Discovery Of Therapies Research Articles

Transplant-Associated Thrombotic Microangiopathy in the Context of Allogenic Hematopoietic Stem Cell Transplantation: Where We Stand.

Transplant-associated thrombotic microangiopathy (TA-TMA) constitutes a significant contributor to the increased morbidity and mortality after allogenic hematopoietic stem cell transplantation (allo-HSCT). TA-TMA is a heterogenous disease, characterized by the triad of endothelial cell activation, complement dysregulation and microvascular hemolytic anemia, which may affect all organs. The lack of consensus diagnostic criteria, along with the common clinical features mimicking other diseases that complicate allo-HSCT, make the diagnosis of TA-TMA particularly challenging. Significant effort has been made to recognize specific risk factors predisposing to the development of TA-TMA and to identify serum biomarkers predicting the development of the disease. With regard to treatment, therapeutic plasma exchange (TPE) has been traditionally used, although with doubtful efficacy. On the other hand, the pivotal role of complement activation in the pathophysiology of TA-TMA has led to the exploration of the therapeutic potential of complement inhibitors in this setting. Eculizumab has been proposed as a first-line therapeutic agent in TA-TMA, owing to the very promising results in both pediatric and adult clinical trials. Pharmacokinetic and pharmacodynamic studies and CH50 levels are of paramount importance in the allo-HSCT setting, as a different dosing schedule (more intensive-in dose and frequency-at the beginning) seems to be required for successful outcomes. Furthermore, Narsoplimab, a MASP-2 inhibitor, recently received a Breakthrough Therapy Designation from the FDA for the treatment of TA-TMA after allo-HSCT. Finally, the decision to withdraw the CNIs, although initially advised by the Bone and Marrow Transplant Clinical Trials Network Committee, remains debatable owing to the controversial results of recent clinical trials. This review summarizes the current updates on pathophysiology, diagnosis and therapeutic approaches and emphasizes future goals and perspectives.

Past Is Prologue: Ethical Issues in Pediatric Psychedelics Research and Treatment.

Recent clinical trials of psychedelic drugs aim to treat a range of psychiatric conditions in adults. MDMA and psilocybin administered with psychotherapy have received FDA designation as "breakthrough therapies" for post-traumatic stress disorder (PTSD) and treatment-resistant depression (TRD) respectively. Given the potential benefit for minors burdened with many of the same disorders, calls to expand experimentation to minors are inevitable. This essay examines psychedelic research conducted on children from 1959 to 1974, highlighting methodological and ethical flaws. It provides ethics and policy recommendations for psychedelics research involving children and adolescents, including recognizing that the psychedelic experience is an ineffable one that makes informed proxy consent for parents, guardians, and others especially challenging. Psychedelic experiences are associated with novel benefits and risks, such as significant personality changes, shifts in fundamental values, and possible re-exposure to traumatic memories. These effects may alter the process of personality development in minors. Recommendations for ethically sound psychedelics research in minors include strict adherence to eligibility criteria, including a comprehensive family and individual psychiatric, substance use, and trauma history. An age-appropriate assent process that includes considerations related to the use of therapeutic touch should be developed. In addition, oversight by data safety monitoring boards and patient and family advocates, coupled with the adoption of pharmacoequity best practices, will help to ensure safety and fairness of psychedelics research in children.

Pharmacological Inventions for Alzheimer Treatment in the United States of America: A Revision Patent from 2010 – 2020

Alzheimer's disease (AD) is the most common form of dementia. There is currently no cure, and the available pharmacological treatment focuses on treating the symptoms. This study aimed to analyze the pharmacological treatments for AD protected in the US Patent Office. The Matheo Patent software was used to search for patents granted in the 2010-2020 period in the USPTO database. The search strategy «Alzheimer» was used in title and abstract and the International Patent Classification (IPC) codes A61P* and A61K*. The selected patents were divided into six categories according to therapeutic target. Complementary information from scientific databases was used to determine the stage of investigation and efficacy of the patented molecules. In the analyzed period, 58 patents were granted: 10 directed to Aβ peptide metabolism and deposition, three to tau, seven to inflammation, nine to cholinergic, two to glutamatergic and 27 to other targets. More than 80.0% belong to holders from the USA, France, and Japan. The molecules Elenbecestat and LY3202626 decreased the burden of Aβ plaques without significant cognitive improvement, Donanemab is in Phase 3 clinical trial, and the FDA has designated it Breakthrough Therapy. CPC-201 and PXT864 demonstrated, in Phase 2, good tolerability and improvement of AD symptoms. Most of the inventions are focused on treating the earliest phase of AD. The most advanced treatments in their research are those focused on treating Aβ accumulation. More studies are needed to prove the efficacy of the patented molecules.

The Co-expression of HER Family Members and CD109 is common in Pancreatic Cancer.

In the absence of biomarkers for the early detection of pancreatic cancer and the development of more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of death from cancer in the Western world. In the past four decades, aberrant expression and activation of human epidermal growth factor receptor (EGFR, also called HER) family members have been reported in a wide range of human cancers. Currently, of the various types of drugs targeting one or more members of the HER family, only the EGFR-specific tyrosine kinase inhibitor erlotinib and more recently Zenocutuzumab, a HER-2/HER3 bispecific antibody, were granted breakthrough therapy designation by the FDA for the treatment of patients with pancreatic cancer. However, the therapeutic benefit may be modest in some patients. Hence there is an urgent need for the identification of biomarkers as prognostic indicators, therapeutic targets, and for the response to therapy and the development of more effective therapeutic agents for this highly heterogeneous cancer. In this study, for the first time, we investigated the relative expression and prognostic significance of all members of the HER family, the type-III EGFR mutant (EGFRvIII), and CD109 in tissue microarrays (TMAs) and whole tumour specimens (WTS) from pancreatic cancer patients by immunohistochemistry. We found the positive expression of wild-type EGFR (wt-EGFR) (63%, 4.7%), HER2 (75%, 14%), HER3 (none, 14%), HER4 (45%, 21%), EGFRvIII (5%, 3%), and CD109 (67%, 55%) in TMAs (USA) and WTS (UK) from pancreatic cancer patients respectively. Our results also show that the co-expression of HER family members with CD109 occurs frequently in patients with pancreatic cancer. In addition, the co-expression of HER4/CD109 may also be associated with poorer overall survival in such patients. In this article, we shall discuss these findings and their implications and future opportunities for more effective targeting of HER positive pancreatic cancer using the HER inhibitors in combination with other drugs and therapeutic interventions.

Ethical challenges and opportunities in the development and approval of novel therapeutics for rare diseases.

The development of novel therapeutics for rare "orphan" diseases has brought a growing tension between the desire to accelerate access to these breakthrough therapies and the need to generate quality evidence regarding their safety and efficacy. Accelerating the pace of drug development and approval may facilitate the rapid delivery of benefits to patients and cost savings for research and development, which theoretically improves affordability of drugs for the health system. However, several ethical challenges arise with expedited approval, compassionate release of drugs, and subsequent study of drugs in "real-world" settings. In this article, we explore the changing landscape of drug approval and the ethical challenges expedited approval creates for patients, caregivers, clinicians, and institutions, and propose tangible strategies to maximize the benefits of "real-world" data acquisition while mitigating risks to patients, clinicians, and institutions.

Regulatory Trends in the Nonclinical Development of Viral Vector-Based Gene Therapies: A Benchmark Analysis of Approved Products

As it is often the case with innovative technologies, regulatory agencies are highly demanding in product safety demonstration from those pioneering breakthrough therapy products. Since the first historically approved gene therapy medicinal product (Gencidine in 2003) by the Chinese National Medicinal Products Administration, gene therapy medicinal products have slowly been emerging in other regions, as illustrated by the first European-approved gene therapy medicinal product (Glybera in 2012) and the first US-approved product (Imlygic in 2015). From then, with the rise of new molecular technologies (e.g., non-viral and viral vector systems), an exponential growth of gene therapies development could be gauged with, for example, the approval of more than thirty gene therapies between 2016-2022. Using a method based on Preferred Reporting Items for Systematic reviews and Meta-Analyses principle, throughout different literature databases, this review is restricted to the evaluation of viral vector-based gene therapy medicinal products (VV-GTMPs). It also considered relevant guidelines and public assessment reports issued by the EMA and / or the FDA on the products these agencies approved. Then, a benchmark was performed to help stakeholders to identify regulatory trends and to design appropriate nonclinical programs establishing the benefit / risk ratio for patients to be enrolled in clinical trials. The analysis was focused on the nonclinical activities (pharmacology, biodistribution / persistence / shedding, and toxicology) performed by Applicants / Sponsors. As of 30 March 2023, 18 VV-GTMPs have been authorized by the EMA and 14 by the FDA to treat either orphan diseases or limited number of oncology patients. The majority of these therapies are based on adeno-associated or retroviral viruses (often lentiviruses able to transfect hematopoietic CD34+ cells or T-cells). Based on an analysis of the ongoing clinical trials, there is now a trend for developing gene therapies for larger patient populations. In conclusion, given the VV-GTMPs diversity and targeted indications, a “one-size fits all” nonclinical development plan cannot be considered by default. Instead, individual, risk-based, tailored nonclinical development programs appear more appropriate to assess such products, taking into consideration the lessons learned from the past. In such fast-evolving environment, regulatory agencies need to adapt their evaluation process very rapidly.

Fundamental and translational research in Cystic Fibrosis – why we still need it

Clinical treatments for cystic fibrosis (CF) underwent significant changes in the last decade as therapies targeting the basic defect in the CFTR protein were approved. Significant scientific progress has also been made in several other areas that may lead in the future to novel therapeutic approaches that can help fight CF in all individuals living with this disease. Thus, focusing on fundamental research in the CF field has and will continue to be of great importance. This has been one of the aims of the European Cystic Fibrosis Society (ECFS), which has promoted the ECFS Basic Science Conference (BSC) every year since 2004. This special issue covers the topics featured and discussed at the 17th ECFS BSC, held in Albufeira (Portugal) in March 2022, and highlights advances in understanding CFTR, in using personalized medicine, and in developing innovative strategies to identify breakthrough therapies. This introduction highlights the topics presented throughout this special issue, thereby underscoring the relevance of fundamental research in CF.

Psychotherapists' openness to engage their patients in Psilocybin-Assisted Therapy for mental health treatment

Despite psychedelic research initially ceasing in the 1970–80s, the findings documented encouraged researchers to re-examine the safety and efficacy of treating mental health with psychedelics. Of particular focus, psilocybin has shown to have therapeutic potential for a variety of mental health problems and was granted breakthrough therapy status by the FDA. Should psilocybin eventually become legally licensed, the success of Psilocybin-Assisted Therapy (PAT) may largely rely on clinicians' openness to engage their eligible patients with PAT. We therefore assessed 119 psychologists' openness to recommend PAT, perceived barriers/facilitators to informing patients about PAT, and factors affecting their openness to involve patients with PAT if FDA approved. While 77.4 % of psychologists agreed they would inform eligible patients about PAT, 91.6 % stated they would still recommend psychotherapies that do not involve psilocybin first. 76.5 % endorsed that knowledge on psilocybin would increase their likelihood to inform patients about PAT. More positive attitudes and beliefs about psilocybin, greater self-reported knowledge of psilocybin, personal history of psychedelic usage, and more positive attitudes towards medical cannabis (MC) was associated with greater openness to engage patients with PAT. Our regression analysis revealed that attitudes towards MC and beliefs about psilocybin were the only significant predictors of psychotherapists' openness towards PAT. These findings provide relevant information to institutions planning educational programs for mental health professionals about psilocybin and Psychedelic-Assisted Therapies.

Triple combination targeting methyltransferase, BCL-2, and PD-1 facilitates antileukemia responses in acute myeloid leukemia.

A recent breakthrough therapy combining the BCL-2 inhibitor venetoclax with hypomethylating agents (HMAs) targeting DNA methyltransferase has improved outcomes for patients with acute myeloid leukemia (AML), but the responses and long-term survival in older/unfit patients and in patients with relapsed/refractory AML remain suboptimal. Recent studies showed that inhibition of BCL-2 or DNA methyltransferase modulates AML T-cell immunity. By using flow cytometry and time-of-flight mass cytometry, the authors examined the effects of the HMA decitabine combined with the BCL-2 inhibitor venetoclax (DAC/VEN therapy) on leukemia cells and T cells in patients with AML who received DAC/VEN therapy in a clinical trial. The authors investigated the response of programmed cell death protein 1 (PD-1) inhibition in the DAC/VEN-treated samples in vitro and investigated the triple combination of PD-1 inhibition with HMA/venetoclax in the trial patients who had AML. DAC/VEN therapy effectively targeted leukemia cells and upregulated the expression of the immune checkpoint-inhibitory receptor PD-1 in T cells while preserving CD4-positive and CD8-positive memory T cells in a subset of patients with AML who were tested. In vitro PD-1 inhibition potentiated the antileukemia response in DAC/VEN-treated AML samples. The combined use of azacitidine, venetoclax, and nivolumab eliminated circulating blasts and leukemia stem cells/progenitor cells and expanded the percentage of CD8-positive memory T cells in an illustrative patient with relapsed AML who responded to the regimen in an ongoing clinical trial. Immunomodulation by targeting PD-1 enhances the therapeutic effect of combining an HMA and venetoclax in patients with AML.

Safety Aspects and Rational Use of Lanadelumab Injections in the Treatment of Hereditary Angioedema (HAE): Clinical Insights.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin/mucosal swelling, and/or attacks of severe abdominal pain when it affects the gastrointestinal tract. The disease might be unexpectedly fatal when the upper airways are compromised. HAE clinical presentation, disease course and prognosis are associated with significant disease burden and severely impaired quality of life. Lanadelumab is a breakthrough therapy for the prevention of attacks in HAE type 1 and 2 patients. This revolutionary approach to administer a single subcutaneous injection (once every two to four weeks) and achieve complete disease control has dramatically improved patient care resulting in significant change in the life of affected families. Current data support the drug's tolerability in adult and adolescent patients without notable safety concerns in both clinical research and real-world settings. Rational use of prophylactic treatments of HAE searches for a socio-economic balance, taking into account the life-long course of the disease, the public health funds who pay the monetary price, and the patients who might need to receive the therapy for a period longer than investigated during the development program. In this review, we address the current evidence on lanadelumab's tolerability, highlighting aspects of the drug's rationale use in clinical practice. Further studies need to investigate whether this therapy might be appropriate in other forms of angioedema, such as idiopathic primary angioedema and HAE with normal C1 inhibitor. Future efforts must focus to improve modern drugs' accessibility in more countries. Although modern prophylactic options lessen the risk of fatal laryngeal attacks, patients must be equipped with reliable on-demand therapies and be trained how to use them as such a risk cannot be fully diminished with potentially life-threatening attacks occurring even in subjects with successful and stable long-term prophylaxis. Notwithstanding, further studies are needed to identify early responders from non-responders and develop therapies for the latter.

NIR-II fluorescence imaging-guided hepatocellular carcinoma treatment via IR-1061-acridine and lenvatinib co-loaded thermal-sensitive micelles and anti-PD-1 combinational therapy

Lenvatinib (LEN) combined with immune checkpoint PD-1 blockade is among the most effective treatment strategies for advanced hepatocellular carcinoma (HCC) and has been deemed a breakthrough therapy by the Food and Drug Administration. However, this combined strategy is associated with disadvantages such as non-tumor targeted aggregation and low oral bioavailability after long-term administration of LEN, and some patients show poor responses to immunotherapy as well. To overcome these drawbacks, SP94 peptide-modified thermal-sensitive micelles (SP94-poly(ethylene glycol)-poly(acrylamide-co-acrylonitrile, SP94-PEG-p(AAm-co-AN)) with an upper critical solution temperature (UCST) of 43 °C were designed. The micelles were further co-loaded with LEN and IR-1061-Acridine (IR-1061-AcD) to simultaneously achieve small molecule targeted drug, photothermal and photodynamic therapy for HCC under the guidance of near-infrared second-region (NIR-II) fluorescence imaging. After intravenous injection, the co-loaded micelles (SP94-PEG-p(AAm-co-AN)/LEN/IR-1061-AcD, SPLI) showed greater accumulation at tumor sites because SP94 has a high affinity for glucoregulatory protein 78 (GRP78), which is overexpressed on HCC cells. Given these HCC-targeted effects, SPLI appeared useful for NIR-II fluorescence imaging, enabling real-time tumor monitoring and surgical resection. In addition, SPLI could extensively induce immunogenic cell death in tumors, resulting in beneficial systemic immune responses. When further combined with anti-PD-1 immunotherapy, SPLI displayed a superior potential in suppressing tumor growth and metastasis while avoiding immune inhibition. Taken together, our study suggests that the aforementioned combinational strategy could serve as a desired multifunctional approach for HCC management.

Be Cautious to Adopt a Second CAR T-Cell Infusion after Failure of CD19/CD22 Cocktail CAR T-Cell Therapy in Relapsed/Refractory B-NHL

Objective: Chimeric antigen receptor (CAR) T-cell infusion (CTI) has emerged as a breakthrough therapy for relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL) patients. Nevertheless, there are still a significant number of patients suffering treatment failure (failed to respond or eventually relapsed after a partial or complete response, PR/CR) post the first time CTI (CTI1). The issue how to salvage this group of patients should be urgently addressed. Our study aimed to provide clues for exploring the potentially effective salvage strategies and finally improving the prognosis of them by analyzing the efficacy and safety especially between the second time CTI (CTI2) and other different therapies (non-CTI2). Methods: Herein,a retrospective analysis was performed on total 61 patients after failure of CD19/22 cocktail CTI1 (ChiCTR-OPN-16008526) between January 2017 and May 2022 in our hospital. Among them, 27 of 61 patients with a prior determination of no antigen loss received CTI2 for compassionate use. The other 34 patients were administrated as non-CTI2 therapies. The clinical characteristics, efficacy, safety, survival analysis and outcome-related risk factors were all evaluated. Results: The CTI2 group achieved a higher overall response rate (ORR) at 30 days assessment (8/27 vs. 2/34, P=0.017). Nevertheless, the non-CTI2 group showed a better event-free survival (EFS) (P=0.007) (Figure1, left panel) and overall survival (OS) (P=0.048) (Figure1, middle panel) than the CTI2 group with a median follow-up of 6.7 months (range, 3-45.5) and 4.7 months (range, 1.1-53). Further analysis on copies of CAR transgene in peripheral blood at 90 days detection revealed that the better CAR T cells expansion was related to a better response in CTI2 group (P=0.012)(data not shown). Additionally, neither of the CTI2 and non-CTI2 was the independent risk factor of survival (HR: 1.665, 95%CI: 0.883-3.141, P=0.115). Either of Ann Arbor stage (HR: 1.970,9 5%CI: 1.944-3.997, P=0.029) or bulky disease (HR: 2.879, 95%CI: 1.321-6.276, P=0.008) at disease onset was the related independent risk factor instead. As shown in Figure1 right panel, the best responses to different salvage therapies suggested that the regimen (Polatuzumab vedotin,-pola, Bendamustine, Rituximab, pola+BR) was likely to be a potentially optimal non-CTI2 salvage therapy, even without statistically significant differences due to the limitation of the sample size. The adverse effects of CTI2 were generally similar to those of non-CTI2. Remarkably the infection-related mortality rate was significantly higher (59% vs. 21%, P=0.025) in CTI2 group. Conclusion: Our study provides novel insights and clues that clinicians should be cautious to adopt a CTI2 after failure of the CD19/22 cocktail CTI1 in R/R B-NHL. It is noteworthy that the choice of pola+BR regimen probably has an advantage in salvage strategies. Large-scale prospective studies are warranted in the future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mitochondrial Regulation of Ferroptosis in Acute Myeloid Leukemia

Background: Investigations into targeting apoptosis in acute myeloid leukemia (AML) have resulted in breakthrough therapies utilizing Bcl-2 inhibition by venetoclax; however, acquired resistance poses major clinical challenges. Non-apoptotic regulated cell death (RCD) pathways have recently drawn attention especially in solid tumors, but studies targeting these pathways including ferroptosis in leukemia are limited. While ferroptosis is well-defined by iron- and lipid peroxidation-dependency, accumulating evidence suggests that there are also context-specific mechanisms. Since leukemia cells exhibit increased oxidative stress with particular dependency of cell survival on mitochondria, we hypothesized that AML exhibits a unique vulnerability to ferroptosis involving mitochondria. We here study targeting ferroptosis pathway in AML and its mitochondrial (mito-) regulation to develop mechanism-based combination with mito-targeting agents. Results: We first analyzed DepMap datasets to determine the essentiality of ferroptosis-regulating genes in cancer cell lines. Among major anti-ferroptosis genes, GPX4 exhibits high essentiality prominently in leukemia cells, suggesting its potential as a therapeutic target. AML patient survival data from TCGA revealed that high GPX4 expression is associated with shorter survival, indicating prognostic impact. GPX4 is the most downstream molecule to block ferroptosis by reducing lipid hydroperoxide. Although GPX4 is essential for mouse embryonic development, acquired depletion is reported to have no significant effect on hematopoietic stem cells, suggesting tolerability of GPX4-targeted therapies for normal hematopoiesis. We demonstrate that GPX4 inhibition with doxycycline-inducible shRNA or the specific inhibitor ML210 induces ferroptosis in leukemia cells, evidenced by iron-dependent lipid peroxidation and blockade of cell death by the iron chelator deferoxamine. Of note, the classical ferroptosis inducers (xCT inhibitors) sulfasalazine and sorafenib did not induce ferroptosis in AML cells, suggesting a specific relevance of GPX4 in AML ferroptosis. Consistent with solid tumor cells, AML cells show early (6h post-treatment) morphological alterations in mitochondria characterized by shrinkage and increased membrane density upon GPX4 inhibition (Figure 1). Importantly, and in contrast to most solid tumor studies, mitochondria-targeted antioxidants MitoQ and MitoTEMPO completely blocked ferroptosis, suggesting that AML ferroptosis is regulated predominantly by mitochondrial rather than cytoplasmic redox metabolism. To further determine the role of mitochondria in ferroptosis, we utilized HL60 rho0 cells that exhibit abrogated mito-respiration due to lack of mito-DNA. Surprisingly, HL60 rho0 cells were nearly 10 times more sensitive to ML210 than HL60 parental cells, in clear contrast to sarcoma studies demonstrating similar or lower sensitivity to ferroptosis of mito-DNA deficient cells. Consistently, degradation of the respiratory complex with hyperactivation of mito-protease ClpP by imipridone ONC212 sensitized cells to GPX4 inhibition in HL60 parental cells but not in rho0 cells, further supporting the role of mito-respiration in the protection of cells against ferroptosis. As venetoclax (Ven) is one of the most widely used mitochondria-targeting agents in AML that also inhibits mito-respiration, we tested the combination of GPX4 inhibitor ML210 and Ven. This combinatorial treatment exerts synergistic anti-leukemia effects in AML cell lines and primary cells from AML patients including those with Ven resistance (Figure 2). Unexpectedly, and as a novel mechanism of GPX4 inhibition-mediated ferroptosis, we found that ML210 induces BAX/BAK-independent cytochrome C release from mitochondria, which is blocked by MitoQ. Combination with Ven further enhanced cytochrome C release, as one of potential mechanisms of the observed synergistic cell death. Conclusion: Our data suggest therapeutic potential of ferroptosis induction in AML by targeting GPX4 with the mechanistic involvement of mito-respiration. The combination of GPX4 and BCL-2 inhibition is synergistic and capable of overcoming Ven resistance. Studies are in progress to elucidate the molecular link between mito-respiration/redox and cytochrome C release and to investigate ferroptosis induction in vivo. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Med Check: Lecanemab; ANEB-001; Azstarys; and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Lecanemab; ANEB-001; Azstarys; and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:27 Oct 2022https://doi.org/10.1176/appi.pn.2022.11.11.2Lecanemab May Slow Decline in Alzheimer’sLecanemab, an investigational anti-amyloid beta protofibril antibody, may slow cognitive decline in Alzheimer’s disease, Biogen Inc. and Esai Co. Ltd. announced in September. Lecanemab is being developed for the treatment of mild cognitive impairment from Alzheimer’s disease and mild or early Alzheimer’s disease with confirmed presence of amyloid pathology in the brain.In the phase 3 Clarity AD trial, 1,795 patients with early Alzheimer’s disease were randomized to receive either placebo or biweekly doses of 10 mg of lecanemab per kilogram of body weight. The primary endpoint was reduced clinical decline, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). At the end of 18 months, CDR-SB scores had declined by 27% less in patients who received lecanemab compared with those who received placebo. The CDR-SB scores were a mean 0.45 points lower for those who received lecanemab compared with those who received placebo.Last year the Food and Drug Administration (FDA) granted Breakthrough Therapy designation to lecanemab based on the results of a phase 2b clinical trial, which examined the impact of treatment with lecanemab on reducing amyloid beta and clinical decline, as measured by changes on the Alzheimer’s Disease Composite Score (ADCOMS). Breakthrough Therapy designation expedites the development and review of drugs for serious conditions.In the trial, 856 patients who had mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia were randomized to receive 2.5 mg/kg, 5 mg/kg, or 10 mg/kg of lecanemab once every two weeks; 5 mg/kg or 10 mg/kg of lecanemab once every four weeks; or placebo for 18 months. Patients who took 10 mg/kg biweekly lecanemab had a 76% probability of achieving 25% less decline on ADCOMS compared with those who took placebo. ANEB-001 May Reverse Cannabinoid IntoxicationA phase 2 trial of the investigational cannabinoid receptor agonist ANEB-001 suggests that the medication may reverse cannabinoid intoxication, Anebulo Pharmaceuticals Inc. announced in September.The trial involved approximately 60 participants, who were given 21 mg of delta-9-tetrahydrocannabinol (THC). They were then given 10 mg of ANEB-001, 30 mg of ANEB-001, or placebo.Those who received placebo reported a substantial increase in feeling high and body sway, decreased alertness, and a slightly increased heart rate from baseline. Participants who received either 10 mg or 30 mg of ANEB-001 experienced significant reductions in the visual analog scale (VAS) score for feeling high, improvement in the VAS alertness scale, and a reduction in THC-induced body sway compared with those who received placebo. Azstarys May Improve Sleep for Children with ADHDAzstarys (serdexmethylphenidate and dexmethylphenidate) may help improve sleep in children with attention-deficit/hyperactivity disorder (ADHD), Corium Inc. announced in September. Azstarys is approved for the treatment of ADHD in patients aged six years and older.In a one-year open-label study, 238 children with ADHD aged six to 12 years received Aztarys for one year. After one month of treatment with Azstarys, the children’s total average sleep disturbance score on the Children’s Sleep Habits Questionnaire (CSHQ) decreased significantly from a mean of 53.4 points to 50.5 points. Furthermore their total mean CSHQ scores remained between 48.9 to 50.1 points for up to 12 months, indicating that the improvements in their sleep were sustained.The results of the study were presented in a poster at the Psych Congress 2022 in New Orleans. FDA Reviews Two-Month Aripiprazole Injection for SchizophreniaIn September, Otsuka America Pharmaceutical Inc. and H. Lundbeck A/S announced that the FDA has accepted for review a New Drug Application (NDA) for aripiprazole two-month, long-acting injectable for the treatment of schizophrenia in adults and for maintenance monotherapy of bipolar I disorder in adults. The NDA is for a formulation designed to be administered via intramuscular injection in the gluteal muscle.The NDA is based on data from a clinical trial involving 266 patients who were randomized to receive either four 920 mg injections of aripiprazole two-month long-acting injectable or eight 400 mg injections of aripiprazole one-month depot. Plasma concentrations of aripiprazole were similar between both groups of patients, and the two-month injectable was well-tolerated and showed no safety concerns compared with the once-monthly injectable. ■ ISSUES NewArchived

Use of US Food and Drug Administration Expedited Drug Development and Review Programs by Orphan and Nonorphan Novel Drugs Approved From 2008 to 2021

The US Food and Drug Administration (FDA) has 4 programs that can be used alone or in combination to expedite drug availability: Accelerated Approval, Breakthrough Therapy, Fast Track, and Priority Review. Drugs using these programs can include novel drugs, which do not contain a previously FDA-approved active moiety, and orphan drugs, intended for diseases or conditions affecting fewer than 200 000 people; to date, no comprehensive evaluation of how these programs have been used in combination has been published. To assess how often and in what combinations expedited programs are used in the development and review of approved novel biologics and small-molecule drugs, stratified by orphan drug status and indication. This cross-sectional study evaluated all novel drugs that were FDA approved between January 1, 2008, and December 31, 2021. The main outcome was the frequency with which expedited programs were used and in what combinations, stratified by orphan drug status and drug type (small molecule vs therapeutic biologic). The unit of analysis was the novel drug-indication pair because a drug can be approved for multiple indications, each of which may use a different expedited program or differ in orphan drug status. The study included 581 novel drug-indication pairs approved during the 14-year study period; 252 (43.4%) were orphan drugs, 139 (23.9%) were therapeutic biologics, and 442 (76.1%) were small-molecule drugs. Use of at least 1 expedited program increased from 11 of 26 drug-indication pairs (42.3%) in 2008 to 41 of 55 (74.5%) in 2021. Of the 363 approved drug-indication pairs using at least 1 expedited program, 225 (62.0%) were orphan drugs; at least 1 expedited program was used by 97 of the 139 approved biologic drugs (69.8%) and by 266 of the 442 approved small-molecule drugs (60.2%). Eighty-two of the 581 novel drug-indication pairs (14.1%) used the Accelerated Approval Program; of those, 65 (79.3%) were oncology drugs and 70 (85.4%) had an orphan designation. The study showed that use of the FDA's expedited programs to bring novel drugs to market in the US increased from 2008 to 2021. The findings suggest that this trend is likely to continue.

ODP170 Check Point Inhibitor Associated Multi-Endocrine Dysfunction Presenting With Euglycemic Ketoacidosis

Abstract Introduction Immune check point inhibitors have become breakthrough therapy for many types of cancers. They inhibit one of two immune regulatory pathways, the cytotoxic T-lymphocyte antigen 4 (CTLA-4), and 'programmed death-1' (PD-1) and (PD-L1) pathways. Removing immune regulation allows for anti-cancer immune responses. They also cause immune related endocrine dysfunction such as hypophysitis, thyroiditis, diabetes mellitus (DM) and primary adrenal insufficiency (AI). We describe a patient on Pembrolizumab (PEM) (an anti-PD-1 inhibitor) who presented with new onset DM, euglycemic diabetic ketoacidosis (DKA) with simultaneous secondary AI. Case report 54-year-old woman with stage 4 non-small cell carcinoma of the lung (NSCLC) with known brain metastasis, was under therapy with carboplastin, paclitaxel and PEM, presented with headache, blurry vision and altered mental status. She had past history of Graves’ disease s/p radioactive iodine therapy, currently on levothyroxine. For two weeks, she had decreased oral intake, and generalized weakness. Upon presentation, she was cachectic, BP 152/65, pulse 117 and confabulating. Laboratory evaluation showed: serum glucose 72 mg/dL, Na 139 mmol/L, K 3.2 mmol/L, Cl 113 mmol/L, HCO3 11 mmol/L, anion gap 15 mmol/L, beta-hydroxybutyrate 4.8 mmol/L, lactic acid 0.7 mmol/L, venous pH 7.2 and base excess -16.6 mmol/L. The delta-delta gap was 10 mmol/L, compatible with a mixed anion-gap and hyperchloremic acidosis (HCA). Antibodies to GAD-65, and Zinc transporter-8 were negative. To evaluate euglycemia despite DKA, levels were obtained for serum cortisol 1 mcg/dL, and ACTH <1 pg/mL confirming secondary AI. MRI neuroimaging showed several metastatic brain lesions, a small pituitary gland without stalk enhancement or thickening. Management of euglycemic ketoacidosis required high dose glucose infusion (>10 g/hour), stress doses of hydrocortisone (HC), and infusion of low chloride solute for HCA. Conclusion Awareness of the potential for multi-endocrine dysfunction, directed us towards the urgent institution of therapy for DKA with supplementation of stress dose HC for presumed AI, the latter as a cause of relative "hypoglycemia". Central AI was confirmed with undetectable levels of cortisol and ACTH. Although less frequent than with CTLA-4 inhibitors, PD-1 inhibitors are associated with hypophysitis even without abnormalities on pituitary MRI. The DM (associated with PD-1 inhibitors) although autoimmune is nature, is "antibody" positive approximately 50% of the time. Further therapy for both euglycemic DKA and HCA required adjustment of the conventional management for DKA. To our knowledge this is the first reported case of Euglycemic DKA and secondary AI due to PD-1 inhibitors per literature review. Reference: Walters AGB, BraatvedtG G. Endocrine adverse effects of immune check point inhibitors . Intern Med J. 2021Jul;51(7): 1016-1020. doi: 10.111/imj . 14992. PMID: 34278695. Hattersley R, Nana M,Lansdown AJ. Endocrine complications of immunopathies: a review . ClinMed(Lond).2021 Mar;21(2): e212-e222. doi: 10.7861/clinmed.2020-0827. PMID: 33762389;PMCID: PMC8002767 Presentation: No date and time listed

Considering Global Development? Insights from Applications for FDA Breakthrough Therapy and EMA PRIME Designations

The United States Food and Drug Administration and the European Medicines Agency (EMA) each have programs to expedite development of products identified as having potential to address unmet medical needs: the Breakthrough therapy (BT) and Regenerative Medicines Advanced Therapies designation programs in the US and the Priority Medicines (PRIME) scheme at EMA. We reviewed commonalities and differences in requests submitted and products designated through these programs, with the intent to explore ways to better support global development. During the period from PRIME’s launch in April 2016 to 31 December 2020, 151 requests were made to both BT and PRIME programs and the agencies reached concordant outcomes to grant or deny requests for almost two thirds of the cases (93/151, 62%), suggesting similar perspectives across international regulators on the potential of the products under study. Forty-two (42/151, 28%) products were granted both BT and PRIME, thus found by both Agencies to have the potential to address an unmet need for a serious condition, and thereby products for which efficient development would be highly desirable. Working toward better engagement on global development strategies is in the best interests of patients and public health. With this in mind, Agencies and sponsors should take advantage of existing collaborative opportunities, such as parallel scientific advice, and work to identify fresh approaches to support global development of products for unmet medical needs.

Advanced Lung Cancer Patients' Use of EGFR Tyrosine Kinase Inhibitors and Overall Survival: Real-World Evidence from Quebec, Canada.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are breakthrough palliative treatments for advanced lung cancer patients with tumors harboring mutations in the EGFR gene. Using healthcare administrative data, three cohorts were created to describe the use of three EGFR-TKIs that are publicly funded in Quebec for specific indications (i.e., 1st-line gefitinib, 1st-line afatinib, and post-EGFR-TKI osimertinib). The main objective was to compare overall survival (OS) among patients receiving these treatments to those in previous experimental and real-world studies. The patients who received EGFR-TKIs for indications of interest between 1 April 2001, and 31 March 2019 (or 31 March 2020, for post-EGFR-TKI osimertinib) were included to estimate the Kaplan-Meier-based median OS for each cohort. An extensive literature search was conducted to include comparable studies. For the gefitinib 1st-line (n = 457), the afatinib 1st-line (n = 80), and the post-EGFR-TKI osimertinib (n = 119) cohorts, we found a median OS (in months) of 18.9 (95%CI: 16.3-21.9), 26.6 (95%CI: 13.7-NE) and 19.9 (95%CI: 17.4-NE), respectively. Out of the 20 studies that we retained from the literature review and where comparisons were feasible, 17 (85%) had similar OS results, which further confirms the value of these breakthrough therapies in real-world clinical practice.

Actualization of Positions of Gliflozins in Treatment Algorithms for Patients with Heart Failure: Chronology of Success

INTRODUCTION: Despite the efforts of the cardiologic communities to introduce approaches to treatment of heart failure (HF) based on the highest level of evidence, HF remains one of the least satisfied demands in the therapy of cardiovascular diseases due to high prevalence, poor prognosis and insufficient use of treatment methods with clinically proven effectiveness. The article considers chronology of study and introduction of sodium-glucose cotransporter 2 inhibitors (syn.: gliflozins; SGLT2is) in clinical practice from the moment of creation of the first drug of this group ― florizin ― and further, stepwise with the change of the therapeutic paradigm as the result of performed clinical trials. Thus, EMPAREG OUTCOME, CANVAS, DECLARE-TIMI 58 studies demonstrated that SGLT2is not only produce a glucosuric effect, but also reduce the development and progression of HF and increase the life expectancy of patients with type 2 diabetes mellitus (DM2) and with reduced left ventricular ejection fraction (LFEF). DAPA-HF, EMPEROR-Reduced studies proved a possibility of improving the outcomes for patients with HF with reduced LVEF irrespective of the presence or absence of DM2, thereby significantly expanding the potential target group for SGLT2is. EMPEROR-Preserved study is the only study of SGLT2is to date (the study drug ― empagliflozin) that has demonstrated high effectiveness of the drug in prevention of cardiovascular mortality and hospitalizations for HF, probably irrespective of LVEF and the existence of DM2. In result, on September 9, 2021, FDA (Food and Drug Administration, USА) assigned the breakthrough therapy status to Jardiance (empagliflozin) drug for treatment of HF with preserved LFEF. EMPA-REG OUTCOME, DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, DAPA-CKD studies have shown SGLT2is to slow down the development of the terminal stage of chronic kidney disease. Finally, the main result of EMPULSE study completed in 2022, was the proven clinical benefit of empagliflozin in hospitalized and stabilized patients with acute HF decompensation irrespective of HF status and existence of DM2.
 CONCLUSION: From the moment SGLT2is have been introduced in the clinical practice, they rapidly and successfully passed the way from the second-line antidiabetic drugs for which it was just enough not to worsen the prognosis for serious cardiovascular complications, to independent and effective class of drugs for treatment of HF (with class I and IIa recommendations). The totality of clinical trials of empagliflozin showed that empaflorizin is so far the only drug of the SGLT2is group with the proven safety and clinical effectiveness including the influence on the prognosis, in patients with HF irrespective of the LVEF status, presence or absence of DM2, for use in outpatient treatment and in stabilized patients in hospital.

A methylation-dependent checkpoint by SETD7 promotes myocardial ischemic injury in mice and men

Abstract Background Despite appropriate revascularization strategies, a significant number of patients with myocardial infarction (MI) develop ischemic heart failure suggesting that breakthrough therapies are yet to be approved in this setting. Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has been shown to methylate and alter the function of a variety of proteins in vitro, however, its function in the heart is poorly understood. Purpose To determine the role of SETD7 in myocardial ischemic injury. Methods Neonatal rat ventricular myocytes (NRVM) were exposed to normal glucose levels or glucose deprivation (GD) for 15 h, in the presence of the selective SETD7 inhibitor (R)-PFI-2 or its inactive enantiomer (S)-PFI-2. Western blot and real-time PCR were employed to investigate the effects of energy stress on SETD7 and the Hippo pathway, while apoptosis and oxidative stress were assessed by Caspase-3 activity assay and mitoSOX staining. YAP transcriptional activity was assessed by chromatin immunoprecipitation assay (ChIP) while its localization and methylation were examined by confocal microscopy and immunoblotting, respectively. SETD7 knockout (SETD7−/−) mice and wild-type (WT) littermates underwent myocardial ischemia-reperfusion (I/R) injury (1h coronary ligation /24 h of reperfusion) followed by assessment of cardiac function by echocardiography. Left ventricular (LV) myocardial samples were collected from I/R mice and patients with ischemic cardiomyopathy (ICM), and isolated cardiomyocytes were treated with (R)-PFI-2. Finally, SETD7 expression was also assessed in peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). Results SETD7 was activated upon energy deprivation in cultured NRVMs and methylated YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes MnSOD and CAT. Pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization thus preventing mitochondrial reactive oxygen species (mtROS) and apoptosis. SETD7 deletion in mice attenuated I/R injury, mtROS and LV dysfunction by restoring YAP-dependent transcriptional programs. SETD7/YAP dysregulation was also observed in LV specimens from ICM patients. Moreover, in cardiomyocytes isolated from I/R mice and ICM patients, (R)-PFI-2 restored YAP nuclear localization, prevented mtROS accumulation while improving myofibrillar protein contractility and Ca2+ sensitivity. Finally, SETD7 was upregulated in PBMCs from STEMI patients and negatively correlated with the expression of MnSOD and CAT. Conclusions SETD7-dependent methylation of YAP is an important mechanism underpinning myocardial oxidative stress and apoptosis during ischemia. Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a potential therapeutic approach to prevent myocardial ischemic damage through modulation of the Hippo pathway. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich