Why Does the Inflation Reduction Act Exclude Expensive Cancer Treatments in Price Negotiations?

PURPOSE: The Inflation Reduction Act (IRA) includes provisions for price negotiations of certain high-spending drugs in Medicare Parts B and D. This provision received considerable attention from those interested in the costs of cancer care since Medicare covers most patients with cancer and many cancer drugs are expensive. We simulate how many cancer drugs may be eligible for IRA price negotiations and examine the reasons that many are likely to be excluded from negotiation. METHODS: This study uses 2021 Medicare Fee-for-Service Part B and Part D prescription drugs expenditure data. Cancer drugs were identified using the SEER Program list of cancer medications. Our measures included total spending, beneficiary users, and spending-per-beneficiary for all cancer drugs covered under Medicare. Each drug was evaluated for eligibility on the basis of IRA negotiation provisions, including estimated loss of patent exclusivity, current competitors, and orphan drug designation. RESULTS: We found that very few cancer drugs will meet the IRA eligibility thresholds to be included in negotiations. We estimate that only 2.2% of beneficiaries with cancer will see lower costs because of the IRA negotiations. The main reason for this is that although novel cancer drug treatments are priced high, they generally treat relatively few beneficiaries and thus do not meet negotiation eligibility criteria, which are primarily based on a ranking of total spending. CONCLUSION: The IRA negotiation provisions will have limited impact on cancer drug prices and will likely leave most patients with cancer exposed to high drug costs.

Technology enabled home-based cardiac rehabilitation among women with cardiovascular disease: A longitudinal cohort study.

Technology-enabled home-based cardiac rehabilitation (HBCR) is an emerging alternative to traditional center-based cardiac rehabilitation (CBCR), but little is known about outcomes in women. We analyzed 753 diverse and medically complex women who participated in HBCR and CBCR within an integrated health system and found both groups had similar clinical outcomes. Results suggest HBCR is a viable alternative to CBCR among women, including women with multiple comorbidities.

Emergency department visits respond nonlinearly to wildfire smoke.

Air pollution negatively affects a range of health outcomes. Wildfire smoke is an increasingly important contributor to air pollution, yet wildfire smoke events are highly salient and could induce behavioral responses that alter health impacts. We combine geolocated data covering all emergency department (ED) visits to nonfederal hospitals in California from 2006 to 2017 with spatially resolved estimates of daily wildfire smoke PM[Formula: see text] concentrations and quantify how smoke events affect ED visits. Total ED visits respond nonlinearly to smoke concentrations. Relative to a day with no smoke, total visits increase by 1 to 1.5% in the week following low or moderate smoke days but decline by 6 to 9% following extreme smoke days. Reductions persist for at least a month. Declines at extreme levels are driven by diagnoses not thought to be acutely impacted by pollution, including accidental injuries and several nonurgent symptoms, and declines come disproportionately from less-insured populations. In contrast, health outcomes with the strongest physiological link to short-term air pollution increase dramatically in the week following an extreme smoke day: We estimate that ED visits for asthma, COPD, and cough all increase by 30 to 110%. Data from internet searches, vehicle traffic sensors, and park visits indicate behavioral changes on high smoke days consistent with declines in healthcare utilization. Because low and moderate smoke days vastly outweigh high smoke days, we estimate that smoke was responsible for an average of 3,010 (95% CI: 1,760-4,380) additional ED visits per year 2006 to 2017. Given the increasing intensity of wildfire smoke events, behavioral mediation is likely to play a growing role in determining total smoke impacts.

Biosimilar Competition and Payments in Medicare: The Case of Trastuzumab.

PURPOSE: Numerous biologic drugs will soon be facing biosimilar competition. We study the case of trastuzumab, a revolutionary drug approved in 1998 to treat human epidermal growth factor receptor 2-positive breast cancer, to understand how trends in the price and treatment cost of the originator brand and biosimilar forms of trastuzumab evolved following biosimilar entry. METHODS: We use average sales price data from the Centers for Medicare and Medicaid Services, adjusted for inflation to real 2020 dollars using the consumer price index, to describe price changes for the originator biologic and biosimilar versions of trastuzumab between 2019, when the first biosimilar was covered by Medicare, and 2022, when a total of five biosimilar competitors were on the market. We also estimate total treatment costs of biologic and biosimilar forms of trastuzumab from 2005 to 2022 and describe changes in their market share. RESULTS: We find that the first biosimilar entrant's price was 15% lower than the originator brand in 2019, and the fifth biosimilar entrant's price in 2022 was 58% lower than the originator brand in 2019. Contrary to expectations from prior research, the originator biologic price in 2022 decreased 29% from its 2019 average sales price. Average treatment cost for the biologic and biosimilar versions of trastuzumab combined was $45,659 US dollars lower in 2022 compared with the year before biosimilar entry, 2018. Finally, biosimilar market share grew from only 7% in the first year of entry to 32% in the second year, when three biosimilars were on the market. CONCLUSION: Biosimilar entry may be an effective means of decreasing the cost of biologic cancer treatments. Our findings suggest that policies that support biosimilar entry and encourage use may expand access to necessary treatment and reduce health care costs.

A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors.

Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S. Food and Drug Administration approval following promising clinical responses in cancer patients. However, the current array of EZH2 inhibitors have poor brain penetrance, limiting their use in patients with central nervous system malignancies, a number of which have been shown to be sensitive to EZH2 inhibition. To address this need, we have identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize P-glycoprotein activity, and here we report the first brain-penetrant EZH2 inhibitor, TDI-6118 (compound 5). Additionally, in the course of our attempts to optimize this compound, we discovered TDI-11904 (compound 21), a novel, highly potent, and peripherally active EZH2 inhibitor based on a 7 member ring structure.

Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules.

Pancreatic adenocarcinoma (PDAC) epitomizes a deadly cancer driven by abnormal KRAS signaling. Here, we show that the eIF4A RNA helicase is required for translation of key KRAS signaling molecules and that pharmacological inhibition of eIF4A has single-agent activity against murine and human PDAC models at safe dose levels. EIF4A was uniquely required for the translation of mRNAs with long and highly structured 5' untranslated regions, including those with multiple G-quadruplex elements. Computational analyses identified these features in mRNAs encoding KRAS and key downstream molecules. Transcriptome-scale ribosome footprinting accurately identified eIF4A-dependent mRNAs in PDAC, including critical KRAS signaling molecules such as PI3K, RALA, RAC2, MET, MYC, and YAP1. These findings contrast with a recent study that relied on an older method, polysome fractionation, and implicated redox-related genes as eIF4A clients. Together, our findings highlight the power of ribosome footprinting in conjunction with deep RNA sequencing in accurately decoding translational control mechanisms and define the therapeutic mechanism of eIF4A inhibitors in PDAC. SIGNIFICANCE: These findings document the coordinate, eIF4A-dependent translation of RAS-related oncogenic signaling molecules and demonstrate therapeutic efficacy of eIF4A blockade in pancreatic adenocarcinoma.

SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs.

This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.

Novel Pure αVß3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations.

The integrin αVß3 receptor has been implicated in several important diseases, but no antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761. Both compounds inhibit αVß3-mediated cell adhesion to αVß3 ligands, but do not induce the conformational change as judged by antibody binding, electron microscopy, X-ray crystallography, and receptor priming studies. Both compounds demonstrated the favorable property of inhibiting bone resorption in vitro, supporting potential value in treating osteoporosis. Neither, however, had the unfavorable property of the αVß3 antagonist cilengitide of paradoxically enhancing aortic sprout angiogenesis at concentrations below its IC50, which correlates with cilengitide's enhancement of tumor growth in vivo.

Toward ß-Secretase-1 Inhibitors with Improved Isoform Selectivity.

BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aß production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited ∼50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class.

Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M4 PAM VU0467154.

Although selective activation of the M1 muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M4 mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M4 mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms. Since the cholinergic system has been implicated in multiple stages of learning and memory, we evaluated the effects of repeated dosing with the highly selective M4 PAM VU0467154 on either acquisition and/or consolidation of learning and memory when dosed alone or after pharmacologic challenge with the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) antagonist MK-801. MK-801 challenge represents a well-documented preclinical model of NMDAR hypofunction that is thought to underlie some of the positive and cognitive symptoms observed in schizophrenia. In wildtype mice, 10-day, once-daily dosing of VU0467154 either prior to, or immediately after daily testing enhanced the rate of learning in a touchscreen visual pairwise discrimination task; these effects were absent in M4 mAChR knockout mice. Following a similar 10-day, once-daily dosing regimen of VU0467154, we also observed 1) improved acquisition of memory in a cue-mediated conditioned freezing paradigm, 2) attenuation of MK-801-induced disruptions in the acquisition of memory in a context-mediated conditioned freezing paradigm and 3) reversal of MK-801-induced hyperlocomotion. Comparable efficacy and plasma and brain concentrations of VU0467154 were observed after repeated dosing as those previously reported with an acute, single dose administration of this M4 PAM. Together, these studies are the first to demonstrate that cognitive enhancing and antipsychotic-like activity are not subject to the development of tolerance following repeated dosing with a selective M4 PAM in mice and further suggest that activation of M4 mAChRs may modulate both acquisition and consolidation of memory functions.

Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides.

Herein we describe the continued optimization of M4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.

Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.

This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.

Optimization of M4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology.

This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.

Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.

Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs.

This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).

Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes.

The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer's Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media. Compound 82879 is unique as structural analogues, including pyrethroid esters, show no effect on apoE expression or secretion. 82879 also stimulates liver x receptor (LXR) target genes including ATP binding cassette A1 (ABCA1), LXRα and inducible degrader of low density lipoprotein receptor (IDOL) at both mRNA and protein levels. In particular, the lipid transporter ABCA1 was increased by up to 10.6-fold upon 82879 treatment. The findings from CCF-STTG1 cells were confirmed in primary human astrocytes from three donors, where increased apoE and ABCA1 was observed along with elevated secretion of high-density lipoprotein (HDL)-like apoE particles. Nuclear receptor transactivation assays revealed modest direct LXR agonism by compound 82879, yet 10 µM of 82879 significantly upregulated apoE mRNA in mouse embryonic fibroblasts (MEFs) depleted of both LXRα and LXRß, demonstrating that 82879 can also induce apoE expression independent of LXR transactivation. By contrast, deletion of LXRs in MEFs completely blocked mRNA changes in ABCA1 even at 10 µM of 82879, indicating the ability of 82879 to stimulate ABCA1 expression is entirely dependent on LXR transactivation. Taken together, compound 82879 is a novel chrysanthemic ester capable of modulating apoE secretion as well as apoE-associated lipid metabolic pathways in astrocytes, which is structurally and mechanistically distinct from known LXR agonists.

Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.

This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.

Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.

This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.