Type 2 Drugs in the Pipeline: an Update

If you Google “type 2 diabetes drugs,” one website lists the names of 92 drugs that medical professionals have prescribed at one time or another to treat diabetes.

You’d think that the diabetes apothecary has a more than a sufficient number of drugs for treating type 2. But scientists and pharmaceutical companies continue looking for new drugs to add to the diabetes medicine cabinet, including novel approaches to controlling blood sugar and weight.

Here’s a look at a few type 2 drugs researchers are working on. Some are close to market while others will take a few years longer before they can pass tests that establish their marketability.

The Arrival of the SGLT2 “Flozins”

Sodium glucose co-transporter-2 (SGLT2) inhibitors are different from most type 2 drugs. Rather than increase insulin production or decrease glucose production, SGLT2s bypass the liver and pancreas and work on the kidneys. In short, the drugs reduce the reabsorption of glucose from the kidneys by making them shunt the glucose into the urinary tract.

The beneficial effects of doing so include negligible risk of hypoglycemia, weight loss, and reduced A1c.

SGLT2 drugs, sometimes referred to as “flozins” because of the last syllables in their name, include canagliflozin (“Invokana,” Johnson & Johnson), dapagliflozin (AstraZeneca and Bristol-Myers Squibb), and empagliflozin (Boehringer Ingelheim and Eli Lilly and Company).

Canagliflozin: The first SGLT2 drug to enter the U.S. market (the FDA approved it in late March), its makers still have to perform five FDA-mandated post-marketing studies, including a study of cardiovascular outcomes.

Dapagliflozin: This drug’s manufacturers are hoping to introduce the second SGLT2 to the U.S. market and have resubmitted it to the FDA for approval. The European Union approved dapagliflozin for sale late last year under the name Forxiga, and the drug is legal in Australia, Brazil, Mexico and New Zealand.) The FDA previously rejected the drug after citing concerns about patients who developed breast and bladder cancer in clinical trials. AstraZeneca and Bristol-Myers are returning with research data they hope will satisfy the FDA’s concerns..

Empagliflozin: The drug is now in extensive Phase 3 trials at 12 sites worldwide. Like its counterparts, empagliflozin works by inducing the kidneys to expel glucose into the urinary stream.

2H10: Fat Blocker and Insulin Helper

Discovered in 1995, VEGF-B is a signaling protein (a protein that mediates a cell’s response to external chemical stimuli) that if blocked prevents fat from accumulating in the muscles-including the heart-and allows cells to resume responding properly to insulin.

Researchers at Sweden’s Karolinska Institute reported on VEGF-B’s properties in 2010, and followed up their finings with experiments on lab rats and mice to see what effects blocking the protein would have. They developed 2H10, an antibody that blocks the actions of VEGF-B and administered it to mice who had been specifically bred to develop diabetes.

The mice given 2H10 did not develop diabetes or insulin resistance, and when cross-bred with mice who could not produce VEGF-B, their descendants never developed diabetes.

Currently, an Australian biopharmaceutical company, CSL Limited, is developing the drug under the project name CSL346 VEGFB. Right now, CSL has the drug listed last in its current queue of eight new products under development, an indication that the drug still has a way to go before reaching marketability.

TAK-875: Lowers Blood Sugar and the Risk of Hypoglycemia

Takeda Pharmaceutical Company Limited is hoping to reach the U.S. market soon with TAK-875, a GPR40 agonist that will probably enter the Japanese market first under the brand name Fasiglifam.

GPR40 is a “G-protein coupled receptor” that is activated by fatty acids and has been found to aids insulin secretion in pancreatic cells.

The biggest promise TAK-875 holds is that besides lowering A1c’s in a statistically significant way, it is associated with very little increase in the risk of hypoglycemia.

Takeda recently announced results of a 24-week Phase 3 trial of the drug among 192 type 2 Japanese patients. The patients received once-daily doses of TAK-875 in 25 mg or 50 mg quantities, or placebo. The glycemic target of under 6.9% A1c was reached by 30.2 percent of patients taking the 25 mg dose and 54.8 percent of patients taking the 50 mg dose. Only 13.8 percent of patients receiving placebo reached the same level.

A Long-Shot Cannabis-Derived Drug

UK-based GW Pharmaceuticals has been experimenting with one of the chemical compounds found in marijuana that has shown some promise in preserving the pancreatic cells that produce insulin. The compound, tetrahydrocannabivarin (THCV), is the basis for an experimental drug, called GWP42004, that the company hopes to market some day as a possible adjunct to metformin.

Typically, type 2s have only half or fewer of the number of beta cells of non-diabetic people. That numbers declines as the disease progresses, so researchers are always seeking ways to slow that decline. GW’s scientists say early indications show that GWP42004 may cause decreased motivation to eat, lower cholesterol and insulin levels, increased glucose uptake, and control of excess liver fat-all potential factors in slowing pancreatic cell decline.

GW has completed a Phase 2a trial on 35 type 2 patients and is planning a larger Phase 2 trial. Approval is years away. Aside from the need for more extensive study, the drug’s cannabis-based origin may drag it into the political realm if there are objections to its pedigree.

LY: Obesity Fighter, Cholesterol Controller

Eli Lilly Co. thinks it may be on the track of a hormone-based injectable type 2 drug that fights weight and cholesterol. Called LY, the experimental drug is based on a hormone called “fibroblast growth factor 21 (FGF21). In a small trial involving 46 type 2 patients, those receiving the highest doses of the drug experienced statistically significant increases in their “good” cholesterol and drops in their “bad” cholesterol.

The patient sample was too small to establish whether the drug also increased insulin sensitivity or blood sugar control. Lilly researchers hope to begin studying larger patient samples and conducting full-blown testing into LY. It will take several years to determine if LY can join other diabetes drugs aimed at staving off cardiovascular disease.

Further-But Not So Light-Reading

An exhaustive look at diabetes drugs in the pipeline is available at http://spectrum.diabetesjournals.org/content/22/2/92.full.pdf. The PDF, aimed at professionals, is heavy on scientific and medical terminology, but offers useful information to the lay reader.