Comparison of canine colostrum and milk using a multi-omics approach.

BACKGROUND: A mother's milk is considered the gold standard of nutrition in neonates and is a source of cytokines, immunoglobulins, growth factors, and other important components, yet little is known about the components of canine milk, specifically colostrum, and the knowledge related to its microbial and metabolic profiles is particularly underwhelming. In this study, we characterized canine colostrum and milk microbiota and metabolome for several breeds of dogs and examined profile shifts as milk matures in the first 8 days post-whelping. RESULTS: Through untargeted metabolomics, we identified 63 named metabolites that were significantly differentially abundant between days 1 and 8 of lactation. Surprisingly, the microbial compositions of the colostrum and milk, characterized using 16S rRNA gene sequencing, were largely similar, with only two differentiating genera. The shifts observed, mainly increases in several sugars and amino sugars over time and shifts in amino acid metabolites, align with shifts observed in human milk samples and track with puppy development. CONCLUSION: Like human milk, canine milk composition is dynamic, and shifts are well correlated with developing puppies' needs. Such a study of the metabolic profile of canine milk, and its relation to the microbial community, provides insights into the changing needs of the neonate, as well as the ideal nutrition profile for optimal functionality. This information will add to the existing knowledge base of canine milk composition with the prospect of creating a quality, tailored milk substitute or supplement for puppies.

Efficacy of Lifitegrast Ophthalmic Solution, 5.0%, in Patients With Moderate to Severe Dry Eye Disease: A Post Hoc Analysis of 2 Randomized Clinical Trials.

IMPORTANCE: An investigation of the treatment effect of lifitegrast ophthalmic solution, 5.0%, in different subgroups by severity of dry eye disease (DED) seems warranted. OBJECTIVE: To explore the heterogeneity across different subgroups of DED and identify which participants were most likely to achieve clinically meaningful benefit with lifitegrast treatment. DESIGN, SETTING, AND PARTICIPANTS: This post hoc responder analysis was performed using the data from the phase 3 OPUS-2 and OPUS-3 studies, which were 12-week, prospective, double-masked, multicenter, placebo-controlled, randomized, parallel-arm clinical trials that previously demonstrated the efficacy of lifitegrast in DED. Pooled data were stratified into 4 subgroups based on severity of inferior corneal staining score (ICSS; ≤1.5 vs >1.5) and eye dryness score (EDS; <60 or ≥60) at baseline. Data were collected from December 7, 2012, to October 5, 2015, and post hoc analysis was performed from April 14, 2020, to July 30, 2021. INTERVENTIONS: Lifitegrast or placebo twice daily for 84 days. MAIN OUTCOMES AND MEASURES: Proportion of participants with (1) a clinically meaningful improvement in signs (ICSS or total corneal staining score [TCSS]) and symptoms (EDS or global visual analog scale [VAS]) and (2) a composite response for a given sign and symptom end point pair at day 84 were measured. Clinically meaningful improvement was defined as at least 30% improvement in symptoms (EDS or global VAS) and either at least a 1-point improvement in ICSS or at least a 3-point improvement in TCSS. For the composite responder analysis, the end point pairs were defined as at least a 30% reduction in EDS and at least a 1-point improvement in ICSS; at least a 30% reduction in EDS and at least a 3-point improvement in TCSS; at least a 30% improvement in global VAS and at least a 1-point improvement in ICSS; and at least a 30% improvement in global VAS and at least a 3-point improvement in TCSS. RESULTS: In total, 1429 participants (716 in the placebo group and 713 in the lifitegrast group) were analyzed (1087 women [76.1%]; mean [SD] age, 58.7 [14.3] years). For the overall pooled population, responder and composite responder rates favored lifitegrast vs placebo (odds ratio range, 1.29 [95% CI, 1.05-1.59] to 2.10 [95% CI, 1.68-2.61]; P ≤ .02). In the composite analysis, the subgroup with ICSS of greater than 1.5 and EDS of at least 60 at baseline (ie, moderate to severe DED) demonstrated a 1.70- to 2.11-fold higher odds of achieving clinically meaningful improvement with lifitegrast across all sign and symptom end point pairs (P ≤ .001). CONCLUSIONS AND RELEVANCE: These post hoc findings suggest that lifitegrast ophthalmic solution, 5.0%, treatment may be associated with a response in participants with moderate to severe signs and symptoms of DED. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02284516.

Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma.

PURPOSE: TAK-639 is a topical, nine-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the treatment of ocular hypertension (OHT) and primary open-angle glaucoma (POAG). TAK-639 is postulated to lower intraocular pressure (IOP) through a novel mechanism of action (MOA) that increases trabecular meshwork outflow. We investigated the safety and tolerability of TAK-639 in subjects with OHT or POAG. METHODS: This was a phase 1, multicenter, randomized, double-masked, placebo-controlled, single- and multiple-dose escalation study. Subjects (aged 18-90 years) with OHT or POAG were randomized 5:2 to TAK-639 or placebo. Three dose levels were planned (0.1%, 0.3%, 0.6% TAK-639), each with four dosing regimens (QD, BID, TID, QID). Safety measures included treatment-emergent adverse events (TEAEs) and ophthalmologic examinations. Pharmacokinetics and pharmacodynamics (reduction of IOP) were also evaluated. RESULTS: In total, 63 subjects were randomized and received 0.1%, 0.3% and 0.6% TAK-639, as single dose, QD, or BID, and 0.1% and 0.3% TID. The study was terminated before 0.6% TID or QID dosing cohorts were studied; instead, 0.6% BID was repeated in a new cohort. TEAEs were instillation related and of mild-to-moderate intensity. There were no TEAEs leading to premature discontinuation, and no serious TEAEs. The most common treatment-related TEAEs were instillation site pain and transient corneal staining with fluorescein. There were no clinically significant concerns across dose groups for all other safety measures, including drop comfort, best corrected visual acuity, slit-lamp biomicroscopy, and corneal epithelial integrity. Little or no systemic exposure was observed. There was a marginal reduction in IOP in one cohort at the highest dose (0.6%) and regimen (BID) tested, suggesting biological plausibility of targeting the trabecular meshwork through this mechanism. CONCLUSION: TAK-639 was generally well tolerated up to 0.6% BID. Further non-clinical studies will improve understanding of the MOA and the penetration of TAK-639 to the anterior chamber.

Progress Report on Neglected Tropical Disease Drug Donation Programs.

PURPOSE: Neglected tropical diseases (NTDs) impose a significant burden on public health, particularly in developing nations. Many can be treated cost-effectively with drugs donated or offered at or below marginal cost. In 2012, the World Health Organization published an NTD roadmap that outlined a strategy for the prevention, control, and eradication of 17 NTDs by 2020. Inspired by this roadmap, executives from 13 pharmaceutical companies, government agencies, and other interested parties signed the London Declaration on Neglected Tropical Diseases in January 2012. In this paper, we will assess progress in meeting commitments on drug donations laid out in the London Declaration. METHODS: We conducted Medline and LexisNexis searches of peer-reviewed publications and trade journals, as well as product development partnership and government reports. Subsequently, we designed a survey instrument and surveyed 10 company signatories (companies with drug donation programs) to the London Declaration to determine current donations and pledges. FINDINGS: Nine of 10 companies with donation programs responded to the survey. The respondents reported substantial progress in meeting the goals laid out in the London Declaration. Survey respondents maintained 17 drug donation programs across 10 disease categories. In 2014, companies donated >1 billion treatments, with a dollar value of nearly $1.5 billion. However, not all donated products were distributed to patients in need. In addition, 4 of the 17 programs were slated to end before 2020, three of the 17 programs did not report explicit program objectives, and 7 of 17 did not measure the impact of programs in terms of numbers of patients treated. None of our survey respondents reported on whether the programs were leading to a reduction in disease prevalence. IMPLICATIONS: Donations are a necessary but insufficient condition for patient access to neglected disease drugs. Additional resources must be allocated to ensure delivery of donated products to patients. In addition, drug donation programs should provide explicit descriptions of program objectives, measurements of the impacts of their programs, and extension of all donation commitments through 2020. To achieve this, multiple stakeholders with a vested interest in reducing the burden of neglected diseases must collaborate in a multipronged approach toward NTD elimination.

Measuring progress in neglected disease drug development.

BACKGROUND: Since the late 1990s, funding for development of neglected disease drugs has increased with an influx of resources from product development partnerships (PDPs). Previous research showed modest gains in drug approvals and products in Phase III of clinical development in the period 2000-2008. OBJECTIVE: We assessed the 2009-2013 period in terms of numbers of products in Phase III development and numbers of approvals. Subsequently, we calculated the PDP share in terms of sponsorship of new approvals. We also identified the numbers of 2000-2013 approvals included in the World Health Organization's Essential Drug List (EDL). METHODS: We identified new approvals and Phase III products targeting neglected diseases in the period 2009-2013 by searching ClinicalTrials.gov, IMS R&D Focus, and Investigational Drugs Database, as well as drug regulatory agency websites. Subsequently, we determined which products approved between 2000 and 2013 have been included in the most recent version of the EDL. RESULTS: We found 20 new approvals targeting neglected diseases in the period 2009-2013. PDPs were the primary sponsor of 57% of new approvals in this time frame. Approvals included 1 new molecular entity, 5 vaccines, 2 new indications, 9 fixed-dose combinations, and 3 new formulations. HIV/AIDS (pediatric indications) and malaria accounted for 60% of approvals in 2009-2013. The average number of new approvals per year for neglected diseases rose from 2.6 in 2000-2008 to 4.9 in 2009-2013. The World Health Organization included 44% of 2000-2013 approved products on the EDL. We found 18 products currently in Phase III of clinical development. Products in Phase III testing included 3 new molecular entities, 6 vaccines, 2 fixed-dose combinations, 5 new indications, and 2 new formulations. CONCLUSIONS: Increased funding through PDPs for neglected disease drug development seems to be producing results. Approvals and products in Phase III testing have shown a steady increase since 2000, with nearly a doubling of products in 2009-2013, compared with 2000-2008, in terms of the annual average yield. However, only 3 new molecular entities have been approved in 14 years. In addition, malaria and HIV (pediatric indications) seem to have benefited most from increased funding, whereas less success has occurred with other diseases. Inclusion of newly approved products on the EDL has been slow and limited, with only 44% of new approvals added to the list. Uneven progress suggests funding could be better targeted. In addition, PDPs could do more to facilitate access, in particular by working closely with the World Health Organization to assess the clinical effectiveness and cost-effectiveness of new approvals.