Analysis of pharma R&D productivity - a new perspective needed.

R&D productivity continues to be the industry's grand challenge. We analyzed the R&D input, output, and outcome of 16 leading research-based pharmaceutical companies over 20 years (2001-2020). Our analysis shows that pharma companies increased their R&D spending at a compound annual growth rate of 6% (2001-2020) to an average R&D expenditure per company of $6.7 billion (2020). The companies in our investigation launched 251 new drugs representing 46% of all CDER-related FDA approvals in the past 20 years. The average R&D efficiency of big pharma was $6.16 billion total R&D expenditures per new drug. Almost half of the leading companies needed to compensate for their negative R&D productivity through mergers and acquisitions.

Acceptability of multiple coated mini-tablets in comparison to syrup in infants and toddlers: a randomised controlled study.

OBJECTIVES: Drug treatment of children is often limited to liquid formulations or manipulation of adult solid oral dosage forms because of the lack of age-appropriate formulations, concerns around particle aspiration and paediatric acceptability. Recent research revealed that the administration of mini-tablets has substantial advantages in improving dose accuracy and avoiding issues related to drug stability, storage conditions, potentially toxic excipients and taste masking (especially effective when the mini-tablets are coated). Most trials were performed with single and multiple uncoated mini-tablets. This study here aimed to investigate young children's acceptability and swallowability of multiple coated placebo mini-tablets compared with glucose syrup. DESIGN: This clinical trial was conducted as a single-centre randomised cross-over study. SETTING: Prospective cross-over study performed at the Children's University Hospital Düsseldorf. PATIENTS: This study was conducted on 50 children in five age groups from 1 to <6 years. INTERVENTIONS: An age-adapted amount of 16-28 mini-tablets and 3-6 mL syrup was administered in randomised order. MAIN OUTCOME MEASURES: Acceptability and swallowability of multiple coated mini-tablets and syrup. RESULTS: In all age groups, administration of multiple coated mini-tablets and syrup showed good acceptability (mini-tablets 80%-100%, syrup 90%-100%) and swallowability (mini-tablets 30%-70%, syrup 20%-80%) without any clinically meaningful difference. This is consistent with results from large studies with uncoated mini-tablets. CONCLUSION: Multiple coated mini-tablets are a suitable age-appropriate alternative to liquid formulations in the paediatric population. No safety concerns with the use of coated mini-tablets were observed in the study. TRIAL REGISTRATION NUMBER: DRKS00010395.

Open innovation: A paradigm shift in pharma R&D?

Open innovation (OI) holds promise to accelerate, diversify, and innovate research and development (R&D) in the pharmaceutical industry. It remains to be assessed in which way and to what extent OI is leveraged in practice by current pharmaceutical R&D organizations. Therefore, here we comprehensively analyzed 21 research-based pharmaceutical companies and benchmarked their implementation of OI. Our data showed that OI is an integral part of R&D of all assessed pharmaceutical companies; models typically used are research collaborations, innovation incubators, academic centers of excellence, public-private partnerships (PPPs), mergers and acquisitions (M&A), licensing, or corporate venture capital (VC) funds. In addition, we conclude that the implementation of OI differs greatly across corporations and, consequently, that R&D organizations of research-based pharmaceutical companies can be classified based on their level of OI implementation into three distinct types: predominantly traditional R&D; network-based R&D; and R&D ecosystems.

Evaluation of cardiac parameters and other safety outcomes of brolucizumab treatment in patients with neovascular age-related macular degeneration.

This was a prospective, single-dose, single-arm, open-label, non-randomized, multicenter clinical study to determine cardiovascular safety after a single brolucizumab 6 mg intravitreal injection in neovascular age-related macular degeneration patients (N = 14). Electrocardiogram (ECG) data were collected at different time points using 12-lead Holter and standard ECG, and patients were followed up to 8 days (end of study) for any signs of ocular and non-ocular adverse events (AEs). No clinically meaningful changes were observed in cardiac parameters. No patient had a ≥30 msec change from baseline in heart rate-corrected QT using Fridericia's formula (QTcF), and no patient had a new QTcF value of ≥450 msec between 20 and 24 h after treatment. No deaths or serious AEs were reported during the study period. These results are in line with the absence of new cardiovascular safety signal based on the ECG recordings collected over the first year of the pivotal studies performed with brolucizumab in DME. Trial Registration: ClinicalTrials.gov identifier: NCT03954626.

LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia.

PURPOSE: To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. METHODS: A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. RESULTS: Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. CONCLUSIONS: In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT03466203.

A framework to guide dose & regimen strategy for clinical drug development.

Optimizing new drug therapies remains a challenge for clinical development, despite the use of ever more sophisticated quantitative methodologies. Although conceptually simple, the idea of finding the right treatment at the right dose for the right patient to ensure an appropriate balance of risks and benefits is challenging and requires a multidisciplinary approach. In this paper, we present a framework developed as a tool for organizing knowledge and facilitating collaboration in development teams.

Systematic risk identification and assessment using a new risk map in pharmaceutical R&D.

Delivering transformative therapies to patients while maintaining growth in the pharmaceutical industry requires an efficient use of research and development (R&D) resources and technologies to develop high-impact new molecular entities (NMEs). However, increasing global R&D competition in the pharmaceutical industry, growing impact of generics and biosimilars, more stringent regulatory requirements, as well as cost-constrained reimbursement frameworks challenge current business models of leading pharmaceutical companies. Big data-based analytics and artificial intelligence (AI) approaches have disrupted various industries and are having an increasing impact in the biopharmaceutical industry, with the promise to improve and accelerate biopharmaceutical R&D processes. Here, we systematically analyze, identify, assess, and categorize key risks across the drug discovery and development value chain using a new risk map approach, providing a comprehensive risk-reward analysis for pharmaceutical R&D.

Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double-blind, phase 2 trial.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

Translational precision medicine: an industry perspective.

In the era of precision medicine, digital technologies and artificial intelligence, drug discovery and development face unprecedented opportunities for product and business model innovation, fundamentally changing the traditional approach of how drugs are discovered, developed and marketed. Critical to this transformation is the adoption of new technologies in the drug development process, catalyzing the transition from serendipity-driven to data-driven medicine. This paradigm shift comes with a need for both translation and precision, leading to a modern Translational Precision Medicine approach to drug discovery and development. Key components of Translational Precision Medicine are multi-omics profiling, digital biomarkers, model-based data integration, artificial intelligence, biomarker-guided trial designs and patient-centric companion diagnostics. In this review, we summarize and critically discuss the potential and challenges of Translational Precision Medicine from a cross-industry perspective.

R&D efficiency of leading pharmaceutical companies - A 20-year analysis.

Comparative analysis of the R&D efficiency of 14 leading pharmaceutical companies for the years 1999-2018 shows that there is a close positive correlation between R&D spending and the two investigated R&D output parameters, approved NMEs and the cumulative impact factor of their publications. In other words, higher R&D investments (input) were associated with higher R&D output. Second, our analyses indicate that there are 'economies of scale' (size) in pharmaceutical R&D.

Big Techs and startups in pharmaceutical R&D - A 2020 perspective on artificial intelligence.

We investigated what kind of artificial intelligence (AI) technologies are utilized in pharmaceutical research and development (R&D) and which sources of AI-related competencies can be leveraged by pharmaceutical companies. First, we found that machine learning (ML) is the dominating AI technology currently used in pharmaceutical R&D. Second, both Big Techs and AI startups are competent knowledge bases for AI applications. Big Techs have long-lasting experience in the digital field and offer more general IT solutions to support pharmaceutical companies in cloud computing, health monitoring, diagnostics or clinical trial management, whereas startups can provide more specific AI services to address special issues in the drug-discovery space.

Glucosuric, renal and haemodynamic effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2, in patients with chronic kidney disease: A randomized trial.

AIM: To investigate the glucosuric, renal and haemodynamic effects of licogliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, in patients with chronic kidney disease (CKD). METHODS: This multiple-dose, parallel-group, phase II mechanistic study randomized 53 participants (aged 18-78 years, body mass index ≤ 50 kg/m2 ) with varying degrees of CKD or normal renal function to treatment with licogliflozin (50 mg once daily) or placebo for 7 days. The effects of licogliflozin on 24-h urinary glucose excretion (UGE24 ), renal function, haemodynamics, pharmacokinetics and safety were assessed. RESULTS: Licogliflozin treatment for 7 days significantly (p < .01) increased UGE24 from baseline in participants with normal renal function (adjusted mean change: 41.8 [33.6, 49.9] g) or with mild (32.6 [24.1, 41.0] g), moderate A (35.7 [28.6, 42.9] g) or moderate B (20.3 [13.1, 27.5] g) CKD, but not in severe (6.2 [-0.71, 13.18] g) CKD. Licogliflozin reduced urinary electrolytes (sodium, potassium and chloride), blood pressure and urinary volume to varying extents among different groups. Significant increases in renin (p < .05), angiotensin II (p < .05) and aldosterone (p < .01) levels were observed. Adverse events were generally mild, and most commonly included diarrhoea (94%), flatulence (68%) and abdominal pain (21%). CONCLUSION: Licogliflozin treatment results in significantly increased UGE and favourable changes in urinary electrolytes and haemodynamics in patients with varying degrees of CKD (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 ).

Vascular effects of serelaxin in patients with stable coronary artery disease: a randomized placebo-controlled trial.

AIMS: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. CONCLUSION: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

The upside of being a digital pharma player.

We investigated the state of artificial intelligence (AI) in pharmaceutical research and development (R&D) and outline here a risk and reward perspective regarding digital R&D. Given the novelty of the research area, a combined qualitative and quantitative research method was chosen, including the analysis of annual company reports, investor relations information, patent applications, and scientific publications of 21 pharmaceutical companies for the years 2014 to 2019. As a result, we can confirm that the industry is in an 'early mature' phase of using AI in R&D. Furthermore, we can demonstrate that, despite the efforts that need to be managed, recent developments in the industry indicate that it is worthwhile to invest to become a 'digital pharma player'.

Investigation and Management of Stool Frequency and Consistency Associated With SGLT1 Inhibition by Reducing Dietary Carbohydrate: A Randomized Trial.

Treatment with licogliflozin, a dual sodium-glucose co-transporter (SGLT)1/2-inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin-induced stools, a randomized, open-label, two-part (N = 24/part), three-period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3-day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well-tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin.