Painful diabetic peripheral neuropathy (PDPN) is pathological pain inperipheral nerves resulting from diabetes or prediabetes. Its most common formof presentation is pathological pain of symmetrical peripheral nerves withpredominant distal limb involvement, which can also present as single neuralgiaor brachial plexus and lumbosacral plexus neuralgia, with symptomscharacterized by bilateral symmetrical distal limb pain, heavier lower limbsthan upper limbs, heavier distal than proximal, and more severe nocturnal pain (1).
PDPNis found in about 50% of patients with diabetes and 13% of patients withimpaired glucose tolerance. Pain seriously affects patients' ability to liveand work, including sleep quality, mood, experience, and mobility (2),and can even pessimistically disappoint because it is unbearable, causingsuicidality. Painful diabetic neuropathy is second only to amputation inreducing the quality of life due to diabetic complications (3).
Controllingdiabetes is the only disease-modifying treatment. However, some clinical trialsover the past 20 years have shown that glycemic control is not sufficient toprevent neuropathy in diabetic patients. Therefore, symptomatic analgesia isimportant in PDPN treatment (4) anddrug therapy is the basis for the treatment. The main drugs include tricyclicantidepressants, 5-HT and NE dual-channel reuptake inhibitors, anticonvulsants,external application drugs, tramadol hydrochloride and morphine analgesic drugs(5).Such analgesic drugs often take several weeks to achieve better analgesiceffect, and sometimes dosage titration is also required in the early stage, so4 to 8 weeks of drug treatment is the basic course of treatment, and sometimeslong-term medication is required to control pain. Increasing numbers of drugshave strong evidence to support their use, but many others have not shownbenefit in clinical trials. Therefore, further research is needed to developnew drugs and identify the medication sequence or combination that best controlneuropathic pain (4).
NRD135S.E1is an orally active small molecule with a novel anduniquemechanismof action by modulating Lyn kinase developed by Swiss biotech company Novaremed,which is a first-in-class and globally innovative non-opioid drug for thetreatment of painful diabetic peripheral neuropathy and other neuralgia.
Novaremedsuccessfully completed three Phase 1 studies and one double-blind,placebo-controlled Phase 2a dose-finding proof-of-concept study in whichNRD135S.E1 showed a clinically relevant reduction in patient-reported pain(measured as an improvement in mean neuropathic pain score) and was very welltolerated at all doses tested.
NRD135s.E1has been granted Fast Track Designation by the US FDA and was selected by theNational Institutes of Health (NIH) in the US as the only oral agent to beincluded in the NIH-HEAL (Help End Long-term Addiction) program. A Phase 2bstudy sponsored by NIH will start soon.
Reference:
1. 于生元等，糖尿病性周围神经病理性疼痛诊疗专家共识，中国疼痛医学杂志 2018,24 (8), 561-567. DOI:10.3969/j.issn.1006-9852.2018.08.001.
2. D M Nathan, et al. The Effect of IntensiveTreatment of Diabetes on the Development and Progression of Long-TermComplications in Insulin-Dependent Diabetes Mellitus. N Engl JMed 1993; 329: 977-86.DOI: 10.1056/NEJM199309303291401
3. Juan Martin Valdivia Valdivia, etal. Surgical treatment of superimposed, lower extremity, peripheral nerveentrapments with diabetic and idiopathic neuropathy. Ann Plast Surg2013; 70: 675-9.DOI: 10.1097/SAP.0b013e3182764fb0.
4. Amanda Peltier, etal. Painfuldiabetic neuropathy[J]. BMJ, 2014, 348: g1799. DOI:10.1136/bmj.g1799.
5. Shridhar Iyer, etal. Pharmacologicmanagement of diabetic peripheral neuropathic pain. ExpertOpin. Pharmacother,2013, 14: 1765 ~ 1775. DOI: 10.1517/14656566.2013.811490.
6. Eva Tiecke, etal. First-in-HumanSingle-Ascending-Dose, Multiple-Dose, and Food Interaction Studies of NRD.E1,an Innovative Nonopioid Therapy for PainfulDiabetic Peripheral Neuropathy. Clinical Pharmacology in Drug Development2022, 0(0) 1–16. DOI: 10.1002/cpdd.1103.
7. Eva Tiecke, etal. NRD.E1,an innovative non-opioid therapy for painful diabetic peripheral neuropathy—Arandomized proof of concept study. Eur J Pain. 2022;00:1–14. DOI: 10.1002/ejp.1989 .
