Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development

Introduction: Opioids are widely used to treat severe pain. Most clinically used opioids activate µ-opioid receptors (MOR). Their ligands induce potent analgesia but also adverse effects. The δ-opioid receptor (DOR) is another member of the opioid receptor family that has been under intense investigation with the aim to avoid MOR-induced side effects.

Areas covered: This article reviews DOR ligands which appeared to be promising after preclinical evaluation. A literature search using Pubmed, Cochrane library, ClinicalTrials.gov, EudraCT, AdisInsight database and EBSCO Online Library was conducted. Out of numerous newly synthesized molecules, only few candidates entered phase I and/or II clinical investigation. The publicly accessible results are presented here.

Expert opinion: Many compounds showed potent DOR-specific pain inhibition in preclinical studies. ADL5859 and ADL5747 entered clinical trials and successfully passed phase I. However, in phase II studies the primary endpoint (pain reduction) was not met and further investigation was terminated. A third compound, NP2, is in phase II clinical evaluation and results are pending. These findings suggest a potential of DOR ligands according to preclinical studies. Further clinical research and secondary analysis of unpublished data is needed to identify molecules which are useful in humans.     

Glutamate receptor antagonists with the potential for migraine treatment

Introduction: Preclinical, clinical, and other (e.g., genetic) evidence support the concept that migraine susceptibility may at least partially result from a glutamatergic system disorder. Therefore, the receptors of the glutamatergic system are considered relatively new targets for investigational drugs to treat migraine. Investigational and established glutamate receptor antagonists (GluRAs) have been shown to possess antinociceptive properties in preclinical models of trigeminovascular nociception and have been evaluated in clinical trials. This review focuses on preclinical and clinical studies of GluRAs for the treatment of migraine.

Areas covered: A PubMed database search (from 1987 to December 2016) and a review of published studies on GluRAs in migraine were conducted.

Expert opinion: All published clinical trials of investigational GluRAs have been unsuccessful in establishing benefit for acute migraine treatment. Clinical trial results contrast with the preclinical data, suggesting that glutamate (Glu) does not play a decisive role after the attack has already been triggered. These antagonists may instead be useful for migraine prophylaxis.

Improving patient care requires further investigating and critically analyzing the role of Glu in migraine, designing experimental models to study more receptors and their corresponding antagonists, and identifying biomarkers to facilitate trials designed to target specific subgroups of migraine patients.     

Investigational drugs in phase I and phase II clinical trials for thalassemia

Introduction: Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials.

Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials. A phase III clinical trial is currently ongoing. Ruxolitinib, a Jak2 inhibitor, has been tested to limit stress erythropoiesis in a phase II clinical trial. In addition, improvement in iron chelation has been developed. Moreover, several trials of gene therapy are currently active in different countries with different lentiviral vectors.

Expert opinion: The most promising molecules are the activin receptor ligand traps. Together with gene therapy these could be an alternative to bone marrow transplant, aiming towards a curative strategy. The main limit to gene therapy seems to be the conditioning regimen, thus an in vivo gene therapy would be more suitable. At pre-clinical level gene editing is showing extremely encouraging results.     

Emerging drugs for migraine treatment: an update

ABSTRACT

Introduction: Migraine is a very frequent and disabling neurological disorder. The current treatment options are old, generally poorly tolerated and not migraine-specific, reflecting the low priority of migraine research and highlighting the vast unmet need in its management.

Areas covered: Advancement in the understanding of migraine pathophysiological mechanisms and identification of novel potentially meaningful targets have resulted in a multitude of emerging acute and preventive treatments. Here we review the known putative migraine pathophysiological mechanisms in order to understand the rationale of the most promising novel treatments targeting the Calcitonin-Gene-Related Peptide receptor and ligand and the 5 hydroxytryptamine (5-HT)1F receptor. Key findings on the phase II and phase III clinical trials on these treatments will be summarized. Furthermore, a critical analysis on failed trials of potentially meaningful targets such the nitric oxide and the orexinergic pathways will be conducted. Future perspective will be outlined.

Expert opinion: The recent approval of Erenumab and Fremanezumab is a major milestone in the therapy of migraine since the approval of triptans. Several more studies are needed to fully understand the clinical potential, long-term safety and cost-effectiveness of these therapies. This paramount achievement should stimulate the development of further research in the migraine field.     

Investigational drugs for the treatment of cancer cachexia: a focus on phase I and phase II clinical trials

Introduction: Cachexia is frequent in chronic diseases and especially during cancer development. Multiple definitions of cachexia have been proposed; it may be considered a multifactorial complex syndrome that presents with progressive unintentional weight loss and wasting of muscle mass and adipose tissue.

Area covered: This article covers phase-I and phase-II clinical trials of investigational drugs for cancer cachexia. We performed a search on PubMed with keywords as cancer cachexia, phase-I/phase-II trial, drug, identifying articles relevant to this review. Studies were conducted using compounds, including anabolic agents such as ghrelin analogs, selective androgen receptor modulators, as well as anti-inflammatory drugs such as thalidomide, OHR, anti-interleukin antibody, cannabinoids, and omega-3 supplements. We also describe the mechanisms of action of these molecules and their phase-I and phase-II study design. The major outcomes were appetite stimulation, weight gain, improvement of muscle mass and function, modulation of inflammation, and quality of life.

Expert opinion: The molecules discussed act on molecular pathways involved in cancer cachexia; they modulate appetite, anabolic effects, inflammation and direct interaction with muscle. Considering the multifactorial aspects of the cachexia syndrome, the combination of these drugs with metabolic and nutritional interventions may represent the most promising therapeutic approach to cancer cachexia.     

偏头痛药物治疗的现状及进展

本文综述常用抗偏头痛药物的药理学特点及临床应用。新药舒马坦具有理想的选择性抗偏头痛活性,布托啡烷等的经鼻喷雾用药系统为以前不能接受治疗的偏头痛患者提供一种新的给药途径,这些新的或正在 研究中的疗法将给临床医师提供治疗偏头痛患者更广泛的选择手段。     

Advances in orally administered pharmacotherapy for the treatment of migraine

Introduction: Migraine is a common and highly disabling neurological disorder whose acute treatment remains problematic and unsatisfactory in a high percentage of cases. Consequently, there remains a need for new symptomatic therapies that can be easily handled by patients (i.e. by oral administration).

Area covered: This review reports on compounds currently under development for the oral treatment of acute migraine attacks, focusing on Calcitonin-Gene-Related-Peptide receptor antagonists, specifically ubrogepant and rimegepant. This article is based on literature obtained from PubMed and publicly available clinical trial data.

Expert opinion: Both reviewed compounds meet the need for rapid and effective pain control, combined with the control of associated bothersome symptoms while also lacking significant adverse events and safety concerns. Though further studies should assess the profile of these compounds comparatively with existing and available treatments (namely triptans), the currently available data points to these new therapies as being very promising new symptomatic oral treatments of migraines.     

Investigational drugs in phase I and phase II clinical trials for hereditary angioedema

Introduction: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is a rare bradykinin-mediated disease characterized by recurrent subcutaneous and/or submucosal angioedematous attacks (HAE attacks), which occur unpredictably. The recurrent HAE attacks do not respond to conventional treatments, and may evolve into a life-threatening condition; therefore, special therapy is required.

Areas covered: The agents used so far for the acute management of HAE attacks act by blocking the release of bradykinin, or its binding to its receptor. By contrast, the investigational medicinal products under evaluation in Phase I and II clinical trials are targeted at the prevention of HAE attacks. Chemically, these new drugs are small synthetic molecules, oligonucleotides, or antibodies, which inhibit either kallikrein, or Factor XII.

Expert opinion: The key considerations for the development of new medicinal products include more straightforward dosing, self-administration, longer duration of action, and keeping the patient attack-free. This review summarizes the status and the findings of the currently ongoing Phase I and Phase II clinical trials of C1-INH-HAE.     

Calcitonin gene-related peptide receptor antagonists for the treatment of migraine: a patent review

Background: Migraine is a debilitating headache disorder which affects ～ 12% of the general population and is the cause of significant loss of productivity (i.e., lost time from work or school) for those afflicted. The current standard of care, the 5-HT_1B/1D agonists known as triptans, is contraindicated in patients with cardiovascular disease due to their inherent vasoconstrictive activity; thus, there is a need to develop an alternative therapy for the treatment of the disorder. Objective: This article reviews patent publications related to the use of small molecule calcitonin gene-related peptide (CGRP) receptor antagonists for the treatment of migraine that have appeared in the literature within the past decade. The commentary is supplemented by information presented in journal articles and focuses on the activity of several major pharmaceutical companies in the field. Conclusion: Two small molecule CGRP receptor antagonists, olcegepant and telcagepant, have been shown to be clinically efficacious in the treatment of migraine, and thus provide validation of this novel therapeutic mechanism.     

5-羟色胺综合征的临床特征、诊断及防治

5-羟色胺综合征是一种由治疗药物引起的可能危及生命的不良反应。发生机制为5-羟色胺(5-HT)在神经系统内积蓄,过度激活突触后5-HT受体,导致5-HT能神经系统活动增强,其临床特征为精神障碍、自主神经功能亢进及神经肌肉功能异常。本综合征常发生于抗抑郁药联用或与其他药物联用时,主要依据临床表现诊断。治疗包括停撤可疑药物、密切观察、控制激越行为、给予5-HT拮抗剂、对症治疗、并发症的处理等。本综合征重在预防。     

Inhaled drug therapy development for the treatment of migraine

Introduction: The inhalation of substances, both medicinally and recreationally, is a commonly used method of drug administration but has been underutilized in the treatment of neurologic disorders such as migraine. Three drugs have been studied as potential inhalable treatments for acute migraine: dihydroergotamine (MAP0004), prochlorperazine (Staccato prochlorperazine), and loxapine (Staccato loxapine).

Areas covered: This review discusses the available literature describing the pharmacokinetics, tolerability and efficacy of MAP0004, Staccato prochlorperazine and Staccato loxapine, including data from Phase II and Phase III clinical trials.

Expert opinion: Inhaled DHE offers rapid absorption with a pharmacokinetic profile similar to IV administration. Improved side effect profile results from more selective binding at antimigraine serotonergic receptors 5-HT_1B and 5-HT_1D. Inhaled prochlorperazine is rapidly absorbed and resulted in statistically significant migraine pain relief at 2 hours compared to placebo but is not currently being pursued by the manufacturer as a potential migraine abortive. Inhaled loxapine is also rapidly absorbed into systemic circulation but Phase IIb trials did not show statistically improved pain relief or pain freedom compared to placebo. MAP0004 will likely provide a good alternative to patients seeking rapid relief without the need for injection or other invasive routes.     

New drugs for the prevention and treatment of migraine: topiramate and BIBN 4096 BS

Migraine is one of the leading causes of disability. Topiramate has multiple mechanisms and may reduce neurotransmission through the trigeminocervical complex to prevent migraine. In clinical trials for the prevention of migraine, the mean monthly migraine frequency decreased from 5.6 to 4.5 in the placebo group and larger decreases were observed with topiramate (100 mg/day, 5.8 to 3.5; 200 mg/day, 5.1 to 3.0). However, topiramate use is associated with a high incidence of adverse events (paraesthesia, fatigue, anorexia, diarrhoea), which may limit the willingness of patients to use topiramate for the prevention of migraine. BIBN 4096 BS is a non-peptide calcitonin gene-related peptide-receptor antagonist that has recently been trialled in migraine attacks. The primary efficacy end point was the reduction of severe or moderate headache prior to treatment to mild or no headache at 2 h. This endpoint was achieved in 21 of 32 (66%) patients with BIBN 4096 BS 2.5 mg, compared to 27% of patients given placebo. Although BIBN 4096 BS is a non-peptide, it is still administered intravenously, which will probably limit its use to medical centres.     

5种药物治疗偏头痛疗效的网状Meta分析

目的综合评价布洛芬、依来曲普坦、拉米地坦、rimegepant和ubrogepant治疗偏头痛的临床疗效。方法检索PubMed、Cochrane Library、Embase、ClinicalTrials、Medline、中国期刊全文数据库和中文科技期刊全文数据库从建库至2020年2月所有关于布洛芬、依来曲普坦、拉米地坦、rimegepant和ubrogepant治疗偏头痛的随机对照试验(RCTs),根据纳入与排除标准筛选文献提取数据,采用Stata 14.0进行数据分析。结果共纳入27项RCTs,合计偏头痛患者20 288例,6种干预措施。网状Meta分析结果显示,在2 h疼痛消除效应方面,5种药物与安慰剂比较均具有显著差异(P <0.05);累计排序概率曲线下面积(SUCRA)排序结果显示依来曲普坦80 mg疗效最优,拉米地坦50 mg疗效最弱。在2 h疼痛减轻效应方面,与安慰剂比较,布洛芬、依来曲普坦和拉米地坦具有显著疗效(P <0.05);SUCRA排序结果显示依来曲普坦80 mg疗效最优,拉米地坦50 mg疗效最弱。结论 5种药物中,依来曲普坦在2 h头痛消除方面的疗效明显优于其余药物;依来曲普坦80 mg对偏头痛的疗效最优,拉米地坦50 mg疗效最弱。     

Menstrual migraine: an updated review on hormonal causes,prophylaxis and treatment

Introduction: In this article, we will discuss pure menstrual migraine without aura (PMM) and menstrually related migraine without aura (MRM). Depending on the frequency and severity of their attacks, patients with PMM will likely need an acute treatment and/or short-term preventive plan. Of note, with the use of acute treatments and short-term preventive therapy there is risk of medication overuse if the patient does have pure menstrual migraine and is being treated for menstrually related migraine.

Areas covered: A PubMed, Cochrane Central, Medline, Ovid search provided articles relating to menstrual migraine pathophysiology and treatment.

Expert opinion: Long-term daily preventive treatment should be considered for patients with MRM and those with severe PMM. Miniprophylaxis can be used in PMM rather than daily preventive treatment. When considering the use of short-term miniprophylaxis, sumatriptan, zolmitriptan, naratriptan, and frovatriptan have shown efficacy; however, frovatriptan appears to be the triptan of choice based on overall efficacy. Oral contraceptives may be considered if patients do not respond to or cannot tolerate typical migraine preventive medications. In patients with migraine with aura, oral contraceptives should be used with caution as this may add to the risk of stroke in this population.     

Investigational drugs in phase II clinical trials for the treatment of neuroblastoma

Introduction: Neuroblastoma (NB) is an embryonal tumor originating from undifferentiated neural crest cell, highly heterogeneous ranging from spontaneous regression to progression despite multimodal treatments. Approximately, 20% of patients are refractory to frontline therapy and 50% will relapse/progress after an initial response. The overall five year survival for high-risk neuroblastoma ranges from 35–45%. Despite enhanced understanding of NB biology and the addition of myeloablative chemotherapy, isotretinoin and immunotherapy, survival for high risk NB remains less than 50%.

Areas covered: This review summarizes and gives a critical overview of phase II trials investigating therapies for relapsed-refractory and high risk neuroblastoma.

Expert opinion: Several novel molecules have been developed and are currently under investigation for the treatment of NB. The trend of novel targeted agents is one towards individualized, tailored therapy, based on the molecular and biological differences that characterize tumors that seem similar based solely on histological analysis. The task of developing new molecules is particularly difficult for NB, given the recurrent development of new patterns of drug resistance. However, even if current research is focused towards identifying the best treatments for each children and young adult with a NB defined disease, a deeper knowledge of the molecular biology and genetics is needed.     

Investigational drugs in phase I and phase II clinical trials for the treatment of community-acquired pneumonia

Introduction: Community acquired pneumonia is one of the main infections, remaining as a global cause of considerable morbidity and mortality. Successful treatment hinges on expedient delivery of appropriate antibiotic therapy tailored to both the likely pathogens and the severity of disease. Although antibiotic resistance is increasing and pharmaceutical companies continue to debate the profitability of introducing new antibacterial agents, an encouraging number of new molecules have recently been unveiled which target multidrug-resistant bacteria.

Areas covered: Herein, the authors summarize the actual situation of novel antibiotics for CAP in phase I & II of development. For each set of compounds, the medical significance and possible clinical placement are discussed. Current treatment options from the most important international guidelines are also reviewed.

Expert opinion: Our review shows that the new antibiotics in the pipeline belong to existing antibiotic classes as β-lactams, macrolides, quinolones, oxazolidinones, tetracyclines, lipoglycopeptides, and cyclic lipopeptides and a few with a narrow spectrum of activity are novel compounds directed against novel targets. With rising outpatient antibiotic resistance in pneumonia, some of the compounds discussed are being considered for more rapid advancement in the pipeline, helping to increase the number of agents in later stages of development.     

The safety and efficacy of the 5-HT 1F receptor agonist lasmiditan in the acute treatment of migraine

Introduction: Migraine is among the most disabling disorders worldwide, with a significant therapeutic need. Triptans are drugs of choice in the acute attack treatment, but they are contraindicated in patients with vascular conditions due to their potential vasoconstrictive properties. Further limitations include side effects, inconsistency in therapeutic action and possible non-response. Lasmiditan, a highly selective 5-HT1F receptor agonist, is a novel acute anti-migraine substance devoid of vasoconstriction.

Areas covered: This article reviews the clinical efficacy and safety of oral and intravenous lasmiditan as a possible acute migraine treatment. We analyze all currently available results in Phase I to III studies.

Expert opinion: Lasmiditan is a promising acute migraine therapy, in particular for patients at cardiovascular risk. Phase II and the first Phase III clinical trials show a significant better headache response in comparison to placebo. The efficacy of lasmiditan proves that vasoconstriction is not essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal contribution, to central neuronal mechanisms in migraine pathophysiology. Lasmiditan penetrates the blood-brain barrier and CNS associated adverse events are common, but mostly in mild to moderate severity. The results of long-term Phase III studies will determine if these adverse events represent a limitation in clinical practice.     

Suloctidil therapy in migraine: an open pilot study

Summary

An open pilot study was carried out in 27 patients with severe and frequent migraine attacks who had failed to respond adequately to other drug therapy, to assess the effectiveness and tolerance of prophylactic treatment with suloctidil. Patients received 600?mg suloctidil daily for 6 weeks. Response, assessed on the reduction in frequency of attacks, was considered as good in 7 patients and as significant improvement in 11 patients. Treatment was rated as of doubtful value or as ineffective in the other 9 patients. One patient stopped treatment because of adverse reactions and 10 others reported mild side-effects.