (see Table 1 below for a summary). Eli Lilly and Co. and Amylin Pharmaceuticals Inc. (AMLN), makers of Byetta, recently announced a new formulation of this drug that changes the dosing from twice daily to weekly. Positive results from this clinical trial are encouraging for many of the patients who are non-compliant with this medication. Roche (RHHBY.PK) also announced that it would begin a phase 3 trial for its PPAR-g agonist R1439, which demonstrated improved cardiovascular morbidity in high-risk diabetes patients.

Xoma

XOMA (XOMA) presented data from one of its diabetes antibody candidates XOMA-52, which is a clinical stage IL-1b antibody for patients with type-2 diabetes. IL-1b plays a role in the auto-inflammatory response leading to decreased beta cell function. XOMA-52 is unique to other IL-1b inhibitors because of its high affinity (K_D is fM) and long half-life (22 days). As a result, patients need to be injected with XOMA-52 once monthly and should increase patient compliance. In addition to safety and pharmacokinetic data, the Phase I trial demonstrated decreased HbA1c levels, a key indicator of blood sugar control, and improved beta cell function. XOMA-52 is an attractive drug candidate because it preserves endogenous insulin production in patients with advancing type-2 diabetes.

In addition to clinical data, XOMA also presented detail mechanistic rodent and in vitro data on XOMA-52, confirming the results seen in the clinical study.

Halozyme

For patients with type-1 diabetes, Halozyme (HALO) recently presented Phase 2 data that showed improved pharmacokinetics and glucodynamics with patients receiving Lilly’s Humalog and co-administration of Halozyme’s PH20 enzyme. PH20 is a recombinant hyaluronidase enzyme that catalyzes the hydrolysis of hyaluronic acid, a major constituent of the interstitial barrier, and increases tissue permeability. This study demonstrated an improved blood glucose metabolism profile in patients taking the combination therapy, reflecting a more physiologic glucose profile thereby likely reducing the amount of exogenous insulin needed along with some potential complications such as hypoglycemia.

Appetite Control

In addition to reformulations, several companies presented data on new drug targets and technologies. VIVUS, Inc. (VVUS) presented data from a year-long Phase 2 trial with Qnexa demonstrating reduced HbA1c levels and helped patients achieve and maintain significant weight loss through appetite suppression. Qnexa is a combination therapy of FDA approved phentermine and topiramate, which in combination have synergistic effects through unique molecular targets resulting in reduced appetite and increased satiety.

Arena Pharmaceuticals, Inc. (ARNA) presented Phase 3 data from its BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management), demonstrating significant weight loss and reduced secondary endpoints associated with cardiovascular disease after one year of treatment compared to placebo. Lorcaserin is a novel serotonin 2C receptor agonist; selective activation of this Gq-coupled GPCR in the hypothalamus leads to appetite control and increased metabolism.

Isis

Isis Pharmaceuticals, Inc. (ISIS) presented preclinical data on ISIS-SGLT2Rx, an antisense biologic targeting knockdown in sodium dependent glucose co-transporter type 2 (SGLT2) levels that resulted in a significant reduction in blood glucose levels in multiple animal species. Isis is experienced in RNA targeting drugs and has already commercialized the world’s first antisense drug.

This novel technology allows Isis to target dysfunctional proteins through decreased transcriptional levels thus modifying signaling pathways not attainable through small molecule inhibition. Antisense technologies may play a key role in finding drugs with unique targets previously unreachable ultimately leading to improved disease management and quality of life.

Sangamo

Sangamo BioSciences, Inc. (SGMO) presented data from its Phase 2 trial for SB-509 as a treatment for diabetic neuropathy (DN) resulting in statistically significant and clinically relevant improvements in subjects. DN is a severe physiological consequence of chronic elevated blood glucose levels and is seen in many patients with advanced diabetes. SB-509 is an injectable plasmid encoding a DNA-binding Zinc Finger DNA-binding Protein (ZFP) Transcription Factor (ZFP TF™) designed to upregulate the endogenous expression of the gene encoding vascular endothelial growth factor (VEGF), a peptide responsible for angiogenesis.

The preclinical and clinical data presented at the ADA gives investors, physicians, and patients a preview of the new drugs and technologies to come. Many of these drugs are several years away from commercialization; however, because of the new technology, new target, or new delivery method, the outlook remains positive for these drugs and companies in the expanding market of diabetes control.

Table 1: Summary

References

1. Canaccord Adams. Diabetes 2007 and Beyond: Innovation, Demographics and Lifestyle Trends Drive Industry Growth. August 2, 2007
2. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65.
3. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53.
4. Kahn SE, Haffner SM, Heise A, et al, for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin or glyburide as monotherapy in type 2 diabetes. N Engl J Med 2006; 355: 2427–43.
5. Nathan DM. Finding new treatments for diabetes—how many, how fast… how good? N Engl J Med 2007; 356: 437–40.

Disclosure: No positions

Comments

[Penn Bioinv...:]

You forgot an important drug candidate from Incyte:
Results Presented at the ADA 69th Scientific Sessions Demonstrate that INCB13739, Incyte’s Oral 11beta-HSD1 Inhibitor, Significantly Improves Glycemic Control, Insulin Sensitivity and Total Cholesterol in Patients with Type 2 Diabetes

Jun 24 07:19 PM