FDA Orphan Research Articles

Elraglusib induces cytotoxicity via direct microtubule destabilization independently of GSK3 inhibition.

Elraglusib (9-ING-41) is an ATP-competitive inhibitor of glycogen synthase kinase-3 (GSK3) with pre-clinical studies demonstrating broad activity against many tumour types. Promising early-phase clinical trial data led to FDA orphan drug status, and a randomized phase 2 study in combination with cytotoxic chemotherapy in pancreatic cancer has recently completed its recruitment. Similarly, single-agent responses in adult T-cell leukaemia/lymphoma and melanoma, and combination treatment data in several other tumour types have been encouraging. The elraglusib mechanism of action is unknown, but it is unlikely to act through GSK3 inhibition because cytotoxicity is observed below the IC50 for GSK3 and other small molecule GSK3 inhibitors do not produce cytotoxic effects, at least in lymphoma cells. We show here that elraglusib perturbs chromosomal alignment to cause a mitotic arrest in multiple tumour lines. This arrest is caused by direct microtubule depolymerization, which prevents the attachment of kinetochores to microtubules. At clinically relevant doses, these mitotically arrested cells eventually undergo mitotic slippage, leading to gross chromosome missegregation, DNA damage and apoptosis. These effects explain the cytotoxicity of elraglusib because temporarily pausing cell cycle progression with the CDK4/6 inhibitor palbociclib abolishes any drug-induced genotoxicity and apoptosis. In summary, elraglusib acts as a direct microtubule destabilizer both in vitro and across multiple cancer types, resulting in mitotic arrest, DNA damage and apoptosis. These effects likely account for its broad pan-cancer activity, which does not rely upon GSK3 inhibition as they are not replicated by other GSK3 inhibitors.

Clinical trial evidence supporting FDA approval of novel orphan drugs between 2017 and 2023

Characterization analysis of 87 pivotal clinical trials for 72 novel orphan drugs (76 orphan indications) approved by the FDA from 2017 to 2023 revealed that the clinical trial evidence supporting FDA orphan drug approvals often lacked high-quality designs, which frequently did not incorporate randomization, blinding, placebo or no treatment control, or clinical endpoint-driven methodologies. Additionally, regulatory flexibility was observed in the quantity of clinical trial evidence required, which included choices such as a single trial plus confirmatory evidence, one large multicenter trial or at least two trials. Furthermore, the overall strength of the clinical trial evidence exhibited variations across different orphan drugs and indications, influenced by features such as the therapeutic area and whether the orphan drug was granted accelerated approvals.

Teaching an old drug new tricks: Regulatory insights for the repurposing of hemin in cardiovascular disease.

Drug repurposing has gained significant interest in recent years due to the high costs associated with de novo drug development; however, comprehensive pharmacological information is needed for the translation of pre-existing drugs across clinical applications. In the present study, we explore the current pharmacological understanding of the orphan drug, hemin, and identify remaining knowledge gaps with regard to hemin repurposing for the treatment of cardiovascular disease. Originally approved by the United States Food and Drug Administration in 1983 for the treatment of porphyria, hemin has attracted significant interest for therapeutic repurposing across a variety of pathophysiological conditions. Yet, the clinical translation of hemin remains limited to porphyria. Understanding hemin's pharmacological profile in health and disease strengthens our ability to treat patients effectively, identify therapeutic opportunities or limitations, and predict and prevent adverse side effects. However, requirements for the pre-clinical and clinical characterization of biologics approved under the U.S. FDA's Orphan Drug Act in 1983 (such as hemin) differed significantly from current standards, presenting fundamental gaps in our collective understanding of hemin pharmacology as well as knowledge barriers to clinical translation for future applications. Using information extracted from the primary and regulatory literature (including documents submitted to Health Canada in support of hemin's approval for the Canadian market in 2018), we present a comprehensive case study of current knowledge related to hemin's biopharmaceutical properties, pre-clinical/clinical pharmacokinetics, pharmacodynamics, dosing, and safety, focusing specifically on the drug's effects on heme regulation and in the context of acute myocardial infarction.

LP-184, a Novel Acylfulvene Molecule, Exhibits Anticancer Activity against Diverse Solid Tumors with Homologous Recombination Deficiency.

New agents with activity against DDR-deficient solid tumors refractory to standard-of-care therapies are needed. We report multiple findings supporting the potential for LP-184, a novel alkylating agent with three FDA orphan drug designations, to fill this void clinically: strong nanomolar potency; sustained, durable regression of solid tumor xenografts; synthetic lethality with HR defects. LP-184 adult phase IA trial to assess safety in advanced solid tumors is ongoing.

Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma

Abstract IA014: From targeted phenotypic screen to NXP800: A clinical stage activator of the integrated stress response for the treatment of ARID1A-mutated ovarian carcinoma

Evaluating the impact of the FDA’s orphan drug designation on share prices of biotechnology companies

This analysis explores the impact of the FDA's orphan drug designation (ODD) on biotechnology companies' share prices in the short and long term. Our analysis reveals that there is a significant immediate increase in share prices following an ODD announcement, which underscores its potential as a robust indicator of short-term investor returns. However, the long-term findings present a more complex picture, with a sustained impact within the biotech industry but a significant depreciation against the broader market over time. These findings elucidate the nuanced effects of regulatory milestones on the financial performance of pharmaceutical companies and highlight the need for more comprehensive studies to further unravel these complex dynamics.

Long-term evaluation of clinical success and safety of omadacycline in nontuberculous mycobacteria infections: a retrospective, multicenter cohort of real-world health outcomes.

Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49-67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo (4 - 14), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

SYST-12 LP-184, A NOVEL ACYLFULVENE-DERIVED TUMOR SITE ACTIVATED SMALL MOLECULE INHIBITS ADULT AND PEDIATRIC CNS TUMOR CELL GROWTH

Abstract Blood-brain barrier (BBB) permeable agents effective against recurrent, chemotherapy-resistant central nervous system (CNS) tumors are urgently needed, particularly in Glioblastoma multiforme (GBM) and atypical teratoid/rhabdoid tumors (ATRT). These represent extremely aggressive and lethal types of CNS malignancies. LP-184 is a next-generation acylfulvene class drug candidate and has received FDA orphan drug designations for the treatment of malignant gliomas and ATRT. LP-184 creates covalent DNA adducts that are selectively repaired via nucleotide excision repair (NER). Repair of LP-184-induced DNA damage is mediated by ERCC complexes. Consistent with this, we observed 3-6X decreased cancer cell viability in U87, M1123 and Mayo39 GBM cells treated with LP-184 in combination with the ERCC3 degrader Spironolactone (SP) relative to LP-184 alone. Mice bearing pre-established subcutaneous U87 xenografts were treated with SP alone, LP-184 alone or their combination. Tumors recurred after initial regression in 5/5 animals treated with LP-184 alone whereas tumors showed durable complete regression without recurrence in 4/5 animals treated with LP-184 + SP. Thus, LP-184 likely functions as a synthetically lethal agent in the presence of DNA repair deficiencies. LP-184 inhibited cell growth in CHLA06 and BT37 ATRT cell lines, with IC50s in the 20-25nM range. LP-184 induced apoptosis 96 hours after treatment in these ATRT cell lines as measured by immunofluorescence for cleaved caspase-3 and Western blot for c-PARP. LP-184 intravenous treatment at 4 mg/kg twice weekly for 2 weeks showed tumor regression in mice implanted with CHLA06 ATRT subcutaneous xenografts, with 112% tumor growth inhibition and 2/10 treated mice being tumor-free at study termination. LP-184 further showed favorable intracranial tumor bioavailability along with in vivo BBB permeability comparable to other CNS cancer drugs. These findings identify LP-184 as a promising new agent and support its further development for treating CNS tumors in adult and pediatric populations.

Age-related survey of clinical genetics literature and related resources.

Genetic conditions affect people throughout their entire lifespan; however, many clinical geneticists focus on the care of pediatric individuals. We analyzed the medical literature and related resources to help assess to what extent adults with genetic diseases were represented. This included general literature searches of PubMed (from 2001 through 2022), specific databases (the FDA orphan drug list and the Clinical Genomic Database) related to management and direct treatment of genetic conditions, and textbooks and morphology guides relevant to the diagnosis of genetic conditions. In the field of genetics/genomics in general, we overall detected a statistically significant emphasis on pediatric populations in the medical literature compared to select other disciplines and compared with the global population distribution. Clinical genetics articles about adults tended to focus on younger adult ages. In clinical genetics, management and treatments, as well as illustrations in several educational/diagnostic resources tended to focus on pediatric populations.

Orphan drug development in alpha-1 antitypsin deficiency

Alpha-1 antitrypsin deficiency (AATD, OMIM #613490) is a rare metabolic disorder affecting lungs and liver. The purpose of this study is to assess the impact of the US orphan drug act on AATD by providing a quantitative clinical-regulatory insight into the status of FDA orphan drug approvals and designations for compounds intended to treat AATD. This is across-sectional analysis of the FDA database for orphan drug designations. Primary endpoint: orphan drug approvals. Secondary endpoint: orphan drug designations by the FDA. Close of database was 16 July 2021. STROBE criteria were respected. Primary outcome: one compound, alpha-1-proteinase inhibitor (human) was approved as an orphan drug in 1987 with market exclusivity until 1994. Secondary outcome: sixteen compounds received FDA orphan drug designation including protein, anti-inflammatory, mucolytic, gene, or cell therapy. Drug development activities in AATD were comparable to other rare conditions and led to the FDA-approval of one compound, based on a relatively simple technological platform. The current unmet medical need to be addressed are extrapulmonary manifestations, in this case the AATD-associated liver disease. Orphan drug development is actually focusing on (1) diversified recombinant AAT production platforms, and (2) innovative gene therapies, which may encompass a more holistic therapeutic approach.

Bucillamine in the treatment of patients with mild to moderate COVID-19: an interview with Michael Frank.

Bucillamine in the treatment of patients with mild to moderate COVID-19: an interview with Michael Frank.

Drugs and biologics receiving FDA orphan drug designation: an analysis of the most frequently designated products and their repositioning strategies

ABSTRACT Background The Orphan Drug Act was created to stimulate the development of drugs and biologics for rare diseases. Investigating products that have received orphan drug designation provide a greater understanding of rare disease drug development, as well as the repositioning business models of developers. Research design and methods We used a dataset containing all orphan drug designations between 1983 and 2019. To analyze the orphan products, we constructed a variable, ‘unique product,’ that allowed for the standardization of generic names of drugs and biologics. Additional analysis was performed on the most frequently designated unique products and their repositioning strategies. Results We found 5,099 orphan drug designations representing 3,269 unique products, of which 508 had an orphan-designated approval from FDA. Unique products with only a single designation represented 2,448 (75%) of the total products and 26 (1%) products had 10 or more designations. Over 60% of these unique products with 10 or more designations were antineoplastics or immunomodulators. Conclusions The most designated unique products revealed a continuum of repositioning strategies, from the repurposing of approved drugs to parallel indication development programs for recently developed drugs. The fact that over 3,000 unique products have been studied for rare diseases indicates that future repositioning opportunities may become increasingly available.

Complete Remission with Devimistat (CPI-613) in Refractory Burkitt Lymphoma

Complete Remission with Devimistat (CPI-613) in Refractory Burkitt Lymphoma

Phase 2 Results of Urinary-Derived Human Chorionic Gonadotropin/Epidermal Growth Factor As Treatment for Life-Threatening Acute Gvhd

Background: Severe organ damage from acute graft-versus-host disease (aGVHD) results in a high risk of morbidity and mortality. Treatments that focus on immunosuppression alone do not consistently improve long-term survival. Modalities that aid in inflammation resolution, immune tolerance, and tissue repair may improve outcomes beyond high-dose corticosteroids and other broad immunosuppressants for life-threatening aGVHD. We studied the addition of urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF, Pregnyl®, Organon, USA) to standard aGVHD therapy in a prospective Phase 2 clinical trial (NCT02525029) conducted at the University of Minnesota and Rush University, extending from our previously published Phase 1 study results (Holtan et al, Blood Advances, 2020) showing uhCG/EGF to be safe and preliminarily efficacious as aGVHD therapy.Methods: Patients with new onset Minnesota (MN) high risk aGVHD (N=22) or with aGVHD requiring 2nd line therapy (N=22) received methylprednisolone 48 mg/m2/day plus 2,000 units/m2 of uhCG/EGF subcutaneously (SQ) every other day for 1 week (high risk arm). Patients in need of 2nd line aGVHD therapy received 2,000 - 5,000 units/m2 SQ every other day, with dose depending on organ severity, for 2 weeks plus standard of care immunosuppression (anti-thymocyte globulin (N=4), etanercept (N=1), ruxolitinib (N=5), sirolimus (N=4), steroid boost (N=8)). Patients who achieved a complete or partial response (CR/PR) after their initial course of therapy received twice weekly maintenance doses for the next 5 weeks. Exploratory metabolomic profiling was performed using mass spectrometry.Results: The median age was 61 years (range 2 years - 72 years, 75% male). The majority of patients had stage 3-4 lower GI GVHD (52%) and overall grade III-IV aGVHD (75%) at time of enrollment, with a median baseline albumin of 2.6 g/dl (range 0.9 - 4 g/dl) and median baseline Karnofsky performance status of 50 (range 20-100). The proportion of patients with a response (CR/PR) at day 28 (primary endpoint) was 68% (57% CR, 11% PR, Figure 1A). Among MN high risk patients receiving 1st line steroids, 64% achieved a CR at day 28 (0% PR). Among patients receiving 2nd line therapy, 50% achieved a CR and 23% PR at day 28. The median overall survival for the entire cohort was 1.2 years (Figure 1B), with a 2-year survival of 67% for responders and 12% for non-responders (p<0.01). Twenty-three died; causes of death included aGVHD (n=9), relapse (n=9), infection (n=3), and organ failure (n=2). Only one dose-limiting toxicity occurred (1 cerebral venous sinus thrombosis, resolved with anticoagulation). Exploratory metabolomic analysis of plasma samples collected during the study suggest potential correlations between blood metabolites and response to therapy. Higher levels of linoleic acid were associated with greater CR/PR rates, while higher levels of lactic acid were associated with treatment failure (Figure 1C).Conclusion: Our Phase 2 study demonstrates that uhCG/EGF is a promising addition to systemic therapy in patients with life-threatening aGVHD. The overall survival result is encouraging considering historical median survival of <0.5 years for patients with both MN high risk and steroid refractory aGVHD. As a commercially available, safe, and inexpensive drug, addition of uhCG/EGF to standard therapy may reduce morbidity and mortality from severe aGVHD. Further studies to explore its role as a steroid-sparing treatment are warranted. [Display omitted] DisclosuresHoltan: Incyte: Consultancy, Research Funding; Generon: Consultancy. Ustun: novartis: Honoraria; Blueprint: Honoraria. Arora: Pharmacyclics: Research Funding; Syndax: Research Funding; Kadmom: Research Funding. Bachanova: Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: CSL Behring: Research Funding; Mitobridge, an Astellas Company: Consultancy, Research Funding. Brunstein: GamidaCell: Research Funding; NANT: Research Funding; FATE: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. OffLabel Disclosure:uhCG/EGF has FDA orphan drug designation to treat acute GVHD.

Small molecule interactions with the SARS-CoV-2 main protease: In silico all-atom microsecond MD simulations, PELE Monte Carlo simulations, and determination of in vitro activity inhibition

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing COVID-19 pandemic. With some notable exceptions, safe and effective vaccines, which are now being widely distributed globally, have largely begun to stabilise the situation. However, emerging variants of concern and vaccine hesitancy are apparent obstacles to eradication. Therefore, the need for the development of potent antivirals is still of importance. In this context, the SARS-CoV-2 main protease (Mpro) is a critical target and numerous clinical trials, predominantly in the private domain, are currently in progress. Here, our aim was to extend our previous studies, with hypericin and cyanidin-3-O-glucoside, as potential inhibitors of the SARS-CoV-2 Mpro. Firstly, we performed all-atom microsecond molecular dynamics simulations, which highlight the stability of the ligands in the Mpro active site over the duration of the trajectories. We also invoked PELE Monte Carlo simulations which indicate that both hypericin and cyanidin-3-O-glucoside preferentially interact with the Mpro active site and known allosteric sites. For further validation, we performed an in vitro enzymatic activity assay that demonstrated that hypericin and cyanidin-3-O-glucoside inhibit Mpro activity in a dose-dependent manner at biologically relevant (μM) concentrations. However, both ligands are much less potent than the well-known covalent antiviral GC376, which was used as a positive control in our experiments. Nevertheless, the biologically relevant activity of hypericin and cyanidin-3-O-glucoside is encouraging. In particular, a synthetic version of hypericin has FDA orphan drug designation, which could simplify potential clinical evaluation in the context of COVID-19.

The drug development pipeline for glioblastoma-A cross sectional assessment of the FDA Orphan Drug Product designation database.

Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest. To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM. Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected. Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline. Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.

Abstract 3038: Evaluation of ROR1-targeted antibody-drug conjugates against ROR1-expressing pediatric preclinical models - a report from the pediatric preclinical testing consortium (PPTC)

Abstract Introduction: ROR1 is an orphan-receptor tyrosine kinase-like surface antigen that is expressed primarily during development but is not expressed on normal adult tissues. ROR1 is expressed on multiple adult hematologic and solid cancers, making it a target for antibody-based therapies. UC-961 (cirmtuzumab), a humanized IgG1 monoclonal antibody, binds with high affinity to a specific extracellular epitope of human ROR1 and rapidly internalizes and traffics to lysosomes. VLS-101 is an ADC developed by conjugating UC-961 to a cleavable linker with an MMAE payload. VLS-211 was generated by conjugating UC-961 with a PNU payload. VLS-101 is in clinical development for adults with hematologic and solid cancers and has received FDA Fast Track and Orphan Drug designation for the treatment of patients with mantle cell lymphoma. To better define the utility of ROR1 as an immuno-oncology target for pediatric cancers, we evaluated VLS-101 and VLS-211 against pediatric preclinical models selected based on ROR1 expression. Methods: Models were selected based on RNA-seq transcript levels for ROR1 with subsequent confirmation by flow cytometry for acute lymphoblastic leukemia (ALL) models. For the ALL models, UC-961 (5 mg/kg), VLS-101 (2.5 and 5.0 mg/kg), and VLS-211 (0.25 and 0.5 mg/kg) were each administered weekly x 3. For the Ewing sarcoma (EWS) models, the dose of VLS-211 was 0.5 and 1 mg/kg. Four models were treated using a twice-weekly or every 4-day treatment schedule while 2 models were treated weekly. Results: Elevated ROR1 gene expression among PPTC models was most notable among the ALL and EWS panels. Leukemia cell surface expression of ROR1 correlated with transcript levels. ALL models with elevated ROR1 expression [TCF3-HLF (1), TCF3-PBX1 (2), ETV6-RUNX1 (2), and BCR-ABL1 (1)] as well as a non-expressing model were tested against the ROR1 ADCs. Activity of each ADC was ROR1 expression-level dependent, and for VLS-211 dose-dependency was noted. At the highest doses of each ADC studied, 2 of 6 (VLS-101) and 3 of 6 (VLS-211) ROR1-expressing models showed objective responses. For most models, median time to event was longer for VLS-211 versus VLS-101. Five EWS models were studied, and expression-level dependent activity was observed for both ADCs. VLS-101 induced tumor regressions in 2 of 5 models, while VLS211 induced regressions in 3 of 5 models. Time to event was generally longer for VLS-211 compared to VLS-101. No objective responses were observed to UC-961 for the ALL and EWS models. Conclusions: VLS-101 and VLS-211 showed expression-level dependent activity against ALL and EWS models. These results support ROR1 as a relevant immuno-oncology target for the subset of B-ALL and Ewing sarcoma cases with elevated ROR1 expression. Further research is required to identify the optimal payload for ROR1 ADCs for use against pediatric cancers. Citation Format: Richard B. Lock, Kathryn Evans, Narimanne El-Zein, Brian J. Lannutti, Katti A. Jessen, Eric J. Earley, Stephen W. Erickson, Malcolm A. Smith, Raushan Kurmasheva, Peter J. Houghton. Evaluation of ROR1-targeted antibody-drug conjugates against ROR1-expressing pediatric preclinical models - a report from the pediatric preclinical testing consortium (PPTC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3038.

Suppression of Inflammatory Cardiac Cytokine Network in Rats with Untreated Obesity and Pre-Diabetes by AT2 Receptor Agonist NP-6A4.

Obesity affects over 42% of the United States population and exacerbates heart disease, the leading cause of death in men and women. Obesity also increases pro-inflammatory cytokines that cause chronic tissue damage to vital organs. The standard-of-care does not sufficiently attenuate these inflammatory sequelae. Angiotensin II receptor AT2R is an anti-inflammatory and cardiovascular protective molecule; however, AT2R agonists are not used in the clinic to treat heart disease. NP-6A4 is a new AT2R peptide agonist with an FDA orphan drug designation for pediatric cardiomyopathy. NP-6A4 increases AT2R expression (mRNA and protein) and nitric oxide generation in human cardiovascular cells. AT2R-antagonist PD123319 and AT2RSiRNA suppress NP-6A4-effects indicating that NP-6A4 acts through AT2R. To determine whether NP-6A4 would mitigate cardiac damage from chronic inflammation induced by untreated obesity, we investigated the effects of 2-weeks NP-6A4 treatment (1.8 mg/kg delivered subcutaneously) on cardiac pathology of male Zucker obese (ZO) rats that display obesity, pre-diabetes and cardiac dysfunction. NP-6A4 attenuated cardiac diastolic and systolic dysfunction, cardiac fibrosis and cardiomyocyte hypertrophy, but increased myocardial capillary density. NP-6A4 treatment suppressed tubulointerstitial injury marker urinary β-NAG, and liver injury marker alkaline phosphatase in serum. These protective effects of NP-6A4 occurred in the presence of obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and without modulating blood pressure. NP-6A4 increased expression of AT2R (consistent with human cells) and cardioprotective erythropoietin (EPO) and Notch1 in ZO rat heart, but suppressed nineteen inflammatory cytokines. Cardiac miRNA profiling and in silico analysis showed that NP-6A4 activated a unique miRNA network that may regulate expression of AT2R, EPO, Notch1 and inflammatory cytokines, and mitigate cardiac pathology. Seventeen pro-inflammatory and pro-fibrotic cytokines that increase during lethal cytokine storms caused by infections such as COVID-19 were among the cytokines suppressed by NP-6A4 treatment in ZO rat heart. Thus, NP-6A4 activates a novel anti-inflammatory network comprised of 21 proteins in the heart that was not reported previously. Since NP-6A4’s unique mode of action suppresses pro-inflammatory cytokine network and attenuates myocardial damage, it can be an ideal adjuvant drug with other anti-glycemic, anti-hypertensive, standard-of-care drugs to protect the heart tissues from pro-inflammatory and pro-fibrotic cytokine attack induced by obesity.

Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases

BackgroundOrphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a “broad disease” categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades.ResultsBetween 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%.ConclusionsAnalysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades.

A phase 1 open label trial of intravenous administration of MVA-BN-Brachyury vaccine in patients with advanced cancer.

2617 Background: Brachyury is a member of the T-box family of transcription factors which is overexpressed in several tumor types and has been associated with treatment resistance, epithelial to mesenchymal transition and metastatic potential. MVA-BN-Brachyury vaccine is a vector-based therapeutic cancer vaccine which demonstrated immunogenicity and safety in previous clinical trials. Preclinical studies suggested that IV administration of vaccines can induce superior CD8 + T-cell responses as compared with SC or IM routes. This is the first-in-human study to evaluate safety and tolerability of IV administration of this vaccine. Methods: Patients with metastatic or unresectable locally advanced malignant solid tumors were treated with MVA-BN-Brachyury vaccine in a phase 1, open-label, 3+3 dose-escalation study. Eligible patients received a total of three vaccine doses intravenously Q3W at 1x107 (DL1), 1x108 (DL2), or 1x109 infections units (Inf.U) (DL3). Patients were admitted for 48 hours for observation after each dose and had imaging at baseline and 1 and 3 months after the last vaccine dose. Primary objective was to determine the safety and tolerability and establish the recommended phase 2 dose (RP2D). Immune assays were performed in the first 10 enrolled patients. Results: In 13 patients (10 chordoma, 1 small cell breast, 1 prostate, 1 colorectal cancer), no dose-limiting toxicities were observed. Right upper quadrant abdominal pain was the only grade 3 TRAE. All other TRAEs were grade 1 or 2; most common was cytokine release syndrome (four grade 2 and one grade 1. As of Feb 2021, 9 patients completed treatment and two planned restaging scans: 5 patients had PD (3 in DL1 and 2 in DL2), 3 had SD (2 in DL2 and 1 in DL3) and 1 had PR (DL3) as their best treatment response per RECIST 1.1. One patient with advanced sacral chordoma had significant reduction of ulcerated skin metastases after 2 doses, followed by 33% shrinkage at the end of trial. Two chordoma patients with SD reported significant pain improvement. Multifunctional Brachyury, CEA, and MUC1 specific T cells were increased after vaccination in in 60%, 67%, and 50% of patients, respectively. Conclusions: MVA-BN-Brachyury IV vaccine is safe across all tested dose levels and suggesting activity in chordoma at DL3 for which this vaccine was granted FDA orphan drug designation. Mild cytokine release syndrome (rigors, chills, fever and hypotension) has been observed in 5 patients and managed with IV fluids and steroids in 2 patients. A dose 1 x 109 Inf.U (DL3) was selected for RP2D based upon available safety data. Further research is pending to evaluate clinical benefit and immunogenicity. Clinical trial information: NCT04134312.