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Elcelyx 'Guts' Conventional Thinking on Metformin

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By Marie Powers
Staff Writer

A San Diego biotech with eight employees grabbed the spotlight at the American Diabetes Association (ADA) Scientific Sessions in Chicago with the revelation that Type II diabetes drug metformin acts in the lower bowel, not in the bloodstream.

Elcelyx Therapeutics Inc. is developing a delayed-release formulation of metformin, called NewMet, based on its gut sensory modulation (GSM) approach. At ADA, the company presented findings from a Phase IIa trial that compared NewMet with generic metformin in Type II diabetes, revealing the generic drug's mechanism of action. Contrary to popular belief, greater exposure in the plasma does not improve the efficacy of metformin – the most prescribed diabetes drug in the world – according to the study.

Using GSM, Elcelyx engineered NewMet to bypass the upper bowel, lowering systemic exposure and improving tolerability while maintaining metformin's glucose-lowering benefit.

Discovery of the mechanism of action was part intuition, part ingenuity. The company was formed in 2010 on the thesis of a weight loss approach involving the activation of taste receptors, explained Elcelyx CEO Alain Baron, a former senior vice president of research at Amylin Pharmaceuticals Inc. and former member of the Life Science Team at Morgenthaler Ventures.

"The idea was that we would activate these receptors of the gut with ingredients that were not absorbed into the bloodstream, because these receptors are actually there to sense nutrients," Baron told BioWorld Today. For example, when taste receptors on the tongue detect sweetness, those same receptors in the gut allow certain cells to sense that carbohydrates are being consumed.

The nutrient receptors are located on enteroendocrine cells located in the lining of the gut that produce key hormones, such as peptide YY (PYY), which signals satiety to the brain, and glucagon-like peptide-1 (GLP-1), which plays an important role in glucose regulation. One of the cells of special interest to Elcelyx, the L cell, became the basis for the company's name.

The company's early work proved that if those receptors were activated by ingredients that were not absorbed into the bloodstream, the cells could be activated and their contents – gut hormones – released, in an approach that became known as GSM.

Baron next theorized that certain existing drugs might work through the same mechanism. With his expertise in metabolic disorders, he quickly keyed on metformin, which is given in large doses and is poorly bioavailable but was shown to release GLP-1 . When coupled with literature suggesting metformin worked better orally than intravenously, Baron deduced that "maybe metformin works not by entering the bloodstream but by activating a receptor at the level of the gut."

To prove the hypothesis, the company formulated generic metformin with a pH-sensitive coating that made it less bioavailable until it reached the lower bowel.

"We were able to demonstrate the effect on the first try," Baron said. Although bioavailability was reduced by approximately half, efficacy was exactly the same.

"We reversed 52 years of dogma," he added.

'We're Looking for a Global Acquirer'

The breakthrough finding suggested a lower metformin plasma concentration might be used safely by patients with moderate and severe renal impairment – a population that is unable to use conventional metformin formulations due to the risk of lactic acidosis caused by high drug levels in the blood.

In the randomized, double-blind, three-way crossover Phase IIa study, 24 patients with Type II diabetes were randomized to twice-daily oral dosing of metformin HCl immediate release (1,000 mg), low-dose NewMet (500 mg) and high-dose NewMet (1,000 mg) for five days each, separated by a one-week washout. The treatments demonstrated similar reductions from baseline values in fasting plasma glucose (16 mg/dL to 22 mg/dL, p < 0.01 for all) and postprandial glucose (8 percent to 12 percent, p < 0.001 for all) despite a 45 percent to 57 percent reduction in circulating metformin in the high- and low-dose NewMet arms, respectively. Similarly, GLP-1 and PYY were increased by more than 50 percent across all treatments.

No safety concerns were noted for either NewMet or metformin, and NewMet had fewer gastrointestinal (GI) side effects than generic metformin.

A second, late-breaker ADA poster presented by Mark Fineman, Elcelyx's senior vice president of R&D, described a model designed to predict metformin plasma concentrations that would occur if patients with Type II diabetes and mild, moderate or severe renal impairment were to take NewMet. Results suggested that patients with renal impairment taking effective doses of NewMet would not have an increased risk of lactic acidosis. The company plans to initiate a pharmacokinetic study this summer in Type II diabetes patients with mild, moderate and severe renal impairment to confirm the predictions of the model.

In the meantime, Elcelyx launched a multicenter, double-blind dose-finding Phase IIb trial in May evaluating once-daily doses of 1,000 mg, 800 mg and 600 mg of NewMet to placebo. There are also two comparator arms with generic extended-release metformin dosed once-daily at 1,000 mg and 2,000 mg. The primary endpoint of the study is fasting plasma glucose at four weeks, with secondary endpoints through 12 weeks including changes in fasting plasma glucose, hemoglobin A1c, body weight and measures of safety and tolerability. The study has fully enrolled 240 patients with Type II diabetes. Top-line data are expected in late August, with the readout for long-term glucose lowering and weight benefits due in October, Baron said.

NewMet's market opportunity could be huge. Although metformin is the preferred first-line pharmacological treatment for Type II diabetes, 40 percent of U.S. patients with the condition do not take the drug, primarily due to GI issues or the contraindication of renal impairment, according to John Buse, professor of medicine and director of the Diabetes Care Center and chief of the division of endocrinology and executive associate dean for clinical research at University of North Carolina School of Medicine in Chapel Hill. Of the 60 percent who take metformin, only about 40 percent are able to titrate to fully effective doses, due to tolerability issues, added Buse, who served as an advisor on the Phase II NewMet study.

"There's an unmet need for metformin in this market," which comprises some 4 million individuals in the U.S. alone, Baron said. "We're not targeting the population that's doing well on current metformin. NewMet would allow more people to be on this foundational therapy and to stay on it throughout their lives, since renal impairment worsens with age."

Baron hopes a big pharma also will see that blockbuster opportunity. The plan is to sell the company – with the concurrent spin-out of a second product, a dietary supplement for weight management – following the Phase IIb study. Provided a pivotal trial begins next year and all goes well, NewMet could be on the market as early as 2016, Baron said.

"We're looking for a global acquirer, and we have no intention of keeping any rights," he said.

Since its inception, Elcelyx has raised $43 million in three financing rounds, with funding from Morgenthaler, Kleiner Perkins Caufield & Byers, Technology Partners and GSM Fund LLC, which was established this year to enable existing investors and insiders to participate in the company's Series C in February.

In other ADA news:

• Astrazeneca plc, of London, and Bristol-Myers Squibb Co., of New York, reported results from a two-week Phase IIa pilot study testing dapaglifozin added to insulin in 70 adults with suboptimally controlled Type I diabetes. Results showed that, of those treated with dapaglifozin, no subjects discontinued due to lack of glycemic control, few genital and urinary tract infections were reported and hypoglycemia was observed in all treatment groups. In addition, mean daily blood glucose derived from seven-point glucose measurements trended downward in all treatment groups through day seven and reductions in total daily insulin dosing at day seven were observed with dapaglifozin.

• Boehringer Ingelheim GmbH, of Ingelheim, Germany, and Eli Lilly and Co., of Indianapolis, reported data from several empaglifozin studies, including results from a 52-week Phase III study showing that empaglifozin produced statistically significant reductions in HbA1c at week 24, with the addition of the sodium glucose co-transporter inhibitor to existing oral glucose-lowering therapy in Type II diabetics with mild to moderate renal impairment. Results also demonstrated a significant reduction in body weight and significant improvements in blood pressure with empaglifozin vs. placebo in patients with mild to moderate renal impairment. In a separate presentation, the companies said 24-week Phase III data showed that empaglifozin as an add-on to metformin plus sulphonylurea demonstrated statistically significant reductions in blood glucose among people who received empaglifozin, as measured by reductions in HbA1c. Data from a separate 24-week Phase III trial showed that empaglifozin as a monotherapy produced statistically significant reductions in HbA1c vs. placebo in patients with Type II diabetes who had not received any treatment for at least 12 weeks prior to randomization. Another presentation highlighted results from a 78-week Phase III study, showing that empaglifozin as an add-on in people with Type II diabetes produced statistically significant reductions in HbA1c vs. placebo. Additional presentations showed that pooled analysis from four pivotal studies of empaglifizon in Type II diabetes showed the drug achieved significant reductions in HbA1c fasting plasma glucose, weight and blood pressure after 24 weeks vs. placebo. That same analysis showed that people treated with empaglifozin vs. placebo experienced an increased frequency of genital infections but not urinary tract infections. Boehringer and Lilly also presented several posters with data on Trajenta (linagliptin), a DPP-4 inhibitor, including data from two Phase III trials in Asians from China, Malaysia and the Philippines, with Type II diabetics achieving improved blood glucose control vs. placebo when linagliptin was given as either a monotherapy or in combination with metformin.

• Eli Lilly and Co., of Indianapolis, presented detailed data from three Phase III AWARD trials testing dulaglutide, a long-acting glucagon-like peptide 1 receptor agonist, as a once-weekly treatment for Type II diabetes, with data showing the drug to be superior to placebo and to Byetta (exenatide, Astrazeneca plc and Bristol-Myers Squibb Co.), metformin and DPP-4 inhibitor Januvia (sitagliptin, Merck & Co. Inc.) in reducing HbA1c levels. In addition, a greater percentage of patients treated with dulaglutide achieved an HbA1c goal of less than 7 percent vs. all active comparators. Lilly also reported results from an additional analysis of Phase II data for LY2605541, a basal insulin analogue, showing that among patients who completed the study, which included eight weeks of treatment with LY2605541 and eight weeks of insulin glargine, Lilly's drug led to significantly lower average blood glucose levels (143.1 mg/dL vs.151.7 mg/dL) with statistically significantly less mealtime insulin per day compared to insulin glargine.

• Isis Pharmaceuticals Inc., of Carlsbad, Calif., reported data from a blinded, randomized, placebo-controlled Phase II study of antisense drug ISIS-APOCIIIRx showing that 11 patients with high triglycerides (200 mg/dL to 500 mg/dL) and Type II diabetes treated with the drug experienced statistically significant reductions of 88 percent from baseline in apolipoprotein C-III and 72 percent from baseline in triglyceride levels with a concurrent 40 percent increase in HDL cholesterol and improvements in other atherogenic lipid parameters. In addition, patients dosed with ISIS-APOCIIIRx showed consistent trends toward enhanced insulin sensitivity, with improvements in multiple measures of glucose control, and use of the drug did not raise LDL. ISIS-APOCIIIRx demonstrated a good safety profile and was well tolerated in all subjects with no discontinuations, clinically meaningful elevations in liver enzymes, flu-like symptoms or significant adverse events. Isis is evaluating ISIS-APOCIIIRx in a separate Phase II study in patients with moderate to severe high triglycerides and plans to report data from that study this summer. Shares of Isis (NASDAQ:ISIS) jumped on the news, opening 13 percent higher and hitting a 52-week high of $28.42, a gain of $6.43, or 29.2 percent, on the day. Volume was more than five times the daily average.

• Janssen Research & Development LLC, of Raritan, N.J., a unit of Johnson & Johnson, reported data from a 52-week Phase III trial showing that 300 mg of Invokana (canaglifozin), a sodium glucose co-transporter 2 inhibitor, provided greater improvements in blood glucose control compared to Januvia (sitagliptin, Merck & Co. Inc.) in adults with Type II diabetes taking metformin. The 100-mg dose provided similar improvements in blood glucose compared to sitagliptin, while both doses of Invokana resulted in greater secondary endpoint reductions in body weight and blood pressure. Results from a second Phase III study showed greater improvements in blood glucose control with the 300-mg dose and similar improvements with the 100-mg dose of Invokana when compared to sulphonylurea glimepiride.

• Lexicon Pharmaceuticals Inc., of The Woodlands, Texas, presented findings on LX4211 , its dual SGLT1/SGLT2 inhibitor, from a 12-week dose-ranging Phase IIb study of 299 patients with Type II diabetes. Patients with high baseline systolic blood pressure (> 130 mmHg) dosed with LX4211 experienced an average reduction of 14 mmHg in systolic blood pressure compared to placebo (p = 0.002). Patients with normal systolic blood pressure at baseline experienced an average reduction of 1 mmHg (p = 0.6). There were no differences between drug and placebo in systolic blood pressure readings below 100 mmHg or orthostatic systolic blood pressure changes. The company also reported reductions in body weight and triglycerides for subgroups with varying body mass indexes (BMIs) and triglyceride levels at baseline. Patients with baseline BMI > 30 treated with 200 mg once-daily, 200 mg twice-daily and 400 mg once-daily treatment all experienced greater average body weight reductions than placebo (p < 0.001). Patients with baseline triglycerides of 200 mg/dL to 500 mg/dL treated with LX4211 experienced significantly greater reductions than those experienced by patients with baseline triglycerides lower than 200 mg/dL in three of four LX4211 doses tested. In addition, the company presented the first preclinical data on its SGLT1 inhibitor LX2761 , showing that use of the compound resulted in no urinary glucose excretion in mice while demonstrating delayed intestinal glucose absorption and increased postprandial GLP-1 levels, both alone and synergistically with DPP-4 inhibitor Januvia (sitagliptin, Merck & Co.). Blood glucose excursions after an oral glucose challenge were still decreased 15 hours after administration of oral LX2761. The compound improved glycemic control in STZ-diabetic mice and in the KKAy mouse model of Type II diabetes, as measured by reductions in hemoglobin A1c and oral glucose tolerance test results.

• Ligand Pharmaceuticals Inc., of San Diego, presented data from preclinical studies of its compound, LGD-6972, showing that the potent and selective antagonist of the glucagon receptor lowered fasting and nonfasting glucose levels in a mouse model of Type I diabetes. The compound also reduced HbA1c, ketone bodies and free fatty acids in diabetic mice, and it had additive effects when used in combination with insulin therapy. The company said it plans to submit an investigational new drug application for LGD-6972 in the second half of the year.

• Nimbus Discovery LLC, of Cambridge, Mass., presented preclinical data showing that its acetyl CoA carboxylase allosteric inhibitor, ND-630, improved insulin sensitivity, produced a dose-dependent reduction in whole body fat markers and decreased triglycerides, fatty acids and cholesterol in diet-induced models of obesity.

• Sanofi SA, of Paris, reported data showing that lixisenatide, a once-daily prandial glucagon-like peptide 1 receptor agonist, decreased HbA1c by reducing postprandial glucose daytime exposure when added to standard of care, which includes basal insulin with or without oral anti-diabetic agents. Lixisenatide is partnered with Copenhagen, Denmark-based Zealand Pharma A/S. In separate news, Sanofi presented Phase III data from the EDITION program for its insulin U300, which showed equivalent blood sugar control with fewer night-time low blood sugar events compared to Lantus (insulin glargine [rDNA origin] injection). Top-line data from a second Phase III study, EDITION II, also showed that U300 demonstrated similar blood sugar reduction while fewer patients experienced night-time low blood sugar events vs. Lantus.

• Zafgen Inc., of Cambridge, Mass., reported that an interim analysis conducted on an ongoing Phase II study of beloranib, a selective methionine aminopeptidase 2 inhibitor, showed rapid, progressive and sustained body weight loss of up to 10 kg together with improvements in cardiovascular risk factors such as triglycerides, LDL cholesterol and C-reactive protein with an encouraging tolerability and safety profile. The obesity therapy is designed to restore the balance and utilization of fat. After 12 weeks, subjects on 0.6 mg, 1.2 mg or 2.4 mg of the drug lost an average of -3.8 kg, -6.1 kg and -9.9 kg, respectively, vs. +1.8 kg for placebo (all p < 0.005 vs. placebo). Complete results of the double-blind, placebo-controlled study, which investigated the safety, tolerability, pharmacokinetics and metabolic effects of beloranib in obese men and women, are expected to report this summer.

• Zealand Pharma A/S, of Copenhagen, Denmark, presented the first data from preclinical studies of its glucagon analogue, ZP-GA-1, suitable for liquid formulation. ZP-GA-1 demonstrated good solubility and chemical and physical stability in liquid formulation compared to native glucagon while retaining high potency at the glucagon receptor and a comparable pharmacokinetic and pharmacodynamic profile. Data from the study showed that injection of ZP-GA-1 (60 nmol/kg) induced a glucose-releasing effect comparable to native glucagon (20 nmol/kg) with respect to time to maximal effect, maximum obtainable glucose excursion and time for blood glucose levels to return to baseline. The company said the data supported ZP-GA-1's potential use to treat and/or prevent severe hypoglycemia in the form of a ready-to-use rescue kit and/or in an artificial pancreas. Separately, Zealand said partner Sanofi SA, of Paris, plans to initiate Phase III studies of the Lantus (insulin glargine)/Lyxumia (lixisenatide) combination product, with first patient dosing expected in the first half of 2014. Lyxumia, a once-daily prandial GLP-1 agonist to treat adults with Type II diabetes, is a Zealand-discovered peptide drug, with worldwide development and commercialization rights exclusively licensed to Sanofi. Since its March launch in Germany, Lyxumia has gained an 8.1 percent share of the GLP-1 market, according to Sanofi's data. In addition, enrollment of up to 6,000 patients in ELIXA is expected to be completed this year. The randomized, double-blind, placebo-controlled global multicenter study is evaluating cardiovascular outcomes in patients during treatment with Lyxumia for Type II diabetes following an acute coronary syndrome. Interim data from the study are being evaluated by the FDA as part of the regulatory data package submitted for Lyxumia, and final study results are expected toward the end of 2014. Zealand said the update on Lyxumia and the development timelines for the Lantus/Lyxumia combination did not change its 2013 financial outlook. (See BioWorld Today, Feb. 5, 2013.)