vixotrigine (BIIB074) / Biogen, GSK - LARVOL DELTA

Therapeutic Approach for Trigeminal Neuralgia: A Systematic Review. (PubMed, Biomedicines) - "Carbamazepine and oxcarbazepine continue to be the first choice for medication for classical TN...Drug combinations using carbamazepine, baclofen, gabapentin, ropivacaine, tizanidine, and pimozide can yield satisfactory results and improve the tolerance to the treatment...Proparacaine, dextromethorphan, and tocainide were reported to be inappropriate for treating TN...New research on other drugs, combination therapies, and newer formulations, such as vixotrigine, is awaited. There is conclusive evidence for the efficacy of pharmacological drugs in the treatment of TN."

Journal • Review • Neuralgia • Pain

Structural mapping of Na1.7 antagonists. (PubMed, Nat Commun) - "A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na channels summarized from the present and previous structures."

Journal • Atrial Fibrillation • Cardiovascular • CNS Disorders • Epilepsy • Pain

Efficacy and safety of vixotrigine in idiopathic or diabetes-associated painful small fibre neuropathy (CONVEY): a phase 2 placebo-controlled enriched-enrolment randomised withdrawal study. (PubMed, EClinicalMedicine) - P2 | "Vixotrigine (at both dosages) was well tolerated in participants with SFN. Biogen, Inc."

Journal • P2 data • Diabetes • Diabetic Neuropathy • Infectious Disease • Metabolic Disorders • Nephrology • Pain • Peripheral Neuropathic Pain

SURGE-1: 802NP301 Efficacy and Safety Study of BIIB074 in Participants With Trigeminal Neuralgia (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Biogen | N=88 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Neuralgia • Pain

SURGE-2t: 802NP302 Efficacy and Safety Study of BIIB074 in Participants With Trigeminal Neuralgia (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Biogen | N=88 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Neuralgia • Pain

Spontaneous activity in organotypic cultures of human spinal cord slices: potential for use in the drug discovery process (Neuroscience 2022) - "Next we used a group of sodium channel modulators (carbamazepine, lacosamide, and mexiletine) that are known to have CNS-related side effects (including dizziness, nausea, mood swings and depression) at their FTPC. Conversely, the SA IC50 for vixotrigine was right-shifted relative to its FTPC range, in agreement with prior studies indicating that it is a well-tolerated drug. In conclusion, these initial data indicate that SA can be reliably measured in adult human CNS tissue up to 3 weeks in vitro and that organotypic hSC slice cultures can provide a valuable translational tool for the evaluation of the safety and possible efficacy of novel CNS drug candidates."

CNS Disorders • Depression • Psychiatry

Evaluation of the Effect of Uridine Diphosphate-Glucuronosyltransferases (UGT) Inhibition by Valproic Acid on Vixotrigine Pharmacokinetics in Healthy Volunteers. (PubMed, Clin Drug Investig) - P1 | "Valproic acid, a uridine diphosphate-glucuronosyltransferase inhibitor, significantly increased vixotrigine systemic exposure."

Journal • PK/PD data • Neuralgia • Pain

Development of a late-stage process to vixotrigine (ACS-Fall 2022) - "The evolution of the process from early development to a commercial-ready process will be presented. Key improvements discussed are: 1) Streamlining and optimization of the early synthesis 2) Design of a continuous process for the synthesis a key intermediate 3) Development of the final API step to produce material with desired particle properties."

Discovery and early development of the use-dependent sodium channel blocker vixotrigine (ACS-Fall 2022) - "The properties that led to the selection of this candidate are described. The choice of initial synthetic strategy and the development of an early scalable synthesis are examined."

Pharmacotherapeutic Management of Trigeminal Neuropathic Pain: An Update. (PubMed, Expert Opin Pharmacother) - "Guidelines reported the most effective treatment for trigeminal neuropathy, in particular trigeminal neuralgia, appears to be carbamazepine or oxcabazepine, but side effects can be treatment limiting. Lamogitrine and gabapentin are also recommended in guidance. In real-world clinical practice, baclofen, cannabinoids, eslicarbazepine, levetiracetam, brivaracetam, lidocaine, misoprostol, opioids, phenytoin, fosphenytoin, pimozide, sodium valproate, sumatriptan, tizanidine, tocainide, tricyclic antidepressants, and vixotrigine are sometimes used, either as monotherapy or in combination...While there is no optimal pharmacotherapy for treating trigeminal neuropathy, advancements in our understanding of the underlying mechanisms of this condition and drug development indicate promise for NaV inhibitors, despite the fact that not all patients respond to them and they may have potentially treatment-limiting side effects. Nevertheless, better understanding of NaV channels may be..."

Journal • Neuralgia • Pain

BIOGEN INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-Q) (Market Screener) - "We have engaged with the FDA regarding the design of the Phase 3 studies of vixotrigine for the potential treatment of TGN and DPN and are now performing an additional clinical trial of vixotrigine, which is expected to be completed by the end of 2022. The performance of this additional clinical trial delayed the initiation of the Phase 3 studies of vixotrigine for the potential treatment of TGN, and, as a result, we recognized an impairment charge of $44.3 million related to vixotrigine for the potential treatment of TGN during the first quarter of 2021."

Clinical protocol • Trial completion date • Diabetic Neuropathy • Neuralgia • Pain • Peripheral Neuropathic Pain

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets. (PubMed, Front Pain Res (Lausanne)) - "Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing "pain" as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a..."

Journal • Review • Hematological Malignancies • Immunology • Inflammatory Arthritis • Lymphoma • Neuralgia • Oncology • Pain • Rheumatoid Arthritis • Rheumatology • T Cell Non-Hodgkin Lymphoma • TAP1

Optimal pH 8.5 to 9 for the Hydrolysis of Vixotrigine and Other Basic Substrates of Carboxylesterase-1 in Human Liver Microsomes. (PubMed, Xenobiotica) - "The hydrolysis reaction was identified to be catalyzed by recombinant human CES1b.Initial observation of only trace level formation of M14 in human liver microsomes at pH 7.4 caused us to doubt the involvement of CES1, an enzyme localized at the endoplasmic reticulum and the dominant carboxylesterase in human liver. Further investigation has revealed that optimal pH for the hydrolysis of vixotrigine and two other basic substrates of CES1, methylphenidate and oseltamivir, in human liver microsomes was pH 8.5 to 9 which is higher than their respective pK suggesting that neutral form of basic substrates is probably preferred for CES1 catalysis in liver microsomes."

Journal • Neuralgia • Pain • CES1

Biogen Announces Positive Topline Results from Phase 2 CONVEY Study in Small Fiber Neuropathy (Businesswire) - P2, N=265; CONVEY(NCT03339336); Sponsor: Biogen; "Biogen Inc...announced positive topline results from its Phase 2 CONVEY study of vixotrigine (BIIB074)...evaluated for the treatment of small fiber neuropathy (SFN)....The CONVEY study 200 mg twice daily arm met its primary endpoint of change from baseline to week 12 of the double-blind period in mean average daily pain (ADP) score....While the 350 mg twice daily arm did not meet the primary endpoint, it met statistical significance in the Patient Global Impression of Change (PGIC) at week 12, an important self-reported measure of a patient’s overall improvement since with the start of the study. The totality of data from the vixotrigine program will inform potential doses for study in future Phase 3 clinical trials."

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

"Nonopioid Med #Vixotrigine Promising for #NeuropathicPain. #Nav1_7 #SodiumChannel https://t.co/knJci9X1UW via @medscape @biogen" (@westr)

Neuralgia • Peripheral Neuropathic Pain

SURGE-1: 802NP301 Efficacy and Safety Study of BIIB074 in Participants With Trigeminal Neuralgia (clinicaltrials.gov) - P3; N=88; Not yet recruiting; Sponsor: Biogen; Trial completion date: Mar 2025 ➔ Aug 2026; Trial primary completion date: Apr 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Neuralgia • Pain • Peripheral Neuropathic Pain

SURGE-2t: 802NP302 Efficacy and Safety Study of BIIB074 in Participants With Trigeminal Neuralgia (clinicaltrials.gov) - P3; N=88; Not yet recruiting; Sponsor: Biogen; Trial completion date: Apr 2025 ➔ Sep 2026; Trial primary completion date: Apr 2024 ➔ Aug 2025

Trial completion date • Trial primary completion date • Neuralgia • Pain • Peripheral Neuropathic Pain

Medical Management of Trigeminal Neuralgia. (PubMed, Neurol India) - "Carbamazepine (CBZ) is the gold standard of treatment for TN. The first-line drugs for the treatment of TN are CBZ and oxcarbazepine (OXC)...The second-line drugs comprise lamotrigine, baclofen, gabapentin, and pregabalin used as monotherapy or in combination with CBZ/OXC...Newer drug like vixotrigine has shown good results in phase two randomized control trials...Combination therapy with second-line or other drugs may become necessary with poor response to CBZ/OXC, or if adverse events occur. Patients should be offered surgical options if there is poor response or tolerance to the medical therapy."

Journal • Review • Neuralgia • Pain • Peripheral Neuropathic Pain

Efficacy and Safety Study of BIIB074 in Participants With Small Fiber Neuropathy (clinicaltrials.gov) - P2; N=265; Terminated; Sponsor: Biogen; N=186 ➔ 265; Trial completion date: Jun 2022 ➔ Apr 2021; Active, not recruiting ➔ Terminated; Trial primary completion date: Jun 2022 ➔ Apr 2021; Sponsor decision to close study early; not due to safety concerns

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Diabetes • Diabetic Neuropathy • Metabolic Disorders • Pain

Efficacy and Safety Study of BIIB074 in Participants With Small Fiber Neuropathy (clinicaltrials.gov) - P2; N=186; Active, not recruiting; Sponsor: Biogen; Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Diabetic Neuropathy • Metabolic Disorders • Pain

Population Pharmacokinetics of Vixotrigine in Healthy Volunteers and Subjects with Trigeminal Neuralgia, Painful Lumbosacral Radiculopathy and Erythromelalgia. (PubMed, Eur J Drug Metab Pharmacokinet) - "The model characterizes the pharmacokinetics of vixotrigine well, and the exposure of vixotrigine was comparable between healthy subjects and patients. None of the covariates evaluated have a clinically relevant impact on the pharmacokinetics of vixotrigine."

Clinical • Journal • PK/PD data • Neuralgia • Pain • Peripheral Neuropathic Pain

Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker. (PubMed, Mol Pharmacol) - "Compared with carbamazepine, vixotrigine shows higher potency and more profound state-dependent inhibition but a similar broad spectrum of action distinct from Nav1.7- and Nav1.8-specific blockers. SIGNIFICANCE STATEMENT: Vixotrigine blocks both peripheral and central voltage-gated sodium channel subtypes. Neurophysiological approaches in recombinant systems and sensory neurons suggest this block is state-dependent."

Journal • CNS Disorders • Epilepsy • Neuralgia • Pain • Peripheral Neuropathic Pain

Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers. (PubMed, Clin Transl Sci) - "Steady state was achieved from day 5 onward. These data indicate that oral vixotrigine is well tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily."

Clinical • Journal • PK/PD data • CNS Disorders • Depression • Mood Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • Psychiatry • Sleep Disorder

SURGE-1: 802NP301 Efficacy and Safety Study of BIIB074 in Participants With Trigeminal Neuralgia (clinicaltrials.gov) - P3; N=88; Not yet recruiting; Sponsor: Biogen; Trial primary completion date: Jan 2024 ➔ Apr 2024

Clinical • Trial primary completion date • Neuralgia • Pain • Peripheral Neuropathic Pain

Evaluation of the Potential Pharmacokinetic Interactions Between Vixotrigine and an Oral Contraceptive. (PubMed, Clin Drug Investig) - P1 | "Coadministration of vixotrigine and an oral contraceptive containing ethinyl estradiol and levonorgestrel had no clinically relevant effect on exposure of all three compounds."

Journal • PK/PD data • Neuralgia • Pain • Peripheral Neuropathic Pain