More than half of all people with diabetes around the world are affected by diabetic peripheral neuropathy, according to the International Diabetes Federation. There is no prescription therapy in the United States currently approved to treat the underlying process of microvascular damage that leads to microvascular complications such as diabetic peripheral neuropathy. LY333531, according to pre-clinical data, is a specific inhibitor of PKC b, an enzyme that has been implicated in the underlying process of microvascular (small blood vessel) damage that leads to diabetic microvascular complications. PKC b Inhibitor is being studied as a possible treatment for multiple diabetic microvascular complications, including diabetic retinopathy and diabetic peripheral neuropathy.
Based upon results collected to date, Lilly will conduct three new global registration trials for the study of diabetic peripheral neuropathy - increasing to six the current number of Phase 3 trials with LY333531 for the treatment of diabetic microvascular complications. The three new trials will begin this year. Lilly plans to file for regulatory approval for the treatment of symptoms of diabetic peripheral neuropathy in 2004 in the United States.
Lilly is also investigating PKC b Inhibitor as a potential treatment for diabetic retinopathy and diabetic macular edema - microvascular complications that can lead to blindness. Registration trials are being conducted, and Lilly plans to file for regulatory approval in Europe for diabetic retinopathy and diabetic macular edema in 2003.
Diabetic peripheral neuropathy is one of three serious diabetic microvascular complications (the others being diabetic retinopathy, which affects eyes, and diabetic nephropathy, which affects kidneys). Diabetic peripheral neuropathy affects nerves outside the brain and spinal cord - primarily in the arms, legs, hands and feet - and can lead to amputations of feet and legs in people with diabetes. Sensory symptoms include numbness, prickling, aching pain, burning pain, lancinating pain or allodynia (pain resulting from a non-noxious stimulus to normal skin).
"Glucose control and symptomatic treatments are currently the only available options for the millions of people suffering from this type of diabetic microvascular complication," explained Aaron Vinik, M.D., of Eastern Virginia Medical Center in Norfolk, Va. and presenter of data at the ADA meeting. "Elevated blood sugar in people with diabetes results in the activation of PKC b, an enzyme that may play an important role in causing microvascular damage leading to blindness and amputations. We found that LY333531 positively impacted nerve function and sensory symptoms, such as tingling or numbness, of diabetic neuropathy."
According to the World Health Organization, diabetes is reaching epidemic proportions and is one of the leading causes of death worldwide. Approximately 150 million people globally have diabetes and the prevalence is expected to double by the year 2025. The ADA estimates that 17 million people in the U.S. are living with diabetes and that approximately 5.9 million people are undiagnosed.
"We are very encouraged to see important early results for LY333531 in diabetic peripheral neuropathy after only one year," commented Skip Vignati, M.D., medical director for the PKC b Inhibitor effort. "We are hopeful that ongoing and future investigation will yield additional evidence of the clinical benefit of this investigational medicine for treatment of diabetic microvascular complications."
In a year-long, double-masked, placebo-controlled, Phase 2 trial, LY333531 treatment was found to improve diabetic peripheral neuropathy, as assessed by neurological examination, objective measures of nerve function and physician assessment.[i] A total of 205 type 1 or 2 diabetes patients with diabetic peripheral neuropathy were randomized to receive 32mg or 64mg of LY333531 or placebo. 32mg LY333531 led to overall improvement in neurological examination, notably in the lower limbs (p = < 0.050 vs. placebo) and reflexes (p = 0.033 vs. placebo) - which are most impacted by diabetic peripheral neuropathy. Similar improvements in two composite scores - which include components of the neurological exam and electrophysiological and quantitative sensory tests - were seen in the 32mg LY333531 group (p = 0.046 and .072 for the two composite scores vs. placebo). These positive findings were corroborated by clinical global impression, an investigator assessment of patient improvement or worsening at study endpoint (p = 0.044 vs. placebo).
In presenting another data set from the same study, Dr. Vinik and colleagues reported that LY333531 improved symptoms associated with diabetic peripheral neuropathy and vibratory sensation (ability to feel an externally applied vibrating stimulus) with a significant correlation between the two.[ii] In the 83 patients that had clinically significant symptoms as determined by the Neuropathy Total Symptom Score-6 (NTSS-6), symptomatic improvement was measured. The NTSS-6 questionnaire measures the frequency and intensity of six symptoms of diabetic peripheral neuropathy: numbness, prickling, aching pain, burning pain, lancinating pain or allodynia. Previously, instruments used to measure diabetic peripheral neuropathy have focused on only four symptoms: pain, burning, numbness and prickling. The incorporation of two additional symptoms created the NTSS-6, which is thought to offer a more complete assessment.
Improvements in NTSS-6 scores were observed with both LY333531 groups (32mg and 64mg), compared with placebo (p = 0.064 for 32mg; p = 0.014 for 64mg). In a subset of 49 patients with earlier diabetic peripheral neuropathy symptoms, a significant improvement in the ability to detect vibration was noted in the 32mg LY333531 group (p = 0.006 vs. placebo) and in the 64mg group (p = 0.028 vs. placebo). The change in this subset correlated with improvement in the NTSS-6.2The investigators concluded that the NTSS-6 is a valid instrument to characterize and follow changes in neuropathic symptoms, which reflect alterations in the underlying pathophysiology of diabetic peripheral neuropathy.[iii] To reach this conclusion, they conducted a number of tests to assess the reliability and construct validity of the NTSS-6, as well as correlations with neurological examination. Significant correlations were observed between change in NTSS-6 scores and changes in neurological parameters that were assessed.
Finally, Dr. Vera Bril and colleagues reported that patients with early diabetic peripheral neuropathy appear to constitute a patient population most amenable to treatment.[iv] They concluded that the ability to detect sural nerve conduction, or sural nerve action potential (SNAP), denoted an earlier degree of diabetic peripheral neuropathy and likelihood to respond to intervention. Identification of a treatable patient population may thus prove useful for future evaluations of LY333531 and other novel therapies focused on diabetic peripheral neuropathy.
The most common side effect among the patients using PKC b Inhibitor in the trial was headache. The rate was comparable to placebo.
Eli Lilly and Company, a leading innovation driven corporation, is developing a growing portfolio of best in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers--through medicines and information--for some of the world's most urgent medical needs.
This news release contains forward-looking statements that reflect management's current beliefs about the potential for PKC b Inhibitor in the treatment of symptoms of diabetic peripheral neuropathy. However, as with any pharmaceutical under development, there are significant risks and uncertainties in the process of development and regulatory review. The product has not yet been proven safe and effective. There are no guarantees that the product will receive necessary regulatory approvals or prove to be commercially successful. For additional information about the factors that affect the company's business, please see Exhibit 99 to the company's latest Form 10-Q, filed May 2002. The company undertakes no duty to update forward-looking statements.
[i] Litchy W, Dyck P, Tesfaye S, et al. Diabetic peripheral neuropathy (DPN) assessed by neurological examination and composite scores (CS) is improved with LY333531 treatment. Presented at 62nd Scientific Sessions of American Diabetes Association, San Francisco, June 15, 2002 (poster # 800).
[ii] Vinik A, Tesfaye S, Zhang D, et al. LY333531 treatment improves diabetic peripheral neuropathy (DPN) with symptoms. Presented at 62nd Scientific Sessions of American Diabetes Association, San Francisco, June 17, 2002 (abstract #321).
[iii] Bastyr E, Zhang D, Bril V, et al. Neuropathy Total Symptom Score-6 questionnaire (NTSS-6) is a valid instrument for assessing the positive symptoms of diabetic peripheral neuropathy (DPN). Presented at 62nd Scientific Sessions of American Diabetes Association, San Francisco, June 15, 2002 (poster #805).
[iv] Bril V, Vinik A, Litchy W, et al. Detectable sural nerve action potential (SNAP) identifies patients with early diabetic peripheral neuropathy (DPN). Presented at 62nd Scientific Sessions of American Diabetes Association, San Francisco, June 15, 2002 (poster #799).
Litchy W, et al, Diabetes 2002,51(suppl 2): A197
Vinik A, et al. Diabetes 2002,51(suppl 2); A197
Bastyr E, et al. Diabetes 2002, 51(suppl 2); A199
Bril V, et al. Diabetes 2002, 51(suppl 2); A197