Expert opinion on investigational drugs最新文献

Introduction: Parkinson's disease (PD) is a common neurodegenerative disease. Glucagon-like peptide-1 (GLP-1) receptor agonists decrease the incidence of developing PD and are being considered for the treatment of PD.

Areas covered: A phase 2 clinical trial of lixisenatide, a GLP-1 receptor agonist, in the early stages of PD. The primary endpoint was the MDS-UPDRS part 3 motor changes in score from baseline to 12 months in the on-medication state, and this was improved by lixisenatide. Post hoc subgroup analysis suggested that this effect of lixisenatide was greater in the <60-year-olds than in the ≥60 years. None of the secondary/exploratory mostly non-motor endpoints were significantly altered by lixisenatide.

Expert opinion: Although the scores between lixisenatide and placebo were statistically significantly different, the difference did not quite reach clinical significance. Lixisenatide, like exenatide, had no effect on the primary or secondary endpoints at 6 months suggesting that any benefits with GLP-1 receptor agonists in PD require long-term treatment. The apparent differences in the two age groups may be due to the bigger deterioration of motor scores in the <60-year-old group. Lixisenatide has promise but does not answer the discussion on GLP-1 receptor agonist treatment for PD.

Background: XKH001 is a recombinant humanized IgG1 monoclonal antibody against IL-25 for the treatment of type 2 inflammatory diseases. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of XKH001 in humans for the first time.

Research design and methods: This clinical investigation adopted a randomized, double-blind, and placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) design.

Results: XKH001 was well tolerated in healthy Chinese subjects. Following repeated administration, XKH001 showed a slow absorption with a median Tmax of 4-7 days and a mean half-life (t1/2) of 22-25 days. The accumulation ratio ranged from 1.34 to 1.99. The exposure was mostly dose proportional, with a mean slope of 0.85-1.06. All subjects tested negative for ADA (except three subjects tested positive). The subjects who received 600 mg XKH001 in the MAD study showed a 78.2 ng/mL decrease in the total immunoglobulin E (IgE) level 85 days after the first administration, while the subjects who received matched placebo exhibited only an 8.6 ng/mL decrease.

Conclusions: XKH001 showed favorable safety and pharmacokinetics profiles and a low immunogenicity in its first-in-human study. The data support its further clinical evaluation in patients with type 2 inflammatory diseases.

Trial registration: The study was registered in ClinicalTrials.gov (NCT05991661).

Background: GR1603 is a monoclonal antibody targeting the type I interferon receptor. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and pharmacodynamics of GR1603 in healthy volunteers.

Methods: Healthy adults (≥18 years old) were enrolled in a placebo control, dose-escalation Phase I clinical trial receiving a single injectable dose of GR1603. Follow-up was 12 weeks. Adverse event (AE) profiles, vital signs, and blood samples were collected for assessment of safety, PK, and expression of type I interferon inducible genes.

Results: Of the 46 subjects, 44 completed treatment. In the experimental group of 34 subjects (mean age 26.6 years), 30 experienced treatment-emergent adverse events (TEAEs), with a total of 102 occurrences, resulting in an incidence rate of 88.2%. The most commonly reported drug-related AEs were upper respiratory tract infection (17.6%), all of which were ≤ grade 2. GR1603 exhibits non-linear PK in the dose range of 0.1 mg/kg to 9 mg/kg. All samples were negative for anti-drug antibodies before and after dosing. The degrees of IFN gene signature were significantly inhibited in the higher dose groups.

Conclusion: The safety/tolerability, PK and exploratory metrics observed in this study support further clinical development of GR1603.

Clinical trial registration: www.chictr.org.cn/searchproj.html identifier is ChiCTR2100045628.

Introduction: Glucagon-like peptide-1 receptor (GLP-1 R) agonists have demonstrated remarkable effectiveness in the treatment of obesity and type 2 diabetes. Although these agents provide beneficial effects for metabolic dysfunction-associated steatohepatitis (MASH) through their glucose-lowering and weight-reducing properties, their efficacy in promoting fibrosis regression remains unproven. Survodutide, an investigational dual agonist that simultaneously targets both the glucagon receptor (GCGR) and GLP-1 R, has emerged as a promising therapeutic candidate for the comprehensive management of obesity and MASH. By engaging these two critical receptors, this drug has the potential to offer a broad spectrum of metabolic benefits, addressing multiple pathogenic mechanisms underlying these interrelated disorders.

Areas covered: This review examines the pharmacological profile, clinical efficacy, and safety data of survodutide derived from phase 1 and 2 clinical trials.

Expert opinion: Survodutide's dual agonism of the GCGR and GLP-1 R may surpass the efficacy of selective GLP-1 R agonists, demonstrating significant potential in resolving MASH and promoting fibrosis regression. The drug is generally well tolerated, with primarily manageable gastrointestinal adverse effects. As survodutide progresses through phase 3 clinical development, its potential to provide a more effective and holistic approach to treating MASH and its comorbidities may significantly improve patient outcomes and quality of life.

Introduction: Hepatic encephalopathy (HE) presents a complex pathophysiology, creating multiple potential treatment avenues. This review covers current and emerging treatments for HE.

Areas covered: Standard therapies, including non-absorbable disaccharides and rifaximin, are widely used but show inconsistent efficacy. Alternatives such as polyethylene glycol and L-ornithine L-aspartate have been effective in certain cases. Advancements in understanding HE reveal a growing need for personalized treatments. Novel approaches targeting immune modulation and neuroinflammation are under investigation, though clinical translation is slow. Nutritional interventions and fecal microbiota transplantation show potential but lack robust evidence. Innovative therapies like gene and cell therapies, as well as extracellular vesicles from mesenchymal stem cells, present promising avenues for liver disease treatment, potentially benefiting HE.

Expert opinion: A key challenge in HE research is the design of randomized clinical trials, which often suffer from small sample sizes, heterogeneity in patient population, and inconsistent blinding. Additionally, the multifactorial nature of HE, together with a high spontaneous response rate, complicates efforts to isolate treatment effects. Despite current limitations, ongoing research and technological advances hold promise for more effective and individualized HE treatments in the future.

Introduction: Selective progesterone receptor modulators (SPRMs), such as mifepristone and ulipristal acetate (UPA), have demonstrated high efficacy and safety as single-dose treatments for medication abortion and emergency contraception (EC). Other obstetrical and gynecologic applications have emerged, both for episodic and ongoing uses. The potential of these compounds to provide estrogen-free, ongoing contraception is promising; however, the rare, but serious, hepatic injury cases seen with UPA have put at least a temporary halt to further research in this area.

Areas covered: This paper reviews the biophysical impacts and clinical applications of SPRMs in women's reproductive health, with a focus on the roles of mifepristone and UPA in family planning. Given the political environment, especially in the United States where these applications may be threatened, extensive description is dedicated to mechanisms of action of these agents.

Expert opinion: Both mifepristone and ulipristal acetate are first-line options for single-use applications. There continues to be a need for estrogen-free ongoing contraception that does not have unpopular impacts on bleeding caused by contraceptive methods and for treatments for heavy menstrual bleeding. However, current restrictions on UPA limit longer term use. Perhaps other SPRMs without hepatic impacts may emerge to fill this need.

Introduction: Type 1 diabetes is a chronic autoimmune condition characterized by the selective destruction of insulin-producing beta cells in the pancreas. The etiology of T1D is multifactorial, with a combination of genetic susceptibility and environmental triggers believed to underlie beta-cell destruction. Preserving and prolonging beta-cell function in T1D is a pivotal therapeutic objective that can mitigate disease progression and improve glycemic control.

Areas covered: Insulin secretagogues have long been used in the management of type 2 diabetes, but do not have a significant beneficial effect in individuals with long-standing type 1 diabetes. Enhancement of beta-cell function early in the course of type 1 diabetes may offer important benefits in glycemic control and reduced hypoglycemia risk. Glucagon-like peptide-1 receptor agonists, glucokinase activators, free fatty acid receptor agonists, and glimins are drug classes which may offer benefit in enhancing insulin secretion in individuals with type 1 diabetes.

Expert opinion: Drugs which enhance insulin secretion in individuals may offer clinical benefits to individuals with type 1 diabetes. However, the lack of beta-cell capacity introduces a challenge without regeneration of insulin-producing cells. Stem cell therapies combined with regulation of islet autoimmunity may offer the best prospect of increased insulin secretion in individuals with T1D.

Introduction: Cholangiocarcinoma is the rare and aggressive tumor with poor prognosis and limited therapeutic options. Recently, there have been promising developments in molecular targeted therapies for patients following the progression of first-line chemotherapy and immunotherapy combinations. Dysregulation of fibroblast Growth Factor Receptor (FGFR) signaling is significantly associated with tumorigenesis of intrahepatic cholangiocarcinoma and has been identified as a targetable alteration. This was possible through the discovery of crucial insights into the biochemical mechanisms and pathophysiology of the FGFR pathway.

Areas covered: This review summarizes the current state of FGFR targeted therapies, mechanisms of resistance, and future directions for FGFR-targeted therapies in patients with cholangiocarcinoma.

Expert opinion: Currently, pemigatinib and futibatinib are FDA approved FGFR-targeted therapies that have demonstrated remarkable responses. However, there is still a significant proportion of patients whose disease remains intrinsically resistant to treatment and most patients eventually develop secondary resistance after an initial response. Additionally, unique side effects of FGFR inhibitors may limit their efficacy in clinical practice and can have detrimental effects on quality of life. Several novel FGFR inhibitors are currently being investigated to overcome resistance mechanisms and reduce toxicities.

Background: This study assessed the pharmacokinetics (PK), pharmacodynamics (PD) and safety of QHRD106, and made a comparison with urinary kallindinogenase (UKN) in healthy volunteers.

Methods: This study comprised a randomized, double-blind, placebo-controlled, single-dose escalation phase and an open-label, multiple-dose escalation phase. Ninety-four subjects received intramuscular injections of QHRD106/placebo only once and 30 subjects received QHRD106 four times. Six subjects received 0.15 PNA units UKN intravenously for 7 d. PK and PD analysis were conducted by using a electrochemiluminescent assay and a liquid chromatography/mass spectrometry methodology, respectively. Cerebral circulation was assessed by the magnetic resonance imaging system.

Results: QHRD106 exhibited a slow absorption profile in the human body. Compared to UKN, QHRD106-induced changes in bradykinin concentration later, but with a noticeably prolonged duration. Compared to baseline, cerebral blood flow exhibited a significant improvement on d 7 after a single dose of 18,900 IU and an improvement from d 2 to d 14 after multiple doses of 8400 IU of QHRD106. QHRD106 appeared generally good safety and no severe adverse events occurred in all the groups.

Conclusions: This study provided initial evidence of potential treatment for ischemic strokes that the QHRD106 injection functioned as a safe and effective long-acting kallikrein drug.

Registration: This study was registered on ClinicalTrials.gov with the identifier NCT06380699 and NCT06388772.

Introduction: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, cytopenias, and organomegaly. Four JAK inhibitors are US-FDA approved for treatment of MF. While these drugs reduce symptom burden and spleen size to varying degrees, they do not affect the natural disease course or decrease the risk of leukemic transformation. Therefore, there is a strong need for newer therapies to further advance the field and improve the outcomes of MF. In this review, we cover novel therapies for MF currently in early stages of development.

Areas covered: We present the latest data from early phase clinical trials in MF using drugs with diverse therapeutic mechanisms, including novel JAK-STAT pathway inhibitors, epigenetic therapies, antifibrotic agents, and immunotherapeutic strategies. Additionally, we cover drugs targeted toward anemia improvement in MF.

Expert opinion: Numerous agents representing diverse drug classes are in clinical development for MF. While deeper and durable improvements in splenomegaly, symptoms, and anemia are the main clinical objectives, a number of putative biomarkers are being assessed as measures of potential 'disease modification.' Although JAK inhibitor monotherapy represents the current standard, it is hoped that JAK inhibitor-based rational combinations and driver mutation-specific therapies will soon usher in a new era.