Small Fiber Neuropathy

Charles River will help bring NT-Z001 to the clinic by leveraging its off-the-shelf plasmid products, custom plasmid capabilities and adeno-associated virus (AAV) production. After charting multiple personalized medicine expansions in recent years, contract manufacturer Charles River Laboratories is back with another gene therapy pact—this time centered on an adeno-associated virus 9 (AAV9) candidate meant to serve as a non-opioid alternative for rare disease patients living with chronic pain. Charles River on Thursday announced a new accord with epigenetic gene therapy outfit Navega Therapeutics as part of the CDMO’s Cell and Gene Therapy Accelerator Program. The deal will grant Navega access to Charles River’s contract development and manufacturing capabilities and advisory services to produce the AAV gene therapy candidate NT-Z001 for phase 1 clinical trials, the companies said in a press release. Navega is positioning its gene therapy candidate to help treat chronic pain associated with rare diseases like small fiber neuropathy and primary erythromelalgia. The drug leverages Navega’s artificial intelligence-enabled zinc-finger gene-editing platform, the company explained. NT-Z001 specifically addresses a gain-of-function mutation in the Nav 1.7 gene, which is linked to inherited erythromelalgia, small fiber neuropathy and other chronic, debilitating pain disorders. Aside from pain tied to rare diseases, Navega figures its gene therapy could eventually address other pain indications, including neuropathic and inflammatory pain. Charles River, for its part, will help bring NT-Z001 to the clinic by leveraging its off-the-shelf plasmid products, custom plasmid capabilities and AAV production. Over the years, Charles River says it has significantly enhanced its cell and gene portfolio through a mix of acquisitions, capacity expansions and manufacturing platform launches, including eXpDNA for plasmids, nAAVigation for AAV and Lentivation for lentiviral vectors. Back in November 2022, the company debuted the expansion of its cell therapy manufacturing facility in Memphis, Tennessee. The plant reveal came just weeks after the CDMO opened a separate plasmid production facility in the U.K. Under the expansion, Charles River added nine processing suites to its 16 clean rooms at the Memphis site. The additions were designed to handle high-volume production—plus options for dual production lines—for late-stage clinical and commercial cell therapies, the company said at the time. Charles River also recently acquired a site in Rockville, Maryland, through its $350-million buyout of gene therapy CDMO Vigene Biosciences back in 2021. The site largely helps with the production of viral vectors, which have experienced supply constraints among advanced cell and gene therapies for several years. Elsewhere on the personalized medicines front, Charles River last year linked up with South Korea’s Rznomics to develop and crank out viral vectors for its partner’s experimental liver cancer gene therapy RZ-001. RZ-001 marks the first ribozyme-based RNA reprogramming approach to receive FDA authorization for evaluation in humans, the companies said last January.

WEDNESDAY, Jan. 10, 2024 -- Patients with post- COVID-19 vaccination postural orthostatic tachycardia syndrome (POTS) all have preexisting conditions, according to a study published in the January issue of Heart Rhythm . Debbie Lin Teodorescu, M.D., from the Cedars-Sinai Medical Center in Los Angeles, and colleagues prospectively collected data from 10 patients in a POTS clinic between July 2021 and June 2022 reporting new or exacerbated POTS symptoms after COVID-19 vaccination. Heart rate variability (HRV) and skin sympathetic nerve activity (SKNA) were compared between the patients and 24 healthy controls. Conditions that could increase the risk for POTS were seen in all patients, including previous COVID-19 infection, hypermobile Ehlers-Danlos syndrome, mast cell activation syndrome, and autoimmune, cardiac, neurological, or gastrointestinal conditions. The researchers found that compared with controls, a lower ambulatory root mean square of successive differences was seen in HRV for patients (46.19 ± 24 versus 72.49 ± 40.8 ms). Reduced mean amplitude was seen in SKNA for patients versus controls (0.97 ± 0.052 versus 1.2 ± 0.31 µV); burst amplitude was also reduced (1.67 ± 0.16 versus 4.3 ± 4.3 µV). All patients reported improvement with the usual POTS care after 417.2 ± 131.4 days of follow-up; relapses of POTS symptoms were reported in two with COVID-19 reinfection and one with small fiber neuropathy. "These findings suggest it may be helpful to keep an eye on patients with underlying health issues after COVID-19 vaccination to monitor for postvaccine POTS," coauthor Peng-Sheng Chen, M.D., also from the Cedars Sinai Medical Center, said in a statement. Abstract/Full Text (subscription or payment may be required) Disclaimer: Statistical data in medical articles provide general trends and do not pertain to individuals. Individual factors can vary greatly. Always seek personalized medical advice for individual healthcare decisions. Posted January 2024 Further Support and Information on COVID-19 COVID-19: Prevention & Investigational Treatments COVID-19 Support Group Coronavirus Disease Guide More news resources FDA Medwatch Drug Alerts Daily MedNews News for Health Professionals New Drug Approvals New Drug Applications Drug Shortages Clinical Trial Results Generic Drug Approvals Subscribe to our newsletter Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

– Treatment with the NaV1.8 inhibitor VX-548 led to statistically significant and clinically meaningful reduction in the primary endpoint of change from baseline in the Numeric Pain Rating Scale (NPRS) – – VX-548 was generally well tolerated – – Vertex plans to advance VX-548 into pivotal development in diabetic peripheral neuropathic pain following discussions with regulators – – VX-548 Phase 2 study in patients with painful lumbosacral radiculopathy, another type of peripheral neuropathic pain, has initiated – – Vertex to host investor call December 13 at 8:00 a.m. ET – BOSTON, MA, USA I December 13, 2023 I Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced positive results from its Phase 2 dose-ranging study of the selective NaV1.8 inhibitor VX-548 in people with painful diabetic peripheral neuropathy (DPN). Treatment with all doses of VX-548 resulted in a statistically significant and clinically meaningful reduction in the primary endpoint of change from baseline in the weekly average of daily pain intensity on a Numeric Pain Rating Scale (NPRS) at Week 12. The study also included an active reference arm of pregabalin to support the evaluation of the VX-548 treatment effect. VX-548 was generally well tolerated at all doses tested in the study. Most adverse events (AEs) were mild to moderate and there were no serious adverse events (SAEs) related to VX-548. “We are very pleased with these results which add to the body of safety and efficacy data for VX-548 and provide further validation of the analgesic effects of NaV1.8 inhibitors,” said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex. “Given the favorable benefit/risk profile of VX-548 seen in this study, we are working with urgency to advance this investigational non-opioid pain medicine into Phase 3 in painful diabetic neuropathy with the goal of changing the standard of care for neuropathic pain, where treatment options are limited. In addition, our Phase 3 studies of VX-548 in acute pain are on track to read out in the first quarter of 2024.” “I am excited by the results from the VX-548 Phase 2 DPN study, which demonstrate a promising safety and efficacy profile and represent a significant milestone in pain management,” said Roy Freeman, M.D., Professor of Neurology, Director of the Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center and a member of Vertex’s Pain Steering Committee. “Based on these Phase 2 results, VX-548 could offer the potential for a new class of medicine for the millions of patients suffering from neuropathic pain who are desperate for new options.” Efficacy Results The study’s primary endpoint was change from baseline in the weekly average of daily pain intensity at Week 12 in patients with painful DPN dosed with VX-548 using the standard pain assessment Numeric Pain Rating Scale, or NPRS. This 11-point scale ranges from 0 (no pain) to 10 (worst pain imaginable). Patients were randomized to four treatment arms: VX-548 once daily at 69 mg (high dose), 46 mg (mid dose), or 23 mg (low dose), or the reference arm of pregabalin 100 mg three times per day (TID) for 12 weeks. All VX-548 treatment groups showed statistically significant and clinically meaningful reductions from baseline in pain with mean change in NPRS at Week 12 of -2.26, -2.11 and -2.18 at the high, mid and low doses, respectively. The pregabalin reference arm mean change from baseline in NPRS at Week 12 was -2.09 and is provided for context. All VX-548 dose groups had sustained mean reductions in pain from baseline starting at Week 1, with pain continuing to decrease until Week 5, which was then maintained throughout the treatment period. Secondary and other endpoints were supportive of the study’s primary endpoint. Importantly, in the responder analysis, more than 30% of patients treated with VX-548 achieved ≥50% reduction in all dose groups, and more than 20% of patients in the mid- and high-dose groups achieved ≥70% reduction in weekly average of NPRS at Week 12 compared to baseline. In the pregabalin reference arm, 22% of patients achieved ≥50% reduction and 10% achieved ≥70% reduction in weekly average of NPRS at Week 12 compared to baseline. Primary Efficacy Outcomes The three VX-548 doses achieved overlapping exposures at the high end of the expected therapeutic range. Safety Results VX-548 was generally well tolerated at all doses studied for up to 12 weeks of treatment. The majority of the AEs were mild or moderate in severity. There were no SAEs related to VX-548 or pregabalin in the study. There was one death in the mid-dose VX-548 group due to atherosclerotic cardiovascular disease, which was not related to study drug. The most common AEs (incidence >5% in either VX-548 combined or pregabalin group, respectively) were creatinine clearance decrease (5.1%, 1.9%), dizziness (0.7%, 9.3%), peripheral edema (0.7%, 5.6%) and weight increased (0%, 7.4%). Related AEs were 14.5% in patients treated with VX-548 and 27.8% in patients treated with pregabalin. Next Steps for the Pain Portfolio Vertex plans to advance VX-548 into pivotal development following discussions with regulators. Vertex has also initiated a second Phase 2 study of VX-548 in peripheral neuropathic pain. This trial will evaluate VX-548 in patients with painful lumbosacral radiculopathy, or LSR, which is pain caused by impairment or injury to nerve roots in the area of the lumbar spine. Additionally, the three Phase 3 studies of VX-548 in acute pain are on track to read out in the first quarter of 2024. In line with its portfolio strategy, Vertex continues to advance preclinical and clinical development of additional NaV1.8 and NaV1.7 inhibitors, for use alone or in combination, in acute and neuropathic pain. Conference Call and Webcast The company will host a conference call and webcast at 8:00 a.m. ET on December 13. To access the call, please dial (833) 630-2124 (U.S.) or +1 (412) 317-0651 (International) and reference the “Vertex Pharmaceuticals Conference Call.” The conference call will be webcast live and a link to the webcast can be accessed through Vertex's website at www.vrtx.com in the "Investors" section. To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast. An archived webcast will be available on the company's website. About the VX-548 Phase 2 Study in Diabetic Peripheral Neuropathy The Phase 2 study was a randomized, double-blind, active-controlled, dose-ranging study evaluating the efficacy and safety of VX-548 in people aged 18 to 80 years with painful diabetic peripheral neuropathy. A total of 192 patients with bilateral pain in the lower extremities due to diabetic peripheral neuropathy for at least one year were enrolled in this study. Patients were randomized to four treatment arms: VX-548 once daily of 69 mg (high dose), 46 mg (mid dose) or 23 mg (low dose), or the reference arm of pregabalin 100 mg three times per day. The primary endpoint of the study was the change from baseline in the weekly average of daily pain intensity on a Numeric Pain Rating Scale (NPRS) at Week 12. About Peripheral Neuropathic Pain Peripheral neuropathic pain, or PNP, is a significant area of unmet need for patients suffering from pain. PNP is a collection of chronic conditions including painful diabetic peripheral neuropathy (DPN), painful lumbosacral radiculopathy (LSR), painful small fiber neuropathy and trigeminal neuralgia. Painful DPN and LSR are two of the largest segments within the estimated 10 million patients who are prescribed a medicine for peripheral neuropathic pain every year in the U.S. About VX-548 VX-548 is an investigational oral, selective NaV1.8 inhibitor that is highly selective for NaV1.8 relative to other NaV channels. NaV1.8 is a voltage-gated sodium channel that plays a critical role in pain signaling in the peripheral nervous system. NaV1.8 is a genetically validated target for the treatment of pain, and Vertex has previously demonstrated positive proof-of-concept results and a well-tolerated profile with VX-548 in two Phase 2 studies of acute pain following abdominoplasty and bunionectomy surgeries. Vertex’s approach is to selectively inhibit NaV1.8 using small molecules with the objective of creating a new class of medicines that have the potential to provide superior relief of pain without the limitations of opioids, including their addictive potential. VX-548 is one of the most recent molecules to enter clinical development from Vertex’s portfolio of NaV1.8 inhibitors. About Vertex Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has approved medicines that treat the underlying causes of multiple chronic, life-shortening genetic diseases — cystic fibrosis, sickle cell disease and transfusion-dependent beta thalassemia — and continues to advance clinical and research programs in these diseases. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including APOL1-mediated kidney disease, acute and neuropathic pain, type 1 diabetes and alpha-1 antitrypsin deficiency. Vertex was founded in 1989 and has its global headquarters in Boston, with international headquarters in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 14 consecutive years on Science magazine's Top Employers list and one of Fortune’s 100 Best Companies to Work For. For company updates and to learn more about Vertex's history of innovation, visit www.vrtx.com or follow us on LinkedIn , Facebook , Instagram , YouTube and Twitter/X . SOURCE: Vertex Pharmaceuticals