Developing treatments for chronic diseases
 

Research & Development - Diabetic Neuropathy

About Diabetic Neuropathy

According to the latest International Diabetes Federation (IDF) Diabetes Atlas sixth edition, 382 million individuals suffer from some form of diabetes worldwide 1. Moreover, the number of individuals suffering from diabetes across the globe is expected to increase by 55% in 2035 to 592 million people. Associated worldwide diabetes health care expenditures are estimated to currently be 548 billion USD and forecasted to increase to 627 billion USD by 2035; with low to middle income countries disproportionately burdened by the disease. According to the American Diabetes Association, there are approximately 25.8 million persons in the U.S. with some form of diabetes (ADA website) and conservative projections estimate that >40 million Americans will have some form of diabetes by 2035 2. The current health care cost of diabetes and its complications in the U.S. is approximately 150 billion USD and is projected to double by 2035 to >300 billion USD 2. Suffice it to say that the current epidemic of diabetes and its complications shows no signs of slowing and will continue to be a significant personal and financial burden on humanity across the globe.

Diabetes is primarily an endocrine disorder involving dysfunctional metabolic regulation of pancreatic, liver, adipose and muscle tissues. Several major complications arise due to metabolic dysfunction including cardiovascular disease, neuropathy, nephropathy, retinopathy and others 3. Of these complications, hyperglycemia mediated dysfunction of the microvasculature along neurological injury contribute to the development of peripheral diabetic neuropathy (PDN) 3, 4. Importantly, PDN affects patients with both Type 1 and Type 2 diabetes with an incidence of approximately 60% (ADA website) costing an estimated $10.9 billion USD for the management of PDN in 2004 alone 5. Current clinical management of PDN is limited in its scope and effectiveness 6. Various therapies include: 1) tight glycemic control, 2) antidepressants, 3) anticonvulsants, 3) opioid analgesics, 4) antiarrythmics, 5) NMDA receptor antagonists, 4) capsaicin and 5) acupuncture 7. However, studies have reported that topical organic nitrate sprays (nitroglycerin & glycerol trinitrate) could provide reduction in pain 8-11. Taken together, it is clear that more effective therapeutic modalities are needed for patients suffering from peripheral diabetic neuropathy.

About TV1001SR

TV1001sr is a twice-daily orally-dosed slow-release formulation of the FDA-approved therapeutic sodium nitrite. Results from Phase IIa clinical trials support the use of sodium nitrite for the treatment and prevention of peripheral artery disease, and as a non-addictive and cost-effective treatment for diabetic neuropathy.

TV1001SR for Diabetic Neuropathy

TV1001SR offers a non-addictive, cost-efficient method for treating pain. In the Phase IIa placebo controlled, dose ranging study conducted with TV1001, the precursor to the reformulated slow-release formulation TV1001SR, patients reported a significant reduction in pain for those randomized to the 40 mg group compared with placebo. Furthermore, in a study carried out by the NIH in which foot ulcers of patients with sickle cell disease anemia were treated with a topical nitrate, subjects reported significantly less pain. By increasing blood flow to the extremities, it is likely that repair to nerve damage will be facilitated, thereby increasing neuronal function and reducing pain.

Development Plans

A Phase IIa Clinical Study will be conducted at the Ohio Pain Clinic by Dr. Amol Soin, testing the sustained-release TV1001SR at 40 mg and 80 mg doses, with primary endpoints of PK and safety, and secondary endpoints measuring pain.

Clinical Development

Circulating nitrite levels are found normally in our blood. However, in two recent studies, the levels of circulating nitrite levels were shown to be depressed in patients with cardiovascular disease. In the first study, researchers found a negative correlation between circulating nitrite levels in the plasma and cardiovascular risks factors: patients with an increase in the number of risk factors associated with cardiovascular disease had a correspondingly lower level of circulating nitrite. In the second study, researchers showed that not only did PAD patients and diabetic patients with PAD have a significantly lower level of circulating nitrite than non-PAD patients, but that when these PAD patient groups exercised, no change in circulating nitrite levels were observed, unlike non-PAD patients where exercise induced a 25-30% increase in circulating nitrite levels. While diabetic patients without PAD had a higher level of resting nitrite levels in the blood, like PAD patients, exercise failed to promote the release of nitrite.  In a subsequent study, this same research team found that when PAD patients were given a large amount of dietary nitrate, a precursor to nitrate, exercise performance was enhanced.  This has important implications in treating PAD patients in that the current standard of care is exercise, to promote blood flow to the affected limb. However, if exercise is not resulting in a release of nitrite, which in turn will limit the amount of nitric oxide made in the limb and the degree of new vascularization, exercise alone may not offer significant benefit. Increasing circulating nitrite levels with TV1001 could alleviate this problem and other cardiovascular problems where circulating nitrite levels are low.

Phase I

TheraVasc has recently completed a Phase I clinical trial under the direction of Dr. Frank Greenway at the Pennington Biomedical Research Center, a leader in obesity and diabetes research.  Dr. Greenway, the Medical Director at Pennington, has substantial experience in conducting clinical trials on obesity on diabetes. A total of 12 diabetic patients were enrolled and received two different formulations of 80 mg of sodium nitrite, an enteric-coated and a non-enteric coated capsule, with a minimum of two weeks between dosing.  There were no serious adverse events, with only three of the twelve subjects reporting any adverse events (headache, flushing, feeling of nausea) all of which resolved within an hour, thus demonstrating that the 80 mg dose is well-tolerated in patients. Circulating nitrite levels were measured at Emory Medical School and University of Alabama, Birmingham using two different methodologies.  The results were similar between the two.  Peak nitrite levels hit the targeted goal of low micromolar circulating concentrations, demonstrating that the 80 mg capsule resulted in the blood levels predicted to achieve therapeutic benefit based on animal studies.  Final analysis of the data will soon be released but it appears the drug is safe and well tolerated at the planned 80 mg dose level.

Phase IIa

Sonic Trial

TheraVasc has recently completed an FDA-authorized placebo controlled, double blind clinical trial across 10 sites throughout the US of an investigational drug for peripheral artery disease (PAD). Sodium nitrite has been demonstrated to promote new blood vessel growth, speed up wound healing and prevent tissue necrosis in animals. In addition to safety, since patients with PAD experience many of these problems, this study sought to determine whether this drug, when given orally, could provide the same benefits to patients with PAD. SG1002 therapy was safe and well tolerated following 10 weeks of twice daily administration. The primary adverse events were headaches and dizziness, which resolved without intervention. PAD subjects with diabetes had a significant improvement in endothelial function and a significant reduction in pain. .

For complete information on this clinical trial, visit ClinicalTrials.gov

 

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