pilavapadin (LX9211) / Lexicon Pharma, BMS - LARVOL DELTA

Renal Function Does Not Affect Pilavapadin Pharmacokinetics: Results from a Phase 1, Open-Label, Parallel-Group Study (ADA 2026) - "Mild to moderate renal impairment does not have a meaningful effect on the PK and safety of pilavapadin in patients with CrCl ≥ 30 mL/min."

Clinical • Late-breaking abstract • P1 data • PK/PD data • Diabetic Neuropathy • Metabolic Disorders

Additional Efficacy Data Support Selection of Pilavapadin 10mg for Phase Three Development in DPNP: Results From PROGRESS (AAN 2026) - "The 10-mg dose was generally well tolerated over 8 weeks, with completion rates comparable to placebo and few discontinuations due to TEAEs. These findings support advancing pilavapadin 10 mg to Phase 3 evaluation in DPNP."

Clinical • Diabetic Neuropathy • Musculoskeletal Pain • Neuralgia • Peripheral Neuropathic Pain

Preclinical Evidence Supporting Pilavapadin as a Novel Oral Therapy for Spasticity (AAN 2026) - "Background Current oral therapies for spasticity, such as baclofen and tizanidine, provide only partial benefit and are often limited by sedation...Results In mice, pilavapadin significantly improved tcMEP latency (5.55 ± 0.22ms at 10 mg/kg; 5.32 ± 0.22ms at 3 mg/kg vs. 10.05 ± 2.59ms for vehicle; both p<0.05) and peak-to-peak amplitude (11,613.75 ± 1154.41 µV at 10 mg/kg; 11,321.67 ± 1321.68 µV at 3 mg/kg vs. 7681.17 ± 1505.12 µV for vehicle; both p<0.001) on day 10, with effects comparable to fingolimod and tizanidine...Conclusions Pilavapadin demonstrated significant, sustained effects measures of spasticity in two validated preclinical models. These findings support further development of pilavapadin as a potential oral therapy for spasticity with a favorable tolerability profile."

Preclinical • CNS Disorders • Depression • Movement Disorders • Multiple Sclerosis

New pharmacological agents and emerging therapeutic targets for painful diabetic neuropathy. (PubMed, Front Endocrinol (Lausanne)) - "Recent clinical trials have demonstrated promising outcomes for pilavapadin (LX9211), an orally administered selective, potent inhibitor of adapter protein-2-associated kinase 1 (AAK1) and vixotrigine, a broad spectrum voltage-gated sodium channels (Navs) inhibitor. Limited evidence exists regarding the therapeutic potential of antidiabetic agents, glucagon-like peptide-1 receptor agonists (GLP-1RAs), being most widely studied in experimental settings. Future large clinical trials are now required to confirm the efficacy of novel promising agents and to delineate further potential favourable effects of antidiabetic agents in clinical settings."

Journal • Review • Diabetes • Diabetic Neuropathy • Metabolic Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • CCR2 • CXCR1 • PARP1 • TRPV1

Pilavapadin, an oral, non-opioid, AAK1 inhibitor for diabetic peripheral neuropathic pain (DPNP): results from a Phase 2b, dose-ranging, randomised, placebo-controlled, multicenter study (EASD 2025) - P2 | "These data support the advancement of pilavapadin 10 mg into Phase 3 trials as a promising non-opioid treatment for DPNP"

Clinical • P2b data • Diabetes • Diabetic Neuropathy • Metabolic Disorders

LX9211, a novel AAK1 inhibitor, alleviates pain in preclinical models of chemotherapy-induced neuropathic pain and multiple sclerosis (NeuPSIG 2025) - "These studies support further clinical evaluation of LX9211 as a novel, non-opioid treatment option for peripheral neuropathic pain."

Preclinical • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain

Study design and rationale of PROGRESS: Pilavapadin in a phase 2b, dose-ranging, double-blind, placebo-controlled study in diabetic peripheral nuropathic pain (NeuPSIG 2025) - "PROGRESS is a Phase 2b study in individuals with DPNP, evaluating the efficacy of pilavapadin to reduce neuropathic pain. This study has a pragmatic trial design allowing the participants to continue on their stable standard-of-care therapy that mirrors how new therapies for this indication will be used in the real-world. Results of this trial may provide evidence to support the further development of pilavapadin for the treatment of DPNP."

Clinical • P2b data • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • RB1

Listening to Patients with Diabetic Peripheral Neuropathic Pain: Insights from a Patient Survey to Inform Advanced Clinical Development of Pilavapadin (PAINWeek 2025) - "Many respondents (74.8%) reported use of pregabalin or gabapentin, with 72% reporting daily use. Two hundred fifty-three respondents took the survey and 38 were screened out. Of the 215 respondents surveyed, 66.5% were female, 76.7% had T2D, 22.3% had T1D, and 96.3% had DPNP symptoms for greater than 1 year. The most commonly experienced DPNP symptoms were: (81.7%) pins/needles, (77.9%) tingling, (73.1%) burning pain, (58.1%) stabbing pain, (57.2%) electric-shock."

Clinical • Metastases • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Neuralgia • Pain • Peripheral Neuropathic Pain • Psychiatry • Sleep Disorder

Study design and rationale of PROGRESS: Pilavapadin in a phase 2b, dose-ranging, double-blind, placebo-controlled study in diabetic peripheral nuropathic pain (NeuPSIG 2025) - "PROGRESS is a Phase 2b study in individuals with DPNP, evaluating the efficacy of pilavapadin to reduce neuropathic pain. This study has a pragmatic trial design allowing the participants to continue on their stable standard-of-care therapy that mirrors how new therapies for this indication will be used in the real-world. Results of this trial may provide evidence to support the further development of pilavapadin for the treatment of DPNP."

Clinical • P2b data • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • RB1

Pilavapadin, an Oral, Non-opioid, AAK1 Inhibitor for Diabetic Peripheral Neuropathic Pain (DPNP)—Results from a Phase 2b, Dose-Ranging, Randomized, Multicenter Study (ADA 2025) - "These data support the advancement of pilavapadin 10 mg into Phase 3 trials as a promising non-opioid treatment for DPNP."

Clinical • Late-breaking abstract • P2b data • Diabetic Neuropathy • Metabolic Disorders

PROGRESS: A Dose-ranging Study in Patients With Diabetic Peripheral Neuropathic Pain (DPNP) (clinicaltrials.gov) - P2 | N=496 | Completed | Sponsor: Lexicon Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Lexicon Pharmaceuticals Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Updates (GlobeNewswire) - "Pilavapadin (LX9211) for DPNP: The Company is moving toward an end of Phase 2 meeting with FDA and targeting initiation of U.S. and ex-U.S. Phase 3 trials in DPNP in 2025, while selecting a future medical meeting for release of additional clinical data later this year....LX9851 for Obesity and Associated Cardiometabolic Disorders: LX9851 is progressing in IND-enabling studies and on track for a 2025 investigational new drug (IND) application submission. Zynquista (sotagliflozin): Discontinued preparation for potential Zynquista launch in type 1 diabetes following receipt of complete response letter from FDA."

Discontinued • IND • New P3 trial • P3 data • Diabetic Neuropathy • Obesity • Peripheral Neuropathic Pain • Type 1 Diabetes Mellitus

Lexicon Pharmaceuticals Announces Topline Results from Phase 2b PROGRESS Study Evaluating Pilavapadin (LX9211) in Adults with Diabetic Peripheral Neuropathic Pain (GlobeNewswire) - P2b | N=416 | PROGRESS (NCT06203002) | Sponsor: Lexicon Pharmaceuticals | "In the PROGRESS study, all pilavapadin treatment arms demonstrated reductions in the mean average daily pain score (ADPS) from baseline to Week 8 with the 10 mg, 20 mg/10 mg and 20 mg dose arms achieving reductions of 1.74, 1.70 and 1.38, respectively, compared to a reduction of 1.31 in the placebo arm...As a result of the lack of separation in ADPS reduction between the 20 mg dose arm and placebo, the study results did not reach statistical significance on the primary endpoint (p=0.11). However, the 10 mg dose arm demonstrated clear evidence of effect by achieving early and clinically meaningful separation from placebo on ADPS that was maintained throughout the study duration. Adverse events were more frequent in the pilavapadin treatment arms, but were significantly improved from the RELIEF-DPN-1 study across all doses. Nearly all adverse events were reported as mild or moderate."

P2b data • Peripheral Neuropathic Pain

Lexicon Pharmaceuticals to Announce Topline Results from Phase 2b PROGRESS Study Evaluating Pilavapadin (LX9211) in Adults with Diabetic Peripheral Neuropathic Pain (GlobeNewswire) - "Lexicon Pharmaceuticals...announced the Company will hold a conference call and webcast on Monday, March 3, 2025 at 8:00 a.m. ET to share topline results from the Phase 2b PROGRESS (A Phase 2b, Dose-ranging, Randomized, Double-blind, PlacebO-controlled, Parallel-GRoup, MulticEnter Study with an Open-label Extension in PatientS with Diabetic Peripheral Neuropathic Pain) study evaluating pilavapadin (LX9211), an oral, non-opioid investigational adaptor-associated kinase 1 (AAK1) inhibitor in adult patients with moderate to severe diabetic peripheral neuropathic pain (DPNP)."

P2b data • Diabetic Neuropathy • Peripheral Neuropathic Pain

LX9211, a rising star for relieving of diabetic peripheral neuropathic pain. (PubMed, J Diabetes Investig) - "Although the higher dose was less effective, side effects like dizziness and nausea were generally mild. These findings highlight the importance of exploring both pharmaceutical and natural treatments, such as flavonoids, for managing DPN."

Journal • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Lexicon Announces Virtual Webcast on LX9211 for Diabetic Peripheral Neuropathic Pain (GlobeNewswire) - "Lexicon Pharmaceuticals...today announced that the company will host a virtual webcast...The event will be held from 9:00 a.m. to 11:00 a.m. ET on January 28, 2025...In advance of topline data from the Phase 2b PROGRESS trial anticipated later this quarter, the event will offer an in-depth overview on LX9211 for the treatment of diabetic peripheral neuropathic pain (DPNP), featuring remarks from Lexicon leaders....In addition to presentations by the Lexicon leadership team, the event will include an expert panel and Q&A session on DPNP..."

Clinical • P2b data • Pain • Peripheral Neuropathic Pain

Lexicon Announces Receipt of Complete Response Letter for Zynquista (sotagliflozin) (GlobeNewswire) - "Lexicon Pharmaceuticals...announced it has received a complete response letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding the New Drug Application (NDA) for Zynquista (sotagliflozin) as an adjunct to insulin therapy for glycemic control in adults with type 1 diabetes and chronic kidney disease (CKD). This expected communication from the FDA aligns with the company’s previously disclosed strategic decision to discontinue launch preparations for Zynquista and focus solely on its clinical development pipeline....'We remain steadfast in our commitment to advancing our clinical pipeline, including our near-term focus on LX9211 for diabetic neuropathic pain (DPNP) with top line data from our PROGRESS Phase 2b study anticipated in Q1 2025'."

CRL • P2b data • Chronic Kidney Disease • Diabetic Neuropathy • Peripheral Neuropathic Pain • Type 1 Diabetes Mellitus

Discovery and evaluation of HW161023 as a potent and orally active AAK1 inhibitor. (PubMed, Bioorg Med Chem Lett) - "LX9211 is currently the only selective small molecule AAK1 inhibitor at the clinical trial stage for diabetic peripheral neuropathic pain, which was found to be safe and well tolerated in healthy participants in phase I clinical trials. The present manuscript described a series of fused-ring derivatives as a novel class of potent AAK1 inhibitors, resulting in the discovery of compound 5, namely HW161023, which showed high inhibitory potency against AAK1 enzyme and satisfactory oral pharmacokinetic profile with weaker HepG2 cell toxicity and hERG inhibition than LX9211."

Journal • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

PROGRESS: A Dose-ranging Study in Patients with Diabetic Peripheral Neuropathic Pain (DPNP) (clinicaltrials.gov) - P2 | N=416 | Active, not recruiting | Sponsor: Lexicon Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Patient Reported Burden of Disease in Postherpetic Neuralgia Pain: Learnings from In-depth Patient Interviews, Sub-study of RELIEF-PHN-1 (PAINWeek 2024) - "LX9211, a potent, small molecule inhibitor of Adapter protein-2 Associated protein Kinase 1 (AAK1), is a novel, non-opioid target for the treatment of NP... Of the 19 patients interviewed, 9 (47%) were female, with a mean age of 67 years. On average, participants had been experiencing symptoms associated with PHN for 6 years. Eight descriptions of symptoms emerged from interview analyses."

Clinical • HEOR • Interview • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain

An overview of the safety and efficacy of LX-9211 in treating neuropathic pain conditions. (PubMed, Expert Opin Investig Drugs) - "In phase 1 and phase 2 clinical trials conducted so far, LX-9211 has been shown to produce few adverse effects as well as cause a significantly greater reduction in pain compared to placebo. However, more clinical studies are needed to further assess its effects in humans to ensure its safety."

Journal • Review • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Patient-Reported Burden of Disease in Diabetic Peripheral Neuropathic Pain—Learnings from In-depth Patient Interviews—Substudy of RELIEF-DPN 1 (ADA 2024) - "RELIEF-DPN 1, a Phase 2 study in adult patients with Type 1 or 2 diabetes and moderate to severe established DPNP, evaluated the safety and efficacy of LX9211, a potent non-opioid inhibitor of AP2-associated protein kinase 1 (AAK1)... This sub-study demonstrates that, from patients' perspectives, symptoms and aspects of daily living impacted by DPNP are considerably burdensome to patients. This study highlights a pressing need for improved therapy and innovation in DPNP management."

Clinical • HEOR • Interview • Diabetic Neuropathy • Metabolic Disorders

Efficacy and Safety of LX9211 for Relief of Diabetic Peripheral Neuropathic Pain (RELIEF-DPN 1): Results of a Double-Blind, Randomized, Placebo-Controlled, Proof-of-Concept Study. (PubMed, Diabetes Care) - "These preliminary findings of improvement in DPNP with LX9211 support further investigation in larger trials."

Journal • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Data From Lexicon’s RELIEF-DPN 1 Phase 2 Study of LX9211 Published Today in Diabetes Care, a Peer-Reviewed Journal of the American Diabetes Association (GlobeNewswire) - P2 | N=319 | RELIEF-DPN 1 (NCT04455633) | Sponsor: Lexicon Pharmaceuticals | "Lexicon Pharmaceuticals, Inc...has published a research paper on the company’s Phase 2 RELIEF-DPN-1 clinical trial investigating LX9211 for the treatment of diabetic peripheral neuropathic pain (DPNP)....The primary efficacy endpoint under evaluation was the change from baseline to week 6 in average daily pain score (ADPS), which was achieved for subjects participating in the low-dose LX9211 arm. Patient reported outcomes were improved in patients treated with LX9211 and LX9211 was generally well tolerated....An abstract of a Lexicon-sponsored study...will be presented at the 84th Scientific Sessions of the American Diabetes Association on Sunday, June 23, 2024, 12:30 - 1:30 p.m. ET, in the Poster Hall (West A-4-B2), Board No. 484."

P2 data • CNS Disorders • Diabetic Neuropathy • Pain • Peripheral Neuropathic Pain

Findings on the Burdens of Diabetic Peripheral Neuropathic Pain (DPNP) Among Three Lexicon-Sponsored Presentations at the 84th Scientific Sessions of the American Diabetes Association (Lexicon Press Release) - "Lexicon Pharmaceuticals, Inc...today announced that three poster presentations will be delivered during the 84th Scientific Sessions of the American Diabetes Association being held June 21 - 24, 2024 at the Orange County Convention Center in Orlando, Florida."

P2 data • CNS Disorders • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain