Discovery Of Therapies Research Articles

The Digitized Memory Clinic.

Several major challenges, including an ageing population and declining workforce and the implementation of recent breakthrough therapies for Alzheimer disease, are prompting a necessary rethink of how people with neurodegenerative dementias are diagnosed and medically managed. Digital health technologies could play a pivotal part in this transformation, with new advances enabling the collection of millions of data points from a single individual. Possible applications include unobtrusive monitoring that aids early detection of disease and artificial intelligence-based health advice. To translate these advances to meaningful benefits for people living with a disease, technologies must be implemented within a system that retains the physician expert as a central figure in decision-making. This Perspective presents a new framework, termed the Digitized Memory Clinic, for the diagnostic pathway of neurodegenerative dementias that incorporates digital health technologies with currently available assessment tools, such as fluid and imaging biomarkers, in an interplay with the physician. The Digitized Memory Clinic will manage people across the entire disease spectrum, from the detection of risk factors for cognitive decline and the earliest symptoms to dementia, and will replace the present paradigm of a pure 'brick-and-mortar' memory clinic. Important ethical, legal and societal barriers associated with the implementation of digital health technologies in memory clinics need to be addressed. The envisioned Digitized Memory Clinic aims to improve diagnostics and enable precise disease-tracking prognostication for individuals with memory disorders and to open new possibilities, such as precision medicine for prevention and treatment.

Clinical Benefit, Price, and Regulatory Approval of Cancer Drugs Granted Breakthrough Therapy Designation in China, 2020-2024

The China National Drug Administration (NMPA) established the breakthrough therapy designation (BTD) in 2020 to encourage the accelerated development of drugs for the prevention and treatment of diseases that are life-threatening. However, the differences between BTD and non-BTD cancer drugs regarding clinical benefit, regulatory approval, and price are unclear. To compare BTD and non-BTD cancer drugs in clinical benefit (defined as efficacy and safety), novelty, time to approval, and average monthly treatment price. This cross-sectional study analyzes the original indication of BTD and non-BTD novel cancer drugs approved by the NMPA between July 8, 2020, and July 8, 2024. Data on efficacy, safety, regulatory approval, and price of cancer drugs were extracted from pivotal clinical trials based on review reports published by the NMPA, peer-reviewed articles or meeting reports, and winning bid prices for cancer drugs in the Chinese provincial-level centralized procurement process. The main outcome was the efficacy and safety associated with BTD vs non-BTD cancer drugs, including progression-free survival (PFS), response rate (RR), duration of response, serious adverse events, grade 3 or higher adverse events, and treatment-related deaths. In addition, the time to approval, novelty, and initial and latest average monthly treatment prices were evaluated, as well as the average annual reduction rate (AARR; the sum of the reduction rates divided by the number of years for the monthly treatment price) for these cancer drugs. Between July 2020 and July 2024, 18 BTD (36%) and 32 non-BTD (64%) cancer drugs were approved by the NMPA. The median (IQR) clinical development time for BTD drugs was significantly shorter than for non-BTD drugs (5.6 [95% CI, 4.3-7.3] vs 6.6 [95% CI, 6.0-8.5] years; P = .02). No significant differences were observed in PFS (HR, 0.44 [95% CI, 0.38-0.52] vs HR, 0.51 [95% CI, 0.40-0.65]; P = .20), PFS gained (median [IQR], 5.4 [3.9-7.0] vs 2.7 [2.6-5.9] months; P = .77), RR (58% [95% CI, 45%-74%] vs 59% [95% CI, 51%-69%]; P = .85), and duration of response (median [IQR], 18.0 [15.0-21.6] vs 11.1 [7.4-17.4] months; P = .09) between BTD and non-BTD drugs. The rates of serious adverse events (37% [95% CI, 26%-52%] vs 32% [95% CI, 27%-36%]; P = .45), adverse events grade 3 or higher (64% [95% CI, 53%-77%] vs 55% [95% CI, 45%-68%]; P = .31), and treatment-related deaths (2% [95% CI, 1%-4%] vs 1% [95% CI, 1%-2%]; P = .10) were similar between BTD and non-BTD drugs. BTD drugs are more likely to be first-in-class drugs (5 of 18 [28%] vs 1 of 32 [3%]; P = .02). Differences in the median (IQR) initial ($5665 [$3542-$9321] vs $3361 [$2604-$5474]; P = .06) and latest ($5665 [$1553-$9321] vs $2145 [$1318-$4276]; P = .18) average monthly treatment prices for BTD drugs and non-BTD drugs were not significant. The median (IQR) AARRs for BTD drugs and non-BTD drugs were 15.2% (0%-46.9%) and 19.8% (1.0%-42.9%), respectively. The findings of this cross-sectional study suggest that BTD has facilitated faster time to market for cancer drugs and improved novelty, but the price of treatment is relatively higher. There was no significant difference on comparative efficacy and safety.

Breast cancer drugs: FDA approval, development time, efficacy, clinical benefits, innovation, trials, endpoints, quality of life, value, and price

ObjectiveThis study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval.MethodsWe identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000–2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response’s relative risk (RR) alongside objective response rate (ORR) were meta-analyzed.ResultsThe median development time for breast cancer drugs was 7.8 years (95% CI 6.2–10.8). 26% of treatments were considered innovative (“first-in-indication”) with 88% acting via a targeted mechanism. 64% were small molecules, 19% antibodies, and 18% antibody-drug conjugates. 38% were approved for HR + and 31% for HER2 + breast cancer. 6 indications were for early and 36 for metastatic breast cancer. Indications utilized FDA’s special programs: orphan (2%), fast track (24%), accelerated approval (19%), priority review (74%), breakthrough therapy (44%). Approval was predominantly supported by phase 3 trials (88%) of randomized controlled design (66%), enrolling a median of 585 patients (IQR 417–752) at 181 centers (IQR 142–223) across 19 countries (IQR 17–20). New drugs’ HR were 0.78 for OS (95% CI 0.74–0.82) and 0.59 for PFS (95% CI 0.54–0.64) with a RR for tumor response of 1.61 (95% CI 1.46–1.76). Median improvements of OS were 2.8 months (IQR 1.8–5.8) and PFS were 4.4 months (IQR 2.2–7.1). In single-arm trials, the average ORR was 31% (95% CI 10–53). In meta-regressions, the correlation between OS/PFS was 0.34 (p = 0.031) and OS/response was 0.01 (p = 0.435). 60% of treatments had a ‘high-value’ ESMO-MCBS score with 14% demonstrating improvements in quality of life. The median price was $16,013 per month (95% CI 13,097–17,617). There was no association between prices and patient benefit. The median value per life year gained was $62,419 (IQR 25,840–86,062).ConclusionsOver the past two decades, the development of innovative and effective drugs transformed the treatment landscape for breast cancer patients. Yet, investigators and regulators must safeguard that highly-priced new drugs demonstrate improvements in patient-centered clinical endpoints: overall survival and quality of life.

RNA sequencing identifies lung cancer lineage and facilitates drug repositioning.

Recent breakthrough therapies have improved survival rates in non-small cell lung cancer (NSCLC), but a paradigm for prospective confirmation is still lacking. Patientdatasets were mainly downloaded from TCGA, CPTAC and GEO. We conducted downstream analysis by collecting metagenes and generated 42-gene subtype classifiers to elucidate biological pathways. Subsequently, scRNA, eRNA, methylation, mutation, and copy number variation were depicted from a phenotype perspective. Enhancing the clinical translatability of molecular subtypes, preclinical models including CMAP, CCLE, and GDSC were utilized for drug repositioning. Importantly, we verified the presence of previously described three phenotypes including bronchioid, neuroendocrine, and squamoid. Poor prognosis was seen in squamoid and neuroendocrine clusters for treatment-naive and immunotherapy populations. The neuroendocrine cluster was dominated by STK11 mutations and 14q13.3 amplifications, whose related methylated loci are predictive of immunotherapy. And the greatest therapeutic potential lies in the bronchioid cluster. We further estimated the relative cell abundance of the tumor microenvironment (TME), specific cell types could be reflected among three clusters. Meanwhile, the higher portion of immune cell infiltration belonged to bronchioid and squamoid, not the neuroendocrine cluster. In drug repositioning, MEK inhibitors resisted bronchioid but were squamoid-sensitive. To conceptually validate compounds/targets, we employed RNA-seq and CCK-8/western blot assays. Our results indicated that dinaciclib and alvocidib exhibited similar activity and sensitivity in the neuroendocrine cluster. Also, a lineage factor named KLF5 recognized by inferred transcriptional factors activity could be suppressed by verteporfin.

Expedited program and utilization for anticancer drug approval in China and the United States

Objective: To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021. Methods: Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison. Results: Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions: Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Equipoise Lost? Trial Conduct Challenges in an Era of Breakthrough Therapies.

FDA Oncology Center's @Falleh_Fallah and colleagues discuss loss of equipoise and other trial conduct challenges in an era of breakthrough therapies - via @JCO_ASCO.

Pharmacokinetics of Psilocybin, a Tryptamine Alkaloid in Magic Mushroom (Psilocybe cubensis): A Systematic Review

ABSTRACT Psilocybin, a major indole alkaloid found in magic mushrooms (Psilocybe cubensis), has recently drawn attention as a breakthrough therapy to treat major depressive disorder. This review aimed to summarize and identify knowledge gaps concerning their pharmacokinetic characteristics of psilocybin and its active metabolite, psilocin. Original studies related to pharmacokinetics of psilocybin conducted in vitro, animals, and humans were systematically collected from PubMed, Scopus, and ScienceDirect, from their inceptions to November 2023. Twenty articles were included in this work and assessed for study quality. A comprehensive review of the pharmacokinetics of psilocybin and psilocin in both animals and humans was performed. Psilocybin is considered a prodrug that is dephosphorylated to psilocin by alkaline phosphatase. Following ingestion, the peak psilocin plasma and brain levels were rapidly achieved in a dose-dependent manner. Psilocin is metabolized primarily through both Phase I and Phase II processes with the half-life of 2–3 hours. This review also identified lack of some pharmacokinetic related information and limitations of available research that may help direct future investigations to better understand the pharmacokinetics and improve study design including dose selection and dosage optimization.

1551P Breakthrough therapy cancer drugs and indications with FDA approval: Development time, innovation, trials, clinical benefit, epidemiology, and price

1551P Breakthrough therapy cancer drugs and indications with FDA approval: Development time, innovation, trials, clinical benefit, epidemiology, and price

Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies

The US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used. To evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy-designated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points. This cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy-designated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024. Descriptive analyses were used to characterize the breakthrough therapy-designated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments. From 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication. In this cross-sectional study of original FDA breakthrough therapy-designated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy-designated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.

Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers.

KRAS is the most frequently dysregulated oncogene with high prevalence in NSCLC, colorectal cancer, and pancreatic cancer. FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation. However, there is still high unmet medical need for new agents targeting broader KRAS-driven tumors. An emerging and promising opportunity is to develop a pan KRAS inhibitor by suppressing the upstream protein SOS1. SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS state to GTP-bound KRAS state. Binding to its catalytic domain, small molecule SOS1 inhibitor has demonstrated the ability to suppress KRAS activation and cancer cell proliferation. RGT-018, a potent and selective SOS1 inhibitor, was identified with optimal drug-like properties. In vitro, RGT-018 blocked the interaction of KRAS:SOS1 with single digit nM potency and is highly selective against SOS2. RGT-018 inhibited KRAS signaling and the proliferation of a broad spectrum of KRAS-driven cancer cells as a single agent in vitro. Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling in tumor xenografts in vivo. Combination with MEK or KRASG12C inhibitors led to significant tumor regression. Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population.

Exploring potential therapeutic combinations for castration-sensitive prostate cancer using supercomputers: a proof of concept study

To address the challenge of finding new combination therapies against castration-sensitive prostate cancer, we introduce Vini, a computational tool that predicts the efficacy of drug combinations at the intracellular level by integrating data from the KEGG, DrugBank, Pubchem, Protein Data Bank, Uniprot, NCI-60 and COSMIC databases. Vini is a computational tool that predicts the efficacy of drugs and their combinations at the intracellular level. It addresses the problem comprehensively by considering all known target genes, proteins and small molecules and their mutual interactions involved in the onset and development of cancer. The results obtained point to new, previously unexplored combination therapies that could theoretically be promising candidates for the treatment of castration-sensitive prostate cancer and could prevent the inevitable progression of the cancer to the incurable castration-resistant stage. Furthermore, after analyzing the obtained triple combinations of drugs and their targets, the most common targets became clear: ALK, BCL-2, mTOR, DNA and androgen axis. These results may help to define future therapies against castration-sensitive prostate cancer. The use of the Vini computer model to explore therapeutic combinations represents an innovative approach in the search for effective treatments for castration-sensitive prostate cancer, which, if clinically validated, could potentially lead to new breakthrough therapies.

REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) mutations.

TPS219 Background: Despite recent advances, tolerable and effective treatments for patients with NSCLC harboring EGFR ex20ins mutations are needed, particularly in the first-line setting where platinum-based chemotherapy remains the standard of care. Zipalertinib (CLN-081/TAS6417), an oral tyrosine kinase inhibitor (TKI) of EGFR with broad activity against EGFR mutations, showed encouraging antitumor activity in heavily pretreated patients with EGFR ex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation by the U.S. Food and Drug Administration in January 2022. Data suggest that combining EGFR TKIs with chemotherapy can improve antitumor efficacy versus chemotherapy or TKI treatment alone in patients with EGFR-mutated nonsquamous NSCLC. REZILIENT3 is a pivotal phase 3 study designed to compare the efficacy and safety of zipalertinib plus first-line standard-of-care platinum-based chemotherapy versus chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations. Methods: This randomized, controlled, open-label, phase 3 study (NCT05973773) will be conducted in two parts. Part A (safety lead-in) will confirm the safety of zipalertinib 100 mg twice daily as the recommended dose in combination with chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations or other uncommon single/compound EGFR mutations. In Part B (randomized part), patients with EGFR ex20ins mutations and at least one measurable lesion (per Response Evaluation Criteria in Solid Tumours, version 1.1) will be randomized 1:1 to zipalertinib plus chemotherapy or chemotherapy alone, stratified by Eastern Cooperative Oncology Group performance status (0/1), brain metastases (yes/no), and geography (Asia/rest of world). Zipalertinib will be administered orally at a starting dose of 100 mg twice daily (pending confirmation in Part A). Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). Patients randomized to chemotherapy alone will be allowed to cross over to zipalertinib monotherapy after documented progressive disease. The primary endpoint in Part B is progression-free survival assessed by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate, safety, intracranial efficacy endpoints, and quality of life. Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 260 patients. Enrollment started in June 2023. Clinical trial information: NCT05973773 .

Cystic fibrosis.

Cystic fibrosis is a rare genetic disease caused by mutations in CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). The discovery of CFTR in 1989 has enabled the unravelling of disease mechanisms and, more recently, the development of CFTR-directed therapeutics that target the underlying molecular defect. The CFTR protein functions as an ion channel that is crucial for correct ion and fluid transport across epithelial cells lining the airways and other organs. Consequently, CFTR dysfunction causes a complex multi-organ disease but, to date, most of the morbidity and mortality in people with cystic fibrosis is due to muco-obstructive lung disease. Cystic fibrosis care has long been limited to treating symptoms using nutritional support, airway clearance techniques and antibiotics to suppress airway infection. The widespread implementation of newborn screening for cystic fibrosis and the introduction of a highly effective triple combination CFTR modulator therapy that has unprecedented clinical benefits in up to 90% of genetically eligible people with cystic fibrosis has fundamentally changed the therapeutic landscape and improved prognosis. However, people with cystic fibrosis who are not eligible based on their CFTR genotype or who live in countries where they do not have access to this breakthrough therapy remain with a high unmet medical need.

Combination Therapy of Lenvatinib and Hepatic Arterial Infusion Chemotherapy Using Cisplatin With Lipiodol and 5-Fluorouracil: A Potential Breakthrough Therapy for Unresectable Advanced Hepatocellular Carcinoma.

In 2021, the LEOPARD trial reported that the combination of lenvatinib+one-shot cisplatin infusion might contribute to improving the results of conventional advanced hepatocellular carcinoma (HCC) treatment. Thus, combination therapy with lenvatinib and catheterization has emerged as a focal point in treating advanced HCC. Conversely, the New FP regimen consists of low-dose cisplatin (CDDP) combined with 5-fluorouracil (5-FU) and lipiodol via hepatic arterial infusion chemotherapy (HAIC), with a high response rate of approximately 70%. Therefore, lenvatinib+New FP (LEN-New FP) may be a more promising treatment for HCC. Here, we report six patients who were administered LEN+New FP and achieved high therapeutic efficacy. Among them, one case had an interesting clinical course, which has been described in detail. This study included six patients who were administered 12 mg or 8 mg of lenvatinib once daily based on a body weight of ≥60 kg or <60 kg, respectively, along with 50 mg of cisplatin in 5-10 mL lipiodol, and a continuous infusion of 5-FU (1500 mg/5 days) infused every 2-4 weeks. Tumor evaluations were performed 4-8 weeks after the initiation of New FP administration and every 8-12 weeks thereafter. The median patient age was 65 years. All patients had a history of prior treatment with atezolizumab and bevacizumab and one of the factors associated with poor overall survival for New FP monotherapy, such as a maximum tumor diameter ≥7 cm and bilobular multifocal distribution. Four (67%) patients had severe vascular invasion. The best objective response and disease control rates were 83% and 100%, respectively. The best response of the target lesion was complete remission in four out of six patients. The LEN-New FP combination for advanced HCC showed a high response rate and was more effective in high-risk patients with factors associated with poor overall survival than that reported with conventional New FP monotherapy. Additionally, LEN-New FP exhibited extremely high objective response and disease control rates and was well tolerated, including in cases where it was considered second- or third-line systemic chemotherapy for advanced HCC. Thus, LEN-New FP can serve as a breakthrough therapy for advanced HCC based on appropriate case selection.

Real-world evidence to support regulatory submissions: Alandscape review and assessment of use cases.

Real-world evidence (RWE) has an increasing role in preapproval settings to support the approval of new medicines and indications. The main objectives of this study were to identify and characterize regulatory use cases that utilized RWE and other related observational approaches through targeted review of publications and regulatory review documents. After screening and inclusion/exclusion, the review characterized 85 regulatory applications with RWE. A total of 31 were in oncology and 54 were in non-oncology therapeutic areas. Most were for indications in adults only (N = 42, 49.4%), while 13 were in pediatrics only (15.3%), and 30 were in both (35.3%). In terms of regulatory context, 59 cases (69.4%) were for an original marketing application, 24 (28.2%) were for label expansion, and 2 (2.4%) were for label modification. Most also received special regulatory designations (e.g., orphan indication, breakthrough therapy, fast track, conditional, and accelerated approvals). There were 42 cases that utilized RWE to support single-arm trials. External data to support single-arm trials were utilized in various ways across use cases, including direct matching, benchmarking, natural history studies as well as literature or previous trials. A variety of data sources were utilized, including electronic health records, claims, registries, site-based charts. Endpoints in oncology use cases commonly included overall survival, progression-free survival. In 13 use cases, RWE was not considered supportive/definitive in regulatory decision-making due to design issues (e.g., small sample size, selection bias, missing data). Overall, RWE is utilized in regulatory approval processes for new indications/label expansion across various therapeutic areas with wide range of approaches. Multifaceted cross-sector efforts are needed to further improve the quality and utility of RWE in regulatory decision-making.

MDMA Therapy for PTSD: Inching Closer to-or Farther From-Approval?

In recent years, scientists have initiated a renaissance in psychedelic research following decades of prohibition. Compounds such as ketamine, LSD, and psilocybin 'once primarily associated with recreational use' are now being investigated for their therapeutic potential, with promising results. An estimated 40-60% of people with post-traumatic stress disorder (PTSD) do not respond to selective serotonin reuptake inhibitors, which are the first-line medications for this condition. However, one standout among these psychedelics is methylenedioxy methamphetamine (MDMA), which has demonstrated exceptional efficacy in treating PTSD and medication-resistant depression. Growing results in research were so positive that, in 2017, the US Food and Drug Administration (FDA) designated MDMA-assisted psychotherapy as a breakthrough therapy. Though MDMA is not yet officially legal or approved for clinical use, Phase 3 trials are underway, and expanded access status was granted in 2020 in the United States and Israel. Preliminary clinical studies are extremely promising, and the FDA could approve MDMA-assisted psychotherapy for PTSD as early as 2024, offering a potential treatment for this crippling mental health condition that affects almost 3.5% of US adults.

Design and methodology of the first open-label trial of MDMA-assisted therapy for veterans with post-traumatic stress disorder and alcohol use disorder: Considerations for a randomized controlled trial

BackgroundPosttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co-occur and are associated with more severe symptomatology than either disorder alone, increased risk of suicide, and poorer response to existing treatments. A promising therapeutic intervention is the integration of 3,4-methylenedioxymethamphetamine (MDMA) and psychotherapy. The Food and Drug Administration (FDA) designated MDMA- assisted therapy (MDMA-AT) as a Breakthrough Therapy for PTSD based on results from six Phase 2 clinical trials. Case data from the first study evaluating MDMA-AT study for AUD found the treatment was well tolerated and alcohol use was significantly reduced post treatment. MethodsThis manuscript reports the premise, design, and methodology of the first open-label trial of MDMA-AT for military veterans (N = 12) with PTSD and AUD. Neuroimaging and biomarker data are included to evaluate brain changes, and neuroinflammation, pre-post treatment. ConclusionsThe clinical component (comorbidity) and the regulatory processes (Schedule I drug) for setting up this clinical trial are long and complex. The research community will benefit from this work to establish common clinical trial outcomes, standardized protocols, and risk assessments for FDA approval. Clinicaltrials.govNCT05943665.

FDA Breakthrough Therapy Designation Reduced Late-Stage Drug Development Time.

The Food and Drug Administration's (FDA's) breakthrough therapy designation (BTD) program was created to increase patient access to safe and effective therapies by supporting the efficient clinical development of qualifying, clinically meaningful therapies. Using a new data set of key development milestones for drugs approved between 2006 and 2020, including both BTD drugs and a set of comparator drugs identified by FDA experts, we estimated the BTD program's impact on time spent in late-stage clinical development, measured as the elapsed time between a drug's end-of-Phase-II meeting with regulators and its approval for marketing. Our analysis suggests that the BTD program lowers late-stage clinical development time by 30percent. Our findings provide insight into future regulatory and innovation policies aimed at driving efficiency in medical product development to ensure timely patient access to the most clinically meaningful therapies.

IS PSYCHEDELIC TREATMENT OF MENTAL HEALTH DISORDERS READY FOR PRIME TIME?

Psychedelics, substances known to alter perception, mood, and consciousness, have been used across various cultures for centuries, often in religious ceremonies to facilitate spiritual experiences. Lysergic acid diethylamide (LSD) was used clinically from the 1950s until its ban in 1967. Recently, there has been a resurgence of interest in psychedelics for treating mental health disorders such as PTSD, anxiety, depression, and substance use disorders. The FDA has designated several psychedelic compounds as "breakthrough therapies," acknowledging their potential for safety and effectiveness. Psychedelics like Psilocybin, LSD, DMT/Ayahuasca, MDMA, Peyote, and Ketamine work through various mechanisms, including agonism at 5HT2A receptors and NMDA antagonism. These substances promote neuroplasticity and can disrupt pathological activity patterns in the brain's default mode network (DMN), facilitating new perspectives and emotional processing. Psychedelic-assisted therapy leverages these properties to help patients gain insight into repressed conflicts and reduce maladaptive defenses. The therapeutic process involves preparation, support during dosing, and integration phases. Safety concerns include hallucinogen persisting perception disorder (HPPD), serotonin toxicity, and potential boundary violations. Despite promising early results, comprehensive research is needed to fully understand the therapeutic potential and limitations of psychedelics. Psychedelic-assisted therapy could offer hope and transformation for millions suffering from mental illnesses if proven safe and effective.

PRGN-2012, a novel gorilla adenovirus-based immunotherapy, provides the first treatment that leads to complete and durable responses in recurrent respiratory papillomatosis patients.

LBA6015 Background: Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Significant morbidity can occur due to airway obstruction and, although rare, transformation into malignant cancer. There are no approved therapeutics. RRP is currently managed with frequent ablative procedures that can lead to irreversible laryngotracheal scarring and disability. PRGN-2012 is a gorilla adenovirus-based gene therapy/immunotherapy designed to generate HPV6/11-specific T cell immunity. The FDA has granted PRGN-2012 Breakthrough Therapy Designation for the treatment of RRP recognizing that this single arm study can serve as pivotal to support a licensing application. Methods: This pivotal trial (NCT04724980) evaluates the safety and efficacy of PRGN-2012 in patients with RRP requiring a minimum of 3 surgeries in the 12 months prior to treatment. Eligible patients received 4 subcutaneous (SC) injections of PRGN-2012 at dose level (DL) 1 (1x1011 Particle Units (PU) per injection; n=3) or DL2 (5x1011 PU per injection; n=35) over 12 weeks. The primary endpoint was the rate of complete response (CR), defined as no requirement for surgery in the 12 months following completion of treatment. Other key endpoints include duration of response, change in extent of papilloma growth (anatomic Derkay score) and vocal function. Results: PRGN-2012 was well-tolerated, with no serious adverse events, grade &gt; 2 treatment-related adverse events, or early treatment discontinuations. The most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. PRGN-2012 treatment at DL2 significantly (p&lt;0.0001) decreased the requirement for surgery, with a median number of surgeries in the 12 month period decreasing from 4 (3-10) prior to treatment to 0 (0-7) surgeries post-treatment. Approximately 90% of patients experienced a decrease in the number of surgeries in the 12 months post-treatment compared to pre-treatment with PRGN-2012. The primary endpoint evaluation demonstrated a confirmed complete response in 17/31 (55%) of evaluable patients. The median duration of complete response has yet to be reached with a median follow up of 15 months (12 - 30) at the time of data cutoff (March 6, 2024). Additionally, PRGN-2012 treatment resulted in a significant reduction in Derkay score, improvement in vocal function and generation of HPV-specific immune responses. Conclusions: These data demonstrate the overall favorable safety profile and significant clinical benefit of PRGN-2012 in adult RRP patients. These findings support PRGN-2012 as a potential therapeutic option for this patient population where no FDA-approved therapeutics exist. Clinical trial information: NCT04724980 .