作者: Mychaskiw, George ; Ahmadzadeh, Shahab ; Everett, Erin S ; Kaye, Alan D ; Shekoohi, Sahar ; Baptiste, Carlo Jean ; Maitski, Rebecca ; Lehuquet, Arianna M ; Barrie, Sonnah ; Mason, Joseph W ; Varrassi, Giustino ; Plessala, Michael J

PURPOSE OF REVIEWDespite ongoing research into alternative postsurgical pain treatments, opioids remain widely used analgesics regardless of associated adverse effects, including dependence and overdose, as demonstrated throughout the current opioid crisis. This is likely related to a failure in proving the efficacy of alternative analgesics in clinical trials, despite strong evidence supporting the potential for effective analgesia through in vitro studies. While NaV1.7 and NaV1.8 channels have shown to be key components of pain perception, studies regarding pharmacological agents utilizing these channels as targets have largely failed to demonstrate the efficacy of these proposed analgesics when compared to current multimodal pain treatment regimens.RECENT FINDINGSHowever, the novel NaV1.8 channel inhibitor, VX-548 has surpassed previously studied NaV1.8 inhibitors in clinical trials and continues to hold promise of a novel efficacious analgesic to potentially be utilized in multimodal pain treatment on postsurgical patients. Additionally, NaV1.8 is encoded by the SCN10A, which has been shown to be minimally expressed in the brain, suggesting a lower likelihood of adverse effects in the CNS, including dependence and abuse. Novel pharmacologic analgesics that are efficacious without the significant side effects associated with opioids have lacked meaningful development. However, recent clinical trials have shown promising results in the safety and efficacy of the pharmacological agent VX-548. Still, more clinical trials directly comparing the efficacy of VX-548 to standard of care post-surgical drugs, including opioids like morphine and hydromorphone are needed to demonstrate the long-term viability of the agent replacing current opioids with an unfavorable side effect profile.

2024-09-01·Bioorganic & Medicinal Chemistry Letters

Identification of N-(((1S,3R,5S)-adamantan-1-yl)methyl)-3-((4-chlorophenyl)sulfonyl)benzenesulfonamide as novel Nav1.8 inhibitor with analgesic profile

Article

作者: Hu, Shilong ; Fu, Yihang ; Ke, Bowen ; Cao, Zhihua ; Qiu, Jie ; Song, Chi ; Yang, Xi ; Chen, Meiyuan ; Liu, Wencheng ; Zhang, Di ; Luo, Menglan

Chronic pain is a common and challenging clinical problem that significantly impacts patients' quality of life. The sodium channel Nav1.8 plays a crucial role in the occurrence and development of chronic pain, making it one of the key targets for treating chronic pain. In this article, we combined virtual screening with cell membrane chromatography techniques to establish a novel method for rapid high-throughput screening of selective Nav1.8 inhibitors. Using this approach, we identified a small molecule compound 6, which not only demonstrated high affinity and inhibitory activity against Nav1.8 but also exhibited significant inhibitory effects on CFA-induced chronic inflammatory pain. Compared to the positive drug VX-150, compound 6 showed a more prolonged analgesic effect, making it a promising candidate as a Nav1.8 inhibitor with potential clinical applications. This discovery provides a new therapeutic option for the treatment of chronic pain.

2023-06-01·iScience

A novel co-target of ACY1 governing plasma membrane translocation of SphK1 contributes to inflammatory and neuropathic pain

Article

作者: Duan, Guangyou ; Li, Ningbo ; Liu, Baowen ; Zheng, Xuemei ; Cui, LingLing ; Wu, Wenyao ; Zhang, Xianwei

Previous studies validate that inhibiting sodium channel 1.8 (Nav1.8) effectively relieves inflammatory and neuropathic pain. However, Nav1.8 blockers have cardiac side effects in addition to analgesic effects. Here, we constructed a spinal differential protein expression profile using Nav1.8 knockout mice to screen common downstream proteins of Nav1.8 in inflammatory and neuropathic pain. We found that aminoacylase 1 (ACY1) expression was increased in wild-type mice compared to Nav1.8 knockout mice in both pain models. Moreover, spinal ACY1 overexpression induced mechanical allodynia in naive mice, while ACY1 suppression alleviated inflammatory and neuropathic pain. Further, ACY1 could interact with sphingosine kinase 1 and promote its membrane translocation, resulting in sphingosine-1-phosphate upregulation and the activation of glutamatergic neurons and astrocytes. In conclusion, ACY1 acts as a common downstream effector protein of Nav1.8 in inflammatory and neuropathic pain and could be a new and precise therapeutic target for chronic pain.

项与 Nav1.8 antisense oligonucleotide (Q-State Biosciences) 相关的新闻（医药）

2024-04-18

·Firstwordpharma

Vertex takes next step for non-opioid pain med with FDA rolling review

Vertex Pharmaceuticals on Thursday announced updates across its suzetrigine (VX-548) pain programme, including the start of an FDA rolling submission seeking approval of the non-opioid drug in moderate-to-severe acute pain. The company says it is on track to complete the filing for the oral selective NaV1.8 pain signal inhibitor this quarter."Given the favourable benefit/risk profile demonstrated by suzetrigine across the entire clinical programme and the positive interactions with regulators, we are excited by the opportunity to rapidly advance suzetrigine…for the millions of patients suffering from acute and peripheral neuropathic pain," stated chief medical officer Carmen Bozic.In a note to clients after the drug succeeded in two Phase III acute pain studies earlier this year, Stifel analysts said they "continue to view VX-548 as a blockbuster potential drug in chronic pain," where opioids are far less acceptable of an option due to potential abuse.The two trials, conducted in patients who had undergone abdominoplasty or bunionectomy surgery, hit their primary endpoints against placebo, but didn't demonstrate superiority over Vicodin (hydrocodone/acetaminophen). Still, Stifel analysts suggested this drawback "may matter less for the long-term prospects" of suzetrigine given the tens of millions of prescriptions written each year for non-opioid analgesics to treat chronic pain.That stance was echoed by key opinion leader Antje Barreveld, an associate professor at Tufts University School of Medicine and clinical researcher at Harvard Medical School, who told FirstWord in an interview that "when it comes to acute pain, any medication that has some applicability in the perioperative world is going to have high uptake. This will be especially so if it is an opioid alternative because we don't have a lot of those."In addition to the acute pain programme, Vertex said it also plans to kick off a Phase III trial of suzetrigine in patients with diabetic peripheral neuropathy (DPN) next half. The move follows a positive Phase II readout in December where suzetrigine appeared to have similar efficacy to Viatris' Lyrica (pregabalin). The programme will consist of two 12-week trials evaluating once-daily suzetrigine against placebo, focusing on changes to weekly average of daily pain intensity scores from baseline as the main measure. A key secondary endpoint will compare the drug to Lyrica.In addition, Vertex continues to enrol its Phase II study of suzetrigine in patients with lumbosacral radiculopathy, another form of neuropathic pain, and is on track to complete recruitment by year's end.Vertex's advancements in pain come shortly after the company agreed to buy out Alpine Immune Sciences for $4.9 billion, its largest acquisition to date. The deal brings Alpine's asset for IgA nephropathy into Vertex's pipeline, bolstering the company's presence in the immunology space (see – Vital Signs: Dissecting dealmaking at Vertex and its Alpine takeout).

临床2期临床3期并购

2024-02-01

·BioSpace

Vertex’s Non-Opioid Pain Drug Failed to Beat Vicodin: Can It Be Improved On?

Pictured: Rows of white pill bottles on a white surface/iStock, Androlia With the opioid epidemic continuing to ravage the U.S., Vertex's announcement Tuesday that its non-opioid pain treatment VX-548 led to “significant improvement” in pain in two Phase III trials was widely hailed as a breakthrough. But the investigational drug did miss the first key secondary endpoint: superiority to a combination of the opioid hydrocodone bitartrate and Tylenol—a duo branded as Vicodin. This raises the question: Is it possible to do better? Both trials—one testing VX-548 following abdominoplasty (tummy tuck) surgery, the other following bunionectomy surgery—hit the primary endpoint of statistically significant reduction of pain intensity from 0 to 48 hours. VX-548 failed, however, to beat Vicodin on the same scale. During an investor call Tuesday, analysts also questioned the drug’s performance on another key secondary endpoint: median time to pain relief. In both indications, VX-548 had a “more rapid onset to meaningful pain relief” than placebo, Vertex reported, with median time to pain relief being two hours in tummy tuck patients and four hours in bunionectomy patients versus eight hours for the placebo group. Analysts on the call also appeared to be seeking faster time to pain relief, with Leerink Partners’ David Risinger asking if Vertex’s Phase I NaV1.8 inhibitors may offer a quicker onset. Vertex CEO Reshma Kewalramani responded, saying, “If it is possible to get even better than VX-548, we are determined to be the ones who do so.” Stuart Arbuckle, the company’s chief operating officer, also responded to questions from analysts, including how payors would respond to the drug’s efficacy. The “significant adverse events” and addictive potential associated with opioids are a major deterrent, he noted, adding that he believes payors will “warmly welcome the advent of a truly non-opioid pain med as this compelling combination of efficacy and safety and tolerability.” When pressed for further details on the missed endpoint, Vertex representatives directed BioSpace to the investor call. The Second Generation VX-548 is a novel NaV1.8 pain signal inhibitor with a rich history. “The mechanistic evidence for [NaV1.8], even in the year 2001, was crystal clear,” said Stephen Waxman, a professor of neurology at Yale School of Medicine. “If you could shut it off, you had a good chance of attenuating pain.” This is around the time Vertex began its efforts against NaV1.8, which would ultimately yield VX-548, Waxman said. Waxman, whose work contributed to the revelation that the NaV1.7, NaV1.8 and NaV1.9 sodium channels played a central role in pain signaling, highlighted three possible reasons for VX-548’s failure to beat Vicodin. “One possibility is that [Vertex] did a good job on dosing but didn’t get it precisely right,” he said. “There could have been a higher dose with higher efficacy.” A second possibility, he said, is that a second-generation drug “will have more potency, more effective distribution, fewer side effects, be able to be dosed better and give better efficacy.” Lastly, Waxman suggested that NaV1.8 may be “important enough in pain signaling that you get this degree of reduction of pain when it is blocked, but there is some redundancy in the pain pathway, so block of NaV1.8 reduces pain but does not totally abolish it.” He likened VX-548 to the early days of the statin drugs. “The very first statin drugs worked, but in retrospect, they were not optimal, and the real bang for the buck in terms of societal impact was in the second and third-generation drugs,” he said. “And that’s where I think we are right now.” As for what a second-generation drug might look like, Waxman noted that there are many approaches to targeting NaV1.8, including small-molecule blockers, peptide blockers, toxin derivatives, antibodies, knockdown therapies and gene therapy approaches. “Now that we know that [NaV1.8] is a druggable target and we know that blocking it reduces pain, we have proof of concept in humans,” Waxman said. “That raises the exciting question of whether there are there other ways to attack 1.8, and there undoubtedly are. It is a very exciting time in the search for new, non-addictive pain medications.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

临床3期临床结果临床1期

2024-01-30

·Firstwordpharma

Vertex’s non-opioid drug succeeds in late-stage pain trials

Vertex Pharmaceuticals will seek FDA approval by mid-year for its non-opioid drug VX-548 following positive results from two Phase III studies in acute pain. Despite besting placebo in the trials, the oral NaV1.8 inhibitor failed to demonstrate superiority over the combination of hydrocodone bitartrate and acetaminophen.Even with the slight blemish on the read-out, CEO Reshma Kewalramani suggested that VX-548 could “potentially fill the gap between medicines with good tolerability, but limited efficacy, and opioid medicines with therapeutic efficacy, but known risks, including addictive potential.” The company plans to seek broad label for the drug in moderate-to-severe acute pain.Results showed that treatment with VX-548 led to statistically significant improvement in pain compared to placebo, as well as a clinically meaningful reduction in pain from baseline, in both the abdominoplasty and bunionectomy trials. Vertex noted Tuesday however that both studies failed to meet the key secondary endpoint testing whether VX-548 was superior to hydrocodone bitartrate plus acetaminophen.In one study, 1118 patients with moderate or severe pain after abdominoplasty surgery were randomised to receive either VX-548, hydrocodone bitartrate/acetaminophen or placebo. For the main goal of the time-weighted sum of the pain intensity difference from 0 to 48 hours (SPID48), the difference between VX-548 and placebo was 48.4 points.The second trial randomised 1073 patients with moderate or severe pain after bunionectomy surgery to receive either VX-548, hydrocodone bitartrate/acetaminophen or placebo. Results for the primary endpoint showed that the difference in SPID48 between VX-548 and placebo was 29.3 points.For the secondary goal of SPID48 compared to hydrocodone bitartrate/acetaminophen, VX-548 demonstrated a non-significant 6.6-point benefit in the abdominoplasty study, while the comparator was 20.2 points better than Vertex’s drug in the bunionectomy trial.More to come.

临床结果临床3期

100 项与 Nav1.8 antisense oligonucleotide (Q-State Biosciences) 相关的药物交易

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