Spending on Phased Clinical Development of Approved Drugs by the US National Institutes of Health Compared With Industry.

Importance: The launch of the Advanced Research Projects Agency for Health to advance new cures and address public concern regarding drug prices has raised questions about the roles of government and industry in drug development. Objectives: To compare National Institutes of Health (NIH) spending on phased clinical development of approved drugs with that by industry. Design: This cross-sectional study examined NIH funding for published research reporting the results of phased clinical trials of drugs approved between 2010 and 2019 and compared the findings with reported industry spending estimates. Data analysis was performed between May 2021 and August 2022 using PubMed data from January 1999 through October 2021 and NIH Research Portfolio Online Reporting Tools Expenditures and Results data from January 1999 through December 2020. Exposures: Drugs approved between 2010 and 2019. Main Outcome and Measures: National Institutes of Health funding for published research describing applied research on approved drugs, basic research on their biological targets, and phased clinical trials related to drugs approved between 2010 and 2019 were evaluated using Mann-Whitney U tests. All costs were inflation adjusted to 2018. Results: National Institutes of Health funding for basic or applied research related to 386 of 387 drugs approved between 2010 and 2019 totaled $247.3 billion. Of this amount, $8.1 billion (3.3%) was related to phased clinical development. This funding contributed to 12 340 publications on phased clinical trial results involving 240 of 387 (62.0%) drugs. Average NIH spending was $33.8 million per drug, including $13.9 million per drug for phase 1, $22.2 million per drug for phase 2, and $12.9 million per drug for phase 3 trials. Spending by NIH on phased development represented 9.8% to 10.7% of estimated industry spending, including 24.6% to 25.3% of estimated phase 1, 21.4% to 23.2% of phase 2, and 3.7% to 4.3% of phase 3 costs. Considering 60 products for which estimated industry costs were publicly available, NIH spending on clinical trials was significantly lower than estimated industry spending (sum of averages, $54.9 million per drug; mean difference, $326.0 million; 95% CI, $235.6-$416.4 million; 2-tailed paired t test P < .001). More than 90% of NIH funding came through cooperative agreements or program projects and centers, while 3.3% of NIH funding came through investigator-initiated research projects. Conclusions and Relevance: In this cross-sectional study, NIH funding for phased clinical development of drugs approved between 2010 and 2019 represented a small fraction of NIH spending on pharmaceutical innovation. This spending focused primarily on early-phase clinical trials and research capacity and was significantly less than estimated industry spending on clinical development. These results may inform the efficient allocation of government funding to advance pharmaceutical innovation.

Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury.

The increasing comorbidity of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) associated with traumatic brain injury (TBI) is a serious medical, economic, and social issue. However, the molecular toxicology and pathophysiological mechanisms of comorbid AUD and PTSD are not well understood and the identification of the comorbidity state markers is significantly challenging. This review summarizes the main characteristics of comorbidity between AUD and PTSD (AUD/PTSD) and highlights the significance of a comprehensive understanding of the molecular toxicology and pathophysiological mechanisms of AUD/PTSD, particularly following TBI, with a focus on the role of metabolomics, inflammation, neuroendocrine, signal transduction pathways, and genetic regulation. Instead of a separate disease state, a comprehensive examination of comorbid AUD and PTSD is emphasized by considering additive and synergistic interactions between the two diseases. Finally, we propose several hypotheses of molecular mechanisms for AUD/PTSD and discuss potential future research directions that may provide new insights and translational application opportunities.

Comparison of Research Spending on New Drug Approvals by the National Institutes of Health vs the Pharmaceutical Industry, 2010-2019.

Importance: Government and the pharmaceutical industry make substantive contributions to pharmaceutical innovation. This study compared the investments by the National Institutes of Health (NIH) and industry and estimated the cost basis for assessing the balance of social and private returns. Objectives: To compare NIH and industry investments in recent drug approvals. Design, Setting, and Participants: This cross-sectional study of NIH funding associated with drugs approved by the FDA from 2010 to 2019 was conducted from May 2020 to July 2022 and accounted for basic and applied research, failed clinical candidates, and discount rates for government spending compared with analogous estimates of industry investment. Main Outcomes and Measures: Costs from the NIH for research associated with drug approvals. Results: Funding from the NIH was contributed to 354 of 356 drugs (99.4%) approved from 2010 to 2019 totaling $187 billion, with a mean (SD) $1344.6 ($1433.1) million per target for basic research on drug targets and $51.8 ($96.8) million per drug for applied research on products. Including costs for failed clinical candidates, mean (SD) NIH costs were $1441.5 ($1372.0) million per approval or $1730.3 ($1657.6) million per approval, estimated with a 3% discount rate. The mean (SD) NIH spending was $2956.0 ($3106.3) million per approval with a 10.5% cost of capital, which estimates the cost savings to industry from NIH spending. Spending and approval by NIH for 81 first-to-target drugs was greater than reported industry spending on 63 drugs approved from 2010 to 2019 (difference, -$1998.4 million; 95% CI, -$3302.1 million to -$694.6 million; P = .003). Spending from the NIH was not less than industry spending considering clinical failures, a 3% discount rate for NIH spending, and a 10.5% cost of capital for the industry (difference, -$1435.3 million; 95% CI, -$3114.6 million to $244.0 million; P = .09) or when industry spending included prehuman research (difference, -$1394.8 million; 95% CI, -$3774.8 million to $985.2 million; P = .25). Accounting for spillovers of NIH-funded basic research on drug targets to multiple products, NIH costs were $711.3 million with a 3% discount rate, which was less than the range of reported industry costs with 10.5% cost of capital. Conclusions and Relevance: The results of this cross-sectional study found that NIH investment in drugs approved from 2010 to 2019 was not less than investment by the pharmaceutical industry, with comparable accounting for basic and applied research, failed clinical trials, and cost of capital or discount rates. The relative scale of NIH and industry investment may provide a cost basis for calibrating the balance of social and private returns from investments in pharmaceutical innovation.

Melatonin in neuroskeletal biology.

Osteoporosis and neurodegenerative diseases are common diseases in the aging population. Studies demonstrate the complex communication among skeletal, muscular, and nervous systems and point to the emerging roles of neuromuscular systems in bone homeostasis. The discovery that the nervous system directly regulates bone remodeling implies that osteoporosis is a neuroskeletal disease. Melatonin, a hormone secreted from the pineal gland, is a melatonin receptor 1A (MT1) and 1B (MT2) agonist and influences the function of diverse systems. Melatonin is a pharmaceutical ingredient in numerous medicines, over-the-counter medicines, nutraceuticals, and dietary supplements, which benefit disease prevention and treatment, including osteoporosis and neurodegenerative diseases. This review aims to summarize the recent advances in preventing senile, postmenopausal, and neurodegenerative osteoporosis with melatonin and provide new insights into how neuromuscular systems influence bone homeostasis. More preclinical and clinical studies in neuroskeletal biology will eventually improve the lives of people fighting osteoporosis.

N-acetyl-L-tryptophan delays disease onset and extends survival in an amyotrophic lateral sclerosis transgenic mouse model.

BACKGROUND: Whether L-NAT, a cytochrome c release inhibitor and an antagonist of NK-1R, provides protection in ALS is not known. RESULTS: L-NAT delays disease onset and mortality in mSOD1(G93A) ALS mice by inhibiting mitochondrial cell death pathways, inflammation, and NK-1R downregulation. CONCLUSION: L-NAT offers protection in a mouse model of ALS. SIGNIFICANCE: Data suggest the potential of L-NAT as a novel therapeutic strategy for ALS and provide insight into its action mechanisms. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, while inflammation has been implicated in its pathogenesis. Both inhibitors of cytochrome c release and antagonists of the neurokinin 1 receptor (NK-1R) have been reported to provide neuroprotection in ALS and/or other neurodegenerative diseases by us and other researchers. However, whether N-acetyl-L-tryptophan (L-NAT), an inhibitor of cytochrome c release and an antagonist of NK-1R, provides neuroprotection in ALS remains unknown. Here we demonstrate that the administration of L-NAT delayed disease onset, extended survival, and ameliorated deteriorations in motor performance in mSOD1(G93A) ALS transgenic mice. Our data showed that L-NAT reached the spinal cord, skeletal muscle, and brain. In addition, we demonstrate that L-NAT reduced the release of cytochrome c/smac/AIF, increased Bcl-xL levels, and inhibited the activation of caspase-3. L-NAT also ameliorated motor neuron loss and gross atrophy, and suppressed inflammation, as shown by decreased GFAP and Iba1 levels. Furthermore, we found gradually reduced NK-1R levels in the spinal cords of mSOD1(G93A) mice, while L-NAT treatment restored NK-1R levels. We propose the use of L-NAT as a potential therapeutic invention against ALS.

Neuroprotective agents target molecular mechanisms of disease in ALS.

Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weight loss and respiratory failure. Evidence suggests that inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and proteasomal dysfunction are all responsible for ALS pathogenesis. We review neuroprotective agents with the ability to reduce ALS-related bodyweight loss, summarize the various therapies tested on animal models targeting the proposed molecular mechanisms, compare their effects on bodyweight loss, muscle damage, disease onset, duration and survival, and analyze their structure-activity relationships, with the overall goal of creating a screening strategy for further clinical application.

Neuroprotection for amyotrophic lateral sclerosis: role of stem cells, growth factors, and gene therapy.

Various molecular mechanisms including apoptosis, inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), though the exact mechanisms have yet to be specified. Furthermore, the underlying restorative molecular mechanisms resulting in neuronal and/or non-neuronal regeneration have to be yet elucidated. Therapeutic agents targeting one or more of these mechanisms to combat either initiation or progression of the disease are under research. Novel treatments including stem cell therapy, growth factors, and gene therapy might prolong survival and delay progression of symptoms. Harnessing the regenerative potential of the central nervous system would be a novel approach for the treatment of motor neuron death resulting from ALS. Endogenous neural replacement, if augmented with administration of exogenous growth factors or with pharmaceuticals that increase the rate of neural progenitor formation, neural migration, and neural maturation could slow the rate of cell loss enough to result in clinical improvement. In this review, we discuss the impact of therapeutic treatment involving stem cell therapy, growth factors, gene therapy, and combination therapy on disease onset and progression of ALS. In addition, we summarize human clinical trials of stem cell therapy, growth factor therapy, and gene therapy in individuals with ALS.