Oncology Drug Research Articles

A Multicenter, Open-Label, Phase 1b/2 Study to Evaluate the Effects of Maplirpacept in Combination with Glofitamab in People with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Background Maplirpacept (PF-07901801) is an anti-CD47 fusion protein constructed to enhance phagocytosis and antitumor activity via inhibition of CD47-mediated signaling. Maplirpacept is currently being investigated in an ongoing Phase 1, multi-center, 1a/1b study in participants with advanced hematologic malignancies (NCT03530683). Early safety and efficacy results for maplirpacept monotherapy have previously been reported in patients with refractory or relapsed lymphomas (Patel et al. Blood 2021;138:3560). Study Design This trial is a multicenter, open-label, Phase 1b/2 study (NCT05896163), to evaluate the effects of maplirpacept in combination with fixed doses of glofitamab, after a single dose of obinutuzumab, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The estimated enrollment is 70 patients; the study will be split into 2 parts (Figure 1). Phase 1b will determine the maximum tolerated dose of maplirpacept, with fixed doses of glofitamab and obinutuzumab. In Phase 2, participants will be randomized to low or high doses of maplirpacept, with fixed doses of glofitamab and obinutuzumab, consistent with the FDA ‘Project Optimus’ initiative for dose optimization and selection in oncology drug development. Study interventions will be given intravenously in 21-day cycles. At Cycle 0, participants will receive a single pre-treatment dose of obinutuzumab followed by 2 step-up doses of glofitamab. The combination of maplirpacept with full dose glofitamab will be given at Cycle 1 Day 1. Maplirpacept will be given weekly for the first 3 cycles, then every 3 weeks. Glofitamab will be given every 3 weeks for up to 11 cycles. Subsequently, participants will continue to receive maplirpacept alone. In Phase 1b, participants will be allocated to sequential doses of maplirpacept, given with fixed doses of glofitamab, after 1 dose of obinutuzumab, to select doses of maplirpacept for further evaluation. The primary endpoint for Phase 1b is to assess dose limiting toxicities up to 21 days following the first dose. In Phase 2, participants will be randomized to 2 different doses of maplirpacept, administered with fixed doses of glofitamab, after 1 dose of obinutuzumab. The primary endpoint for Phase 2 is objective response as per the Lugano 2014 response criteria. Secondary endpoints include frequency of adverse events and clinical laboratory abnormalities, objective response (Phase 1b only), duration of response, complete response, duration of complete response, progression free survival, serum concentration vs time for maplirpacept and glofitamab, and immunogenicity of maplirpacept and glofitamab. Adult patients with histologically confirmed relapsed or refractory DLBCL (including DLBCL NOS, primary mediastinal large B cell lymphoma and transformed follicular lymphoma, T cell/histiocyte-rich large B-cell lymphoma, Grade 3b follicular lymphoma or composite lymphoma with a DLBCL component with a subsequent DLBCL relapse), will be eligible (Table 1). Participants with histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma are eligible, except for participants with history of Waldenström macroglobulinemia. Treatment with at least 1 prior line of anti-CD20 antibody-based therapy will be included. For Phase 2, no more than 2 prior lines of systemic therapy will be permitted. Patients who are not candidates for, or who are unwilling to undergo high dose chemotherapy and subsequent stem cell transplant and/or are unable or unwilling to receive chimeric antigen receptor T-cell therapy (e.g. for logistical reasons) will be eligible. All patients should have adequate bone marrow, hepatic, and renal function (eGFR ≥45 mL/min) and ECOG performance status ≤2. Exclusion criteria include prior treatment with an anti-CD47 agent, prior anti-CD20xCD3 containing regimen, refractoriness to an obinutuzumab monotherapy containing regimen, prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment, high grade B-cell lymphoma with BCL2 and Myc rearrangement, active bacterial, viral, fungal, mycobacterial, parasitic, or other infection.

Evaluating the impact of novel oncology drug coverage through patient assistance programs in British Columbia (BC), Canada.

13 Background: Despite a universal public healthcare system, Canadian oncology patients often enroll in patient assistance programs (PAPs) through drug manufacturers to access oncology drugs that are awaiting funding decisions by national and provincial regulatory bodies. Our multicenter study evaluated the pharmacoeconomic and clinical impact of PAPs for cancer patients in BC. Methods: Eligible patients were diagnosed with cancer and enrolled in a PAP for an oncology drug between January 1, 2016 - December 31, 2019 in 3 BC centres. Charts were reviewed for treatment details and survival data. We referenced median overall survival (mOS) or median progression-free survival (mPFS) data from phase III trials. mPFS data was used if mOS was unavailable or not statistically significant. For each drug indication, the hazard ratio from trial data was multiplied by the mOS or mPFS of our cohort to estimate the mOS or mPFS if the drug was not received. Life-years gained (LYG) was defined as the difference between the actual mOS or mPFS in our cohort and the estimated mOS or mPFS if the drug was not received. Mean OS was used if median OS was not reached by the cut-off date January 1, 2021. Quality-adjusted life years (QALY) and cost per drug were obtained from the Canadian Agency for Drugs and Technologies in Health (CADTH). QALY gained per drug was calculated as QALY multiplied by LYG. Assuming $100,000 Canadian dollars (CAD) for 1 QALY gained (based on prior studies), the economic value of QALY gained was calculated as $100,000 CAD multiplied by QALY gained per drug. Results: Our cohort consisted of 1025 patients that accessed 40 oncology drugs via PAP. By the cut-off date, 290 patients continued on treatment while 735 had stopped, most often due to disease progression (69%) or toxicity (14%). 74 patients then accessed another drug in their second exposure to PAP, and 5 patients accessed drugs in their third exposure to PAP. Median time from Health Canada approval to public funding was 2.04 years (IQR 1.53 – 2.34). QALY gained per drug ranged from 0.007-2.997 years for OS and 0.001-1.339 years for PFS. This translated to a total of 268.3 QALY gained in OS and 117.6 QALY gained in PFS. In the first exposure group, total economic value gained from PAP was $26,788,512 for those with OS benefits, $11,763,571 for those with PFS benefits, and total drug costs were $94,150,774. In the second exposure group, total economic value gained was $566,253 for those with OS benefits, $947,134 for those with PFS benefits, and total costs were $4,917,017. In the third exposure group, $44,754 total economic value was gained and total costs were $931,207. Conclusions: Nearly $100 million CAD of non-public funding was required to bridge gaps between regulatory approval and public funding. The economic value and QALY gained from PAPs are substantial. Future studies should focus on strategies to optimize the funding process for novel cancer therapies.

Review time of oncology drugs and its underlying factors: an exploration in China.

Introduction: How the launch delay of drugs and other factors of interest can influence the length of the review period by drug agencies is still unknown, and understanding this can help better strike the trade-off related to review speed. Methods: We included all new oncology drug applications submitted to China's National Medical Product Administration (NMPA) between 1 January 2018 and 31 December 2021, and ultimately succeeded in achieving marketing approval. For each drug, the length of the NMPA review process and other major characteristics were collected, including the registration class, approval class, priority review designation, and launch delay relative to the United States, as well as the number of patients enrolled, comparator, and primary endpoint of the pivotal trials supporting the approval. Linear regression model was employed to analyze the effects of factors of interest on the NMPA review time. Results: From 2018 to 2021, NMPA received 137 oncology applications that were ultimately approved. Half of the approvals [76 (55.5%)] were first licensed in the US, leaving a median launch delay of 2.71years (IQR, 1.03-5.59) in China. In the pivotal studies, the median enrollment was 361 participants (IQR, 131-682), and the use of control groups [90 (65.7%)] and surrogate endpoints [101 (73.7%)] was prevalent. The median review time was 304days (IQR, 253-376). Multivariate analysis for log-transformed review time showed that larger enrollment ( 92) was associated with a drop of 20.55% in review time (coefficient = -0.230; 95% CI, -0.404 to -0.055; p = 0.010); and a short delay (0 delay 1.95years) was associated with a drop of 17.63% in review time (coefficient = -0.194; 95% CI, -0.325 to -0.062; p = 0.004). Discussion: The short launch delay relative to the US was one important driver to the review speed of NMPA, which might suggest its latent regulatory reliance on the other global regulator during the post-marketing period when new information on the drug's clinical benefit was still lacking.

Prescription savings across oncology: A cost comparison of Mark Cuban Cost Plus Drugs pharmacy against 2021 Medicare Part B and Part D claims.

18 Background: The Mark Cuban Cost Plus Drug Company (MCCPDC) was established in 2022 to provide more affordable and transparent access to prescription medications. While prior work has demonstrated the cost-efficacy of MCCPDC, there remains a need to increase awareness of this public-benefit corporation, especially among healthcare professionals and patients using oncologic drugs covered by Medicare Part D and B. Methods: We identified 9 cancer-directed drugs available for purchase on the MCCPDC pharmacy. Potential savings were estimated by substituting the unit price for Medicare claims with the pricing models offered by MCCPDC. We evaluated oncologic claims utilizing 2021 Medicare Part B and D Spending by Drug data. We extracted the total dosage units, beneficiaries, and average spending per dosage unit for each respective drug. The unit price was determined from Medicare claims and then compared against cost projection using MCCPDC 30-count (30c) and 90-count (90c) supplies. When MCCPDC offered multiple dosages, the most expensive dose was chosen to provide a conservative estimate. We used the National Average Drug Acquisition Cost (NADAC) database to adjust for raw ingredient and manufacturing cost changes between 2021-2023. Results: Across the 9 selected oncological drugs, estimated Medicare Part D and B spending totaled $1.21 billion. When filled at the 30c and 90c MCCPDC unit price point, projected costs were $203 million and $147 million respectively (% savings; 83%, 88%). All drugs claimed on Medicare Part D demonstrated an advantaged 90c price point when filled through MCCPDC (% savings range: 40-98%). At the 30c price point, only anastrozole was unfavorable (% loss; 7%). Out of the three drugs claimed on Medicare Part B, capecitabine and temozolomide demonstrated savings at both 30c and 90c unit price points (% savings range; 28-80%). Methotrexate remained unfavorable at either MCCPDC price point when compared to Medicare B coverage (% loss; 18%, 129%). In total and across Medicare Part D and B claims, estimated savings when filled at the MCCPDC 90c unit price point are $1.06 billion. Conclusions: We demonstrate a potential annual savings of $1.06 billion with MCCPDC compared to Medicare D and B coverage. An awareness of current drugs offered by MCCPDC and particularly those with a highly favorable price point may allow healthcare professionals to more effectively navigate the socioeconomic barriers to care often faced by patients. [Table: see text]

Ectopic Expression of Human, Mouse, and Fruit Fly Aryl Hydrocarbon Receptor in <i>Drosophila</i> <i>melanogaster</i> Tissues

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor and its target genes play a fundamental role in detoxification, regulation of developmental processes, maintenance of homeostasis, as well as in the occurrence of oncological and autoimmune diseases and drug metabolism. The high conservatism of vertebrate AHR allowed us to study its functions in vivo using transformed Drosophila melanogaster fruit flies with human or mouse AHR gene and compare the ectopic effect of their expression with the expression of spineless gene, Drosophila AHR homologue. This work demonstrates for the first time that vertebrate AHR exhibits its functional activity in Drosophila embryogenesis, in leg imaginal discs and in somatic cells of female reproductive system in the absence of exogenous ligands.

Innovation in cancer policy & health systems education during hematology-oncology (HO) fellowship training: Single center experience.

446 Background: Cancer care delivery and outcomes in the US are influenced by a complex health system and regulatory environment. To our knowledge, a structured approach to education on these topics during HO training is lacking. We sought to evaluate baseline knowledge and establish a longitudinal curriculum aimed at educating HO trainees on cancer policy. Methods: First year HO trainees at Johns Hopkins were surveyed on their prior education related to affordability, social determinants of health, and oncologic drug development. Based on these results, a longitudinal curriculum with 10 didactic sessions led by invited content experts was developed and implemented into the 2022-23 academic year schedule. Impact of curriculum was evaluated through anonymous surveys at the beginning and end of each teaching session. Results: Pre-curricular intervention survey was completed by 12 fellows (100% response rate; 58% female, 41.6% White; 16.6% IMGs). All had treated patients that were uninsured (100%, n = 12), unable to afford care (100%, n = 12), or lacked stable housing, transportation, food and employment (100%, n = 12). Smaller number had counseled patients on clinical trial enrollment (50%, n = 6) or discussed trial endpoints (33%, n = 4). Systems education prior to fellowship varied by topic: social determinants of health (33%, n = 4), critical appraisal of clinical trials (33%, n = 4), oncologic care in low-resource settings (41.6%, n = 5), high-value care (66%, n = 8), health insurance (91%, n = 11). Pre and post-surveys demonstrated each teaching session was associated with a significant improvement in fellows’ confidence in understanding pre-set lecture objectives (Table; cumulative mean improvement 1.14 from “neutral” pre-intervention, to “agree” or “strongly agree” post-intervention). Conclusions: We demonstrate lack of education on practice-relevant systems topics in HO trainees at time of subspecialty education initiation. Our longitudinal systems education curriculum improved trainee awareness and understanding of these complex topics. Future efforts will build on this scalable curriculum utilizing trainee feedback and departmental buy-in with the goal of training an oncologic workforce better equipped to counsel patients, navigate structural barriers, and appraise evidence.[Table: see text]

The Hyaluronan/CD44 Axis: A Double-Edged Sword in Cancer.

Hyaluronic acid (HA) receptor CD44 is widely used for identifying cancer stem cells and its activation promotes stemness. Recent evidence shows that overexpression of CD44 is associated with poor prognosis in most human cancers and mediates therapy resistance. For these reasons, in recent years, CD44 has become a treatment target in precision oncology, often via HA-conjugated antineoplastic drugs. Importantly, HA molecules of different sizes have a dual effect and, therefore, may enhance or attenuate the CD44-mediated signaling pathways, as they compete with endogenous HA for binding to the receptors. The magnitude of these effects could be crucial for cancer progression, as well as for driving the inflammatory response in the tumor microenvironment. The increasingly common use of HA-conjugated drugs in oncology, as well as HA-based compounds as adjuvants in cancer treatment, adds further complexity to the understanding of the net effect of hyaluronan-CD44 activation in cancers. In this review, I focus on the significance of CD44 in malignancy and discuss the dichotomous function of the hyaluronan/CD44 axis in cancer progression.

The reimbursement decision speed for oncology new drugs in China and its determinant factors.

China has initiated national price negotiations to improve access to innovative drugs. Learning the factors that contributed to the time gap from marketing authorization to reimbursement leads to more clarity to decision-making, which remains under-researched in China. We collected new oncology drug approvals that were marketed before 30 Jun 2022, using the Listed Drug Database of the Chinese drug agency. Major information of each approval was obtained from the published review report, including the first approval region (China or the US) and the receipt of expedited review pathways (priority review and conditional approval). The reimbursement lists issued by China National Healthcare Security Administration from 2015 to 2023 were used to determine the reimbursement status of drugs. The duration from marketing authorization to reimbursement was defined as the reimbursement decision speed, and the Cox regression was performed to explore the underlying factors. A total of 186 oncology approvals were included. More than half of the approvals qualified for reimbursement (110[59.14%]), and the median reimbursement decision speed was accelerated from 540.5 days in the third-round negotiation to 448 days in the seventh-round. Domestic new drugs had a higher probability of being adopted by the Chinese payer than drugs developed by foreign companies (adjusted HR = 3.73, 95% CI 2.42 to 5.75; P < 0.001). Furthermore, new drug applications receiving the regular review pathway were more likely to be reimbursed (adjusted HR = 2.15, 95% CI 1.13 to 4.08; P = 0.020) compared to those approved under the conditional approval pathway. These findings indicate that the Chinese government is actively working toward improving access to new oncology drugs. The faster reimbursement decision speed for domestic drugs might be attributed to their pricing advantages and the regulator's efforts to stimulate innovation in the domestic pharmaceutical industry. However, concerns about the uncertainty in drug benefits can affect the reimbursement decision-making, which suggests the delicate tradeoff between drug accessibility and risk involved in the reimbursement process.

Mass spectrometry quantifies target engagement for a KRASG12C inhibitor in FFPE tumor tissue

BackgroundQuantification of drug-target binding is critical for confirming that drugs reach their intended protein targets, understanding the mechanism of action, and interpreting dose-response relationships. For covalent inhibitors, target engagement can be inferred by free target levels before and after treatment. Targeted mass spectrometry assays offer precise protein quantification in complex biological samples and have been routinely applied in pre-clinical studies to quantify target engagement in frozen tumor tissues for oncology drug development. However, frozen tissues are often not available from clinical trials so it is critical that assays are applicable to formalin-fixed, paraffin-embedded (FFPE) tissues in order to extend mass spectrometry-based target engagement studies into clinical settings.MethodsWild-type RAS and RASG12C was quantified in FFPE tissues by a highly optimized targeted mass spectrometry assay that couples high-field asymmetric waveform ion mobility spectrometry (FAIMS) and parallel reaction monitoring (PRM) with internal standards. In a subset of samples, technical reproducibility was evaluated by analyzing consecutive tissue sections from the same tumor block and biological variation was accessed among adjacent tumor regions in the same tissue section.ResultsWild-type RAS protein was measured in 32 clinical non-small cell lung cancer tumors (622–2525 amol/µg) as measured by FAIMS-PRM mass spectrometry. Tumors with a known KRASG12C mutation (n = 17) expressed a wide range of RASG12C mutant protein (127–2012 amol/µg). The variation in wild-type RAS and RASG12C measurements ranged 0–18% CV across consecutive tissue sections and 5–20% CV among adjacent tissue regions. Quantitative target engagement was then demonstrated in FFPE tissues from 2 xenograft models (MIA PaCa-2 and NCI-H2122) treated with a RASG12C inhibitor (AZD4625).ConclusionsThis work illustrates the potential to expand mass spectrometry-based proteomics in preclinical and clinical oncology drug development through analysis of FFPE tumor biopsies.

Reporting reimbursement price decisions for onco-hematology drugs in Spain.

Even using well-established technology assessment processes, the basis of the decisions on drug price and reimbursement are sometimes perceived as poorly informed and sometimes may be seen as disconnected from value. The literature remains inconclusive about how Health Technology Assessment Bodies (HTAb) should report the determinants of their decisions. This study evaluates the relationship between oncology and hematology drug list prices and structured value parameters at the time of reimbursement decision in Spain. The study includes all new onco-hematological products (22), with a first indication authorized between January 2017 and December 2019 in Spain and pricing decisions published up until October 2022. For each product, 56 contextual and non-contextual indicators reflecting the structured multiple criteria decision analysis (MCDA) - Evidence-based Decision-Making (EVIDEM) framework were measured. The relationship between prices and the MCDA-EVIDEM framework was explored using univariate statistical analyses. Higher prices were observed when the standard of care included for combinations, if there were references to long-lasting responses, for fixed-duration treatment compared to treatment until progression and treatment with lower frequencies of administration; lower prices were observed for oral administration compared to other routes of administration. Statistically significant associations were observed between prices and the median duration of treatment, the impact on patient autonomy, the ease of use of the drug, and the recommendations of experts. The study suggests that indicators related to the type of standard of care, references to long-lasting responders, the convenience of the use of the drug, and the impact of treatment on patient autonomy, as well as contextual indicators such as the existence of previous clinical consensus, are factors in setting oncology drug prices in Spain. The implementation of MCDA-EVIDEM methodologies may be useful to capture the influence on pricing decisions of additional factors not included in legislation or consolidated assessment frameworks such as the European Network for Health Technology Assessment (EunetHTA) core model. It may be opportune to consider this in the upcoming revision of the Spanish regulation for health technology assessments and pricing and reimbursement procedures.

Lengthy and Variable Delays in Oncology Drug Coverage Determination

This cohort study examines the variability in time to pharmacy and therapeutics committees’ determinations of coverage of approved oncology drugs across multiple payers.

Revealing Allosteric Mechanism of Amino Acid Binding Proteins from Open to Closed State.

Amino acid binding proteins (AABPs) undergo significant conformational closure in the periplasmic space of Gram-negative bacteria, tightly binding specific amino acid substrates and then initiating transmembrane transport of nutrients. Nevertheless, the possible closure mechanisms after substrate binding, especially long-range signaling, remain unknown. Taking three typical AABPs-glutamine binding protein (GlnBP), histidine binding protein (HisJ) and lysine/arginine/ornithine binding protein (LAOBP) in Escherichia coli (E. coli)-as research subjects, a series of theoretical studies including sequence alignment, Gaussian network model (GNM), anisotropic network model (ANM), conventional molecular dynamics (cMD) and neural relational inference molecular dynamics (NRI-MD) simulations were carried out. Sequence alignment showed that GlnBP, HisJ and LAOBP have high structural similarity. According to the results of the GNM and ANM, AABPs' Index Finger and Thumb domains exhibit closed motion tendencies that contribute to substrate capture and stable binding. Based on cMD trajectories, the Index Finger domain, especially the I-Loop region, exhibits high molecular flexibility, with residues 11 and 117 both being potentially key residues for receptor-ligand recognition and initiation of receptor allostery. Finally, the signaling pathway of AABPs' conformational closure was revealed by NRI-MD training and trajectory reconstruction. This work not only provides a complete picture of AABPs' recognition mechanism and possible conformational closure, but also aids subsequent structure-based design of small-molecule oncology drugs.

Trends in oncology drug lags in Japan from 2001 to 2020: A cross-sectional study.

Anticancer drugs are essential in the treatment of serious diseases, but their applications are limited by drug lags. This study investigated the characteristics of anticancer drugs approved in Japan over the past 20 years and compared the drug lag trends between Japan and the US. We assessed the changes in drug lag between Japan and the US and the factors affecting the drug lags using publicly available data for anticancer drugs approved in Japan from January 2001 to December 2020. A total of 299 anticancer drugs were approved in Japan in the last 20 years. The approval lag median between the US and Japan was 498 days (16.6 months), peaking in 2002, and decreasing annually thereafter. The minimum approval lag was 173.5 days (5.7 months) in 2018. Multivariate regression analysis revealed that "global simultaneous strategy," "catch-up strategy," and "immunotherapy" are major factors shortening the drug lag. In the past decade, 226 anticancer drugs were approved in Japan. The drug lag for anticancer drugs between Japan and the US peaked in 2002, after which it declined sharply to less than a year. However, the lag was shortest in 2018.

Characteristics of clinician input in Canadian funding decisions for cancer drugs: a cross-sectional study based on CADTH reimbursement recommendations

ObjectiveTo examine characteristics of clinician input to the pan-Canadian Oncology Drug Review (pCODR) for cancer drug funding recommendations from 2016 to 2020.Design, setting and participantsDescriptive, cross-sectional study including 62 reimbursement...

From bench to bedside, 2-in-1 design expedites phase 2/3 oncology drug development.

From bench to bedside, 2-in-1 design expedites phase 2/3 oncology drug development.

ClinicalOmicsDB: exploring molecular associations of oncology drug responses in clinical trials.

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established ontology for easier navigation. The web application provides users with three options to explore molecular associations of oncology drug responses, focusing on studies, treatments or genes, respectively. Gene set analysis further connects treatment response to pathway activity and tumor microenvironment attributes. The user-friendly web interface of ClinicalOmicsDB streamlines interactive analysis. A Rust-based backend speeds up response time, and application programming interfaces and an R package enable programmatic access. We use three case studies to demonstrate the utility of this resource in human cancer studies. ClinicalOmicsDB is freely available at http://trials.linkedomics.org/.

Controlling the protein corona of polymeric nanocapsules: effect of polymer shell on protein adsorption.

Understanding the interactions between nanocarriers and plasma proteins is essential for controlling their biological fate. Based on the reported potential of polymeric nanocapsules (NCs) for the targeted delivery of oncological drugs, the main objective of this work has been to investigate how the surface chemical composition influences their protein corona fingerprint. Thus, we developed six NC prototypes with different polymer shells and physicochemical properties and quantified the amount of protein adsorbed upon incubation in human plasma. Using sequential window acquisition of all theoretical mass spectra (SWATH-MS) and following the Minimum Information about Nanomaterial Biocorona Experiments (MINBE) guidelines, we identified different protein corona patterns. As expected, the presence of polyethylene glycol (PEG) in the polymer shell reduced the protein corona, particularly the adsorption of immunoglobulins. However, by comparing the different prototypes, we concluded that the protein adsorption pattern was not exclusively driven by PEG. In fact, a highly PEGylated prototype exhibited intense apolipoprotein IV adsorption. On the other hand, we also observed that polymeric NCs containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) exhibited high adsorption of vitronectin, a protein that is known for enhancing the uptake of nanosystems by lung epithelium and several cancer cells. Overall, the gathered information allowed us to identify promising polymeric NCs with an expected prolonged circulation time, enhanced tumor targeting, liver accumulation, and preferential uptake by the immune system. In this sense, the analyses of the protein corona performed along this work will hopefully contribute to advancing a new generation of rationally designed nanometric drug delivery systems.

Progress and Challenges of the New Conditional Approval Process in China: A Pooled Analysis From 2018 to 2021

PurposeTo speed the review and approval of drugs and address pressing medical needs, China began to advocate for the implementation of the conditional approval process in 2017. We aimed to assess the implementation of the conditional approval process in China and further analyze its potential problems and future challenges. MethodsThis study examined the new drug approval with conditions in China between 2018 and 2021, based on an analysis of drug technical review documents from the Center for Drug Evaluation (CDE). Using publicly available information, we further analyzed the characteristics and results of pivotal clinical trials of conditionally approved drugs, postmarketing study requirements and progress. FindingsBetween 2018 and 2021, China conditionally approved 50 drugs, with 80% (40/50) being antineoplastic agents. Premarketing pivotal trials predominantly used single-arm clinical trials (83.7%, 41/49), while postmarketing trials mainly employed randomized controlled clinical trials (81.0%, 34/42). In oncology drugs, conditionally approved drugs with progression-free survival (PFS) and overall survival (OS) as primary endpoints achieved significant clinical value in terms of efficacy. However, there were also pivotal clinical trials with response rate (RR) as the primary endpoint that demonstrated lower clinical benefits (8.9% of drugs with RR below 20%). Safety analysis revealed substantial variations in the proportions of grade ≥3 adverse events (AEs) and serious adverse events (SAEs) across pivotal trials (Grade ≥ 3 AEs: 9.0%–99.0%; SAEs: 8.0%–83.0%). For nononcology drugs, pivotal trials also demonstrated an acceptable risk–benefit ratio but exhibited methodological issues. Meanwhile, Most postmarketing studies lacked completion date restrictions (43.2%, 17/47), and no requirements were specified for the transition to full approval. Furthermore, surrogate endpoints were primarily utilized both pre- and postmarketing, but the rational selection of surrogate endpoints remains to be investigated. ImplicationsThe conditional approval process expedites patient access to drugs for serious diseases. However, challenges pertaining to evidence assessment during approval and design flaws in postmarketing studies exist in China's conditional approval system, necessitating future improvements.

Think Globally, Act Globally: The Key Role Global Hubs Play in Oncological Drug Development

When global health crises such as the COVID-19 pandemic and HIV/AIDS epidemic occur, drug developers and researchers have an opportunity to highlight the benefits of implementing international clinical development plans to make treatments available as quickly as possible for patients around the world. However, when these public crises are not a factor, organizations typically wait until a product is nearing its approval stage before planning for and developing an international strategy.

Selective turn-on sensing of adenosine diphosphate and phosphate anions by ruthenium (II) polypyridine anchored p-tert-butylcalix[4]arene platform

BackgroundNucleoside polyphosphate (NPP) anions are important for enzymatic activity and should be monitored by scientists in industry and medicine. By elucidating enzyme kinetics and processes, it aids in the discovery of effective inhibitors and activators. Nucleoside polyphosphate (NPP) anions are used by kinases, GTPases, and glycosyltransferases (GTs). Phosphorylation of certain amino acid residues (Ser, Thr, and Tyr) on proteins requires the breakdown of ATP by protein kinases, which produces ADP. Protein kinases, breakdown of ATP, and NPP are the focus of oncology drug development because the aberrant control of kinase activity is a common cause of cancer. ResultsHowever, a discriminative turn-on fluorescent property is exhibited by non-fluorescent p-tertbutylcalix[4]arene modified 1,2,3-triazole containing bis-ruthenium polypyridyl complex (RL) upon the addition of phosphate anions such as (dihydrogen pyrophosphate (H2P2O72−) and dihydrogen phosphate (H2PO4−)) in CH3CN solvent and Adenosine Diphosphate (ADP) in CH3CN/HEPES (pH = 7.4) buffer (9/1, v/v). The probe RL shows a better-recognizing ability with pyrophosphate anion (H2P2O72−) than dihydrogen phosphate anion (H2PO4−). With H2P2O72− and H2PO4− anions, the RL detection limit was calculated to be as low as 83 nM and 198 nM, respectively. SignificanceThe calix[4]arene macrocycle's excellent size and binding cone conformation make it a good host–guest interface for the pyrophosphate anion and ADP. The bis-ruthenium polypyridyl complex's connection to the p-tertbutyl calix[4]arene moiety creates the ADP selectivity turn-on sensor. When moving from mono-nuclear to bi-nuclear ruthenium complex anchored on p-tertbutyl calix[4]arene, the probe can differentiate ADP, ATP, and AMP. Furthermore, this platform is a great resource for creating devices to simultaneously assess phosphate anions in environmental samples.