Expert Opinion on Biological Therapy最新文献

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, by preventing the degradation of LDL receptors, either through interference in the binding of PCSK9 to LDL receptors or through silencing of PCSK9 at a molecular level, have revolutionized lipid-lowering treatment and offer the opportunity to further improve clinical outcomes for patients with hypercholesterolemia.

Areas covered: We discuss the role of PCSK9 as a therapeutic target for hypercholesterolemia, describe the pharmacodynamics, pharmacokinetics, and metabolism of recaticimab, and report the recent clinical trials with this 'humanized' IgG1 monoclonal antibody (mAb) against PCSK9.

Expert opinion: Recaticimab has a high affinity for PCSK9 that confers a prolonged duration of action. Recaticimab durably decreases LDL-cholesterol, non-HDL-cholesterol and apoB, but can also lower Lp(a). Recaticimab may offer advantages over current mAbs in clinical use in terms of its long half-life, dosing interval of up to 12 weeks, and potentially a lower cost; however, long-term concerns regarding immunogenicity remain. Longer-term studies in a variety of more diverse patient cohorts will be needed to further evaluate the efficacy, safety, and durability of recaticimab and to ascertain the optimal dosing schedule for cardiovascular outcome studies.

Introduction: Epidermal growth factor receptor (EGFR) mutations represent targetable alterations in non-small cell lung cancer (NSCLC). The treatment landscape in the frontline setting for patients with advanced EGFR-mutated NSCLC is evolving with increasing treatment options. EGFR tyrosine kinase inhibitors (TKIs) have significantly improved outcomes, but resistance inevitably develops, necessitating alternative strategies.

Areas covered: Patritumab deruxtecan is a novel antibody-drug conjugate targeted human epidermal growth factor receptor-3 (HER3), delivering a topoisomerase-I inhibitor payload to HER3-expressing cancer cells. Phase I and II studies have demonstrated efficacy in patients with EGFR-mutant NSCLC with disease progression after prior therapies, including third-generation EGFR TKIs and platinum-based chemotherapy. The phase-II trial reported an objective response rate of 39% and a median progression-free survival of 5.5 months. Patritumab deruxtecan is associated with notable toxicities, including grade 3 and higher hematologic adverse events, gastrointestinal toxicity, and interstitial lung disease (ILD). ILD occurred in 5.3% of patients in the Phase-II study. Early detection and management are crucial for minimizing the risk of complications.

Expert opinion: Patients with advanced EGFR-mutant NSCLC who have received TKI therapy and chemotherapy have limited treatment options. Patritumab deruxtecan demonstrates clinical activity in this population with manageable side effects, addressing an unmet need for patients.

Introduction: Latin American (LatAm) countries face significant increases in healthcare expenditure, driven largely by population growth and aging, and the rising prevalence of cancer and other chronic diseases. Growing demand and high costs of biologic medicines present barriers to patient access in this region. Biosimilars can improve the affordability and accessibility of biologics, supporting long-term healthcare sustainability. However, their uptake in LatAm has generally been slow.

Areas covered: Challenges and barriers to the use of biosimilars and potential strategies to increase biosimilar uptake in LatAm, drawing on learnings from Europe and the U.S.A.

Expert opinion: Potential initiatives to drive biosimilar uptake across LatAm include (1) harmonized regulatory processes for biosimilars, with reimbursement policies that prioritize their use and incentives to encourage prescribing; (2) education for key stakeholders to limit misinformation about biosimilars, provide reassurance about safety and efficacy, and increase understanding and acceptance; (3) simplified health technology assessment processes for biosimilars that expedite or adapt some aspects of the traditional approach; and (4) coordinated regional efforts to enable national healthcare systems to purchase medicines in the most cost-effective way, with value frameworks to support decision-making and the implementation of centralized purchasing, competition policies, and risk-sharing agreements.

Background: Many ulcerative colitis (UC) patients require the use of second-line agents after the failure of anti-TNF therapy.

Research design and methods: We conducted a multicenter, retrospective study including 683 chronically active, moderate-to-severe UC patients who failed first-line anti-TNFs. The rate of treatment persistence and colectomy-free survival was assessed up to 3 years after the initiation of second-line therapy. Predictors for colectomy and persistence were investigated.

Results: After the failure of the first-line anti-TNF, ustekinumab had superior persistence and colectomy-free survival rates compared to tofacitinib (p = 0.05; p = 0.001) and vedolizumab (p = 0.02; p = 0.05), but significant difference was only found in persistence rates in comparison with anti-TNFs (p < 0.001). Regardless of the number of prior anti-TNFs, significantly higher persistence (p = 0.05) and colectomy-free survival rates (p = 0.01) were observed over 2 years with ustekinumab than with vedolizumab or tofacitinib, whereas ustekinumab's superiority over tofacitinib seemed to disappear by the third year. Hypoalbuminaemia (p = 0.002) and shorter disease duration at second-line initiation (p = 0.03) increased, while concomitant immunomodulators (p = 0.05) reduced the risk for colectomy. Shorter disease duration (p = 0.01) and primary non-response to the previously used anti-TNF (p < 0.001) negatively influenced persistence with second-line non-TNF-targeted agents.

Conclusion: After first-line anti-TNF failure, switching to a non-anti-TNF agent is worth considering in moderate-to-severe UC.

Introduction: Ulcerative colitis (UC) includes a dysregulated immune response. The conventional therapy includes immunosuppressants, and biologics targeting inflammatory mediators, but these are often inadequate, or subjects become unable to tolerate them.

Areas covered: QUASAR: the induction and maintenance components of the phase 3 trial of guselkumab, which inhibits IL-23 by dual mechanisms, in subjects with moderate-to-severe UC. QUASAR enrolled those that had an inadequate response and/or intolerance to corticosteroids, immunosuppressants, biologics, or Janus kinase (JAK) inhibitors. In both parts of the trial, guselkumab improved clinical remission with no excess of adverse events.

Expert opinion: For those enrolled throughout, after the maintenance part, the benefit with guselkumab on clinical remission was 24% percentage points (45 vs 21%), which is relatively small. There is no direct comparison of guselkumab with other IL-23 inhibitors in UC. Indirectly comparing trials suggests the clinical remission rates at the end of the trials was higher with guselkumab than with the other approved IL-23, inhibitors, mirikizumab or risankizumab (17 or 15% points, respectively). Thus, guselkumab may be more efficacious than the other 1 L-23 antagonists, possibly due to its additional action to block the CD64 receptor. However, this needs to be tested in a direct comparison trial.

Introduction: Biosimilars promote price competition, improving affordability and access to biologics without compromising on quality, efficacy, and safety. Biosimilar approvals initially followed a cautious approach, with regulatory requirements developed independently across jurisdictions, complicating global development and increasing costs. Advancements in analytical sciences and two decades of accumulated experience with biosimilar approvals offer an opportunity to reevaluate regulatory requirements.

Areas covered: A structured literature review was conducted using PubMed, Embase, and Web of Science, to identify challenges related to biosimilarity demonstration, offer a comprehensive understanding of regulatory requirements for biosimilars globally, and identify opportunities for regulatory convergence. Following title, abstract, and full-text screening, 61 articles were included.

Expert opinion: Biosimilar guidelines from stringent regulatory authorities such as EMA and USFDA are robust, yet further alignment of regulatory standards in the US and EU is possible to reflect scientific progress and clinical experience. Regulatory requirements for biosimilars in emerging markets appear to be disproportionate to scientific advancements and accumulated knowledge with biosimilars approval and clinical experience. Global harmonization of biosimilar guidelines, based on gained developments and regulatory experience, could accelerate development and approval process. This would facilitate earlier and enhanced access to safe and affordable biologics.