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.

Comparative benefits and harms of individual opioids for chronic non-cancer pain: a systematic review and network meta-analysis of randomised trials.

BACKGROUND: Most systematic reviews of opioids for chronic pain have pooled treatment effects across individual opioids under the assumption they provide similar benefits and harms. We examined the comparative effects of individual opioids for chronic non-cancer pain through a network meta-analysis of randomised controlled trials. METHODS: We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials to March 2021 for studies that enrolled patients with chronic non-cancer pain, randomised them to receive different opioids, or opioids vs placebo, and followed them for at least 4 weeks. Certainty of evidence was evaluated using the GRADE approach. RESULTS: We identified 82 eligible trials (22 619 participants) that evaluated 14 opioids. Compared with placebo, several opioids showed superiority to others for analgesia and improvement in physical function; however, when restricted to pooled-effect estimates supported by moderate certainty evidence, no differences between opioids were evident. Among opioids with moderate certainty evidence, all increased the risk of gastrointestinal adverse events compared with placebo, although no opioids were more harmful than others. Low to very low certainty evidence suggests that extended-release vs immediate-release opioids may provide similar benefits for pain relief and physical functioning, and gastrointestinal harms. CONCLUSIONS: Our findings support the pooling of effect estimates across different types and formulations of opioids to inform effectiveness for chronic non-cancer pain.

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.

Addition of corticosteroids to local anaesthetics for chronic non-cancer pain injections: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Despite common use, the benefit of adding steroids to local anaesthetics (SLA) for chronic non-cancer pain (CNCP) injections is uncertain. We performed a systematic review and meta-analysis of English-language RCTs to assess the benefit and safety of adding steroids to local anaesthetics (LA) for CNCP. METHODS: We searched MEDLINE, EMBASE, and CENTRAL databases from inception to May 2019. Trial selection and data extraction were performed in duplicate. Outcomes were guided by the Initiative in Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT) statement with pain improvement as the primary outcome and pooled using random effects model and reported as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CIs). RESULTS: Among 5097 abstracts, 73 trials were eligible. Although SLA increased the rate of success (42 trials, 3592 patients; RR=1.14; 95% CI, 1.03-1.25; number needed to treat [NNT], 13), the effect size decreased by nearly 50% (NNT, 22) with the removal of two intrathecal injection studies. The differences in pain scores with SLA were not clinically meaningful (54 trials, 4416 patients, MD=0.44 units; 95% CI, 0.24-0.65). No differences were observed in other outcomes or adverse events. No subgroup effects were detected based on clinical categories. Meta-regression showed no significant association with steroid dose or length of follow-up and pain relief. CONCLUSIONS: Addition of cortico steroids to local anaesthetic has only small benefits and a potential for harm. Injection of local anaesthetic alone could be therapeutic, beyond being diagnostic. A shared decision based on patient preferences should be considered. If used, one must avoid high doses and series of steroid injections. CLINICAL TRIAL REGISTRATION: PROSPERO #: CRD42015020614.

Development of a virtual reality platform for effective communication of structural data in drug discovery.

In drug discovery, structural knowledge of a target enables structure-based design approaches and thereby reduces the time and labor required to develop a therapy. Whilst molecular graphics frameworks coupled with computational analysis are now ubiquitous tools for the structural and computational biologist, sharing the detailed visualization and derived structural information with non-expert users still presents a challenge. Here we describe an intuitive virtual world for viewing, manipulating, and modifying chemical and macromolecular structures in a fully immersive and collaborative 3D environment. By reducing the barriers to viewing and interacting with structural data, structural analysis can be democratized to a general scientist, which in turn fosters novel collaboration, ideas, and findings in structural biology and structure-based drug discovery.

Wide-angular-range and high-resolution beam steering by a metasurface-coupled phased array.

Optical beam steering has broad applications in lidar, optical communications, optical interconnects, and spatially resolved optical sensors. For high-speed applications, phased-array-based beam-steering methods are favored over mechanical methods, as they are unconstrained by inertia and can inherently operate at a higher speed. However, phased-array systems exhibit a tradeoff between angular range and beam divergence, making it difficult to achieve both a large steering angle and a narrow beam divergence. Here, we present a beam-steering method based on wavefront shaping through a disorder-engineered metasurface that circumvents this range-resolution tradeoff. We experimentally demonstrate that, through this technique, one can continuously steer an optical beam within a range of 160° (80° from normal incidence) with an angular resolution of about 0.01° at the cost of beam throughput.

Imaging moving targets through scattering media.

Optical microscopy in complex, inhomogeneous media is challenging due to the presence of multiply scattered light that limits the depths at which diffraction-limited resolution can be achieved. One way to circumvent the degradation in resolution is to use speckle- correlation-based imaging (SCI) techniques, which permit imaging of objects inside scattering media at diffraction-limited resolution. However, SCI methods are currently limited to imaging sparsely tagged objects in a dark-field scenario. In this work, we demonstrate the ability to image hidden, moving objects in a bright-field scenario. By using a deterministic phase modulator to generate a spatially incoherent light source, the background contribution can be kept constant between acquisitions and subtracted out. In this way, the signal arising from the object can be isolated, and the object can be reconstructed with high fidelity. With the ability to effectively isolate the object signal, our work is not limited to imaging bright objects in the dark-field case, but also works in bright-field scenarios, with non-emitting objects.

Biochemical characterization of two haloalkane dehalogenases: DccA from Caulobacter crescentus and DsaA from Saccharomonospora azurea.

Two putative haloalkane dehalogenases (HLDs) of the HLD-I subfamily, DccA from Caulobacter crescentus and DsaA from Saccharomonospora azurea, have been identified based on sequence comparisons with functionally characterized HLD enzymes. The two genes were synthesized, functionally expressed in E. coli and shown to have activity toward a panel of haloalkane substrates. DsaA has a moderate activity level and a preference for long (greater than 3 carbons) brominated substrates, but little activity toward chlorinated alkanes. DccA shows high activity with both long brominated and chlorinated alkanes. The structure of DccA was determined by X-ray crystallography and was refined to 1.5 Å resolution. The enzyme has a large and open binding pocket with two well-defined access tunnels. A structural alignment of HLD-I subfamily members suggests a possible basis for substrate specificity is due to access tunnel size.

Glare suppression by coherence gated negation.

Imaging of a weak target hidden behind a scattering medium can be significantly confounded by glare. We report a method, termed coherence gated negation (CGN), that uses destructive optical interference to suppress glare and allow improved imaging of a weak target. As a demonstration, we show that by permuting through a set range of amplitude and phase values for a reference beam interfering with the optical field from the glare and target reflection, we can suppress glare by an order of magnitude, even when the optical wavefront is highly disordered. This strategy significantly departs from conventional coherence gating methods in that CGN actively "gates out" the unwanted optical contributions while conventional methods "gate in" the target optical signal. We further show that the CGN method can outperform conventional coherence gating image quality in certain scenarios by more effectively rejecting unwanted optical contributions.

Focusing through dynamic tissue with millisecond digital optical phase conjugation.

Digital optical phase conjugation (DOPC) is a new technique employed in wavefront shaping and phase conjugation for focusing light through or within scattering media such as biological tissues. DOPC is particularly attractive as it intrinsically achieves a high fluence reflectivity in comparison to nonlinear optical approaches. However, the slow refresh rate of liquid crystal spatial light modulators and limitations imposed by computer data transfer speeds have thus far made it difficult for DOPC to achieve a playback latency of shorter than ~200 ms and, therefore, prevented DOPC from being practically applied to thick living samples. In this paper, we report a novel DOPC system that is capable of 5.3 ms playback latency. This speed improvement of almost 2 orders of magnitude is achieved by using a digital micromirror device, field programmable gate array (FPGA) processing, and a single-shot binary phase retrieval technique. With this system, we are able to focus through 2.3 mm living mouse skin with blood flowing through it (decorrelation time ~30 ms) and demonstrate that the focus can be maintained indefinitely-an important technological milestone that has not been previously reported, to the best of our knowledge.

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.

Alteration of substrate specificity of alanine dehydrogenase.

The l-alanine dehydrogenase (AlaDH) has a natural history that suggests it would not be a promising candidate for expansion of substrate specificity by protein engineering: it is the only amino acid dehydrogenase in its fold family, it has no sequence or structural similarity to any known amino acid dehydrogenase, and it has a strong preference for l-alanine over all other substrates. By contrast, engineering of the amino acid dehydrogenase superfamily members has produced catalysts with expanded substrate specificity; yet, this enzyme family already contains members that accept a broad range of substrates. To test whether the natural history of an enzyme is a predictor of its innate evolvability, directed evolution was carried out on AlaDH. A single mutation identified through molecular modeling, F94S, introduced into the AlaDH from Mycobacterium tuberculosis (MtAlaDH) completely alters its substrate specificity pattern, enabling activity toward a range of larger amino acids. Saturation mutagenesis libraries in this mutant background additionally identified a double mutant (F94S/Y117L) showing improved activity toward hydrophobic amino acids. The catalytic efficiencies achieved in AlaDH are comparable with those that resulted from similar efforts in the amino acid dehydrogenase superfamily and demonstrate the evolvability of MtAlaDH specificity toward other amino acid substrates.

A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity.

Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders.

Focusing on moving targets through scattering samples.

Focusing light through scattering media has been a longstanding goal of biomedical optics. While wavefront shaping and optical time-reversal techniques can in principle be used to focus light across scattering media, achieving this within a scattering medium with a noninvasive and efficient reference beacon, or guide star, remains an important challenge. Here, we show optical time-reversal focusing using a new technique termed Time Reversal by Analysis of Changing wavefronts from Kinetic targets (TRACK). By taking the difference between time-varying scattering fields caused by a moving object and applying optical time reversal, light can be focused back to the location previously occupied by the object. We demonstrate this approach with discretely moved objects as well as with particles in an aqueous flow, and obtain a focal peak-to-background strength of 204 in our demonstration experiments. We further demonstrate that the generated focus can be used to noninvasively count particles in a flow-cytometry configuration-even when the particles are hidden behind a strong diffuser. By achieving optical time reversal and focusing noninvasively without any external guide stars, using just the intrinsic characteristics of the sample, this work paves the way to a range of scattering media imaging applications, including underwater and atmospheric focusing as well as noninvasive in vivo flow cytometry.

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.

A new crystal form of restriction endonuclease EcoRII that diffracts to 2.8 A resolution.

EcoRII, a type IIe restriction endonuclease, has been crystallized in space group P2(1), with unit-cell parameters a = 58.3, b = 127.8, c = 59.9 A, beta = 91.4 degrees. There are two monomers in the asymmetric unit and the solvent content is estimated to be 49% by volume. The crystals diffract to 2.8 A resolution, which is much higher than that of the previously reported cubic crystal form, which diffracted to 4 A resolution.