Ferring Pharmaceuticals (Denmark)

The stability of therapeutic proteins is crucial for maintaining their efficacy and safety. Misfolded or aggregated proteins can accelerate aggregation by a seeding effect, altering protein stability and interactions. Heat-induced aggregates can pose a risk because they can have perturbed structures that expose aggregate-prone regions. This study explored seeding by heat-induced protein aggregates on the stability and aggregation of two therapeutic proteins, human growth hormone (hGH) and a monoclonal Antibody (Antibody A), during storage of two weeks at three relevant temperatures of 4 °C, room temperature (RT, 21-23 °C), and 40 °C. Grwoth of aggregates were seen in the sub-micron-sized aggregates by Dynamic Light Scattering at 4 °C or RT. Furthermore, heated Antibody A showed signs of reversibility of higher-order structure after storage. Samples stored at 4 °C and RT showed similar stability and aggregation behaviour. While two weeks of storage at 40 °C accelerated the structural degradation of both proteins, it did not accelerate aggregation or particle formation for either hGH or Antibody A.

Outdoor pig production systems can increase exposure to helminth infections such as Ascaris suum. Anthelmintic drug treatments are currently the primary strategy for controlling such infections; however, this approach is considered unsustainable due to the risk of parasites developing anthelmintic resistance. This study investigated the potential anthelmintic effect of a 2% w/w fermented rapeseed–seaweed (FRS) dietary supplement administered over an 11–12 week period in growing-finisher pigs. Outcomes assessed included parasitic fecal egg counts (FEC), serology, gut microbiota composition, and systemic inflammation. The FRS supplement consisted of 6% Saccharina latissima, 6% Ascophyllum nodosum, and 88% rapeseed meal (based on dry matter) and was provided in two different batches. Supplementation with FRS tended to lower FEC and reduce the incidence of A. suum infection. However, this effect varied between batches. FRS also influenced gut microbiota composition: pigs that were fed the second batch of FRS showed an increased relative abundance of several Bacteroidetes members (e.g., Prevotella), while unsupplemented pigs were enriched with various taxa from the Firmicutes phylum, such as Clostridium spp. Furthermore, pigs fed the second batch of FTR showed reduced daily weight gain compared to those fed the control diet. Overall, our results indicate that FRS modulates the gut microbiota toward a composition potentially associated with improved gut health and may have promise as a prebiotic or novel feed additive to help reduce helminth infections.

This article compares and explores vacuum foam-drying as an alternative drying technology to freeze-drying and spray drying for a recombinant human lipase as the model protein. Materials characteristics such as structure, surface composition and the solid-state properties of the dry materials were compared and investigated. Moreover, the technical functionality in terms of reconstitution characteristics and the lipase stability were also investigated. The stability of the lipase was evaluated through activity measurements. Sucrose and dextran D40 (40 kDa) were used as matrix former and the surfactant α-dodecyl maltoside was used as surface active additive. The study demonstrated that the drying technique greatly influenced the material structure and composition which in turn affected the reconstitution characteristics. The lipase was overrepresented at the material surface in declining order spray-dried > vacuum foam-dried > freeze-dried. The lipase activity was retained up to 10 % lipase content in solids, but at 20 % lipase a loss of activity was observed for all drying techniques. Phase separation in the solid material may be an explanation. Vacuum foam-drying shows promise as an alternative drying technique for the lipase, and potentially other proteins.

Abstract Study question Can key elements of ovarian physiology be accurately modelled, thereby providing a tool to generate novel insights and guide development of new therapeutics? Summary answer A physiological computational model was developed to describe follicle growth and follicle size distributions observed in agonist and antagonist ovarian stimulation (OS) protocols. What is known already The outcome of OS remains unpredictable despite identification of several prognostic factors. The average first cycle pregnancy rate is 30-40% across fertility centres, highlighting the need for improved stimulation protocols. This is an active area of clinical research; however, clinical trials are costly, time-consuming, and frequently have outcomes that are unexpected or difficult to interpret. We integrated available physiological knowledge of human follicle growth and development and clinical trial data into a computational model to enable in silico simulations with the aim to optimise clinical trial design. Study design, size, duration Computational model building was performed using a mechanistic approach aimed at capturing well-understood physiology that is relevant in OS protocols. Model inputs included patient characteristics (such as anti-Müllerian hormone (AMH) level), OS regimen and pituitary downregulation with gonadotrophin releasing hormone (GnRH) agonist or antagonist. Key outputs of the model included follicle number and mean size, duration of stimulation and serum hormone concentrations (oestradiol, testosterone, inhibin B and androstenedione). Participants/materials, setting, methods Published physiological data on regulation of follicle development and hormone production informed model design. Following implementation of the model in the Python platform, data from two OS clinical trials were used to calibrate (partially censored) and test the model. The two trials provided data on the effects of the recombinant follicle stimulating hormone preparation follitropin delta over a range of fixed doses and compared the effects of follitropin delta in agonist and antagonist OS protocols. Main results and the role of chance The computational model describes the interplay between pituitary gonadotrophins ovarian steroid hormones and follicle growth and development. Processes spanning the cellular level (such as steroidogenesis and receptor dynamics in theca and granulosa cells), the ovaries (follicle number and size) and the organism (pharmacokinetics and hypothalamic-pituitary-ovarian axis) are included as a system of coupled differential equations. Approximately 70 compartments, 500+ parameters and 1700+ reactions constitute the model framework. Follicles are recruited in the model at variable times, starting from 7 days prior to the start of stimulation. Follicles are initialised with individual sensitivity to gonadotrophins and growth rates. The fate of each follicle (dominance or atresia) is governed by these properties, which determine whether the balance shifts towards proliferation or atresia under the influence of gonadotrophins. Model-simulated numbers of follicles, their average size and mean serum hormone concentrations match closely with observed values in the two clinical trials. For each of these variables, their dependence on time, the dose of follitropin delta, AMH level and downregulation protocol were described with good precision. The inter-patient variability in the simulated number of follicles and in serum hormone levels matched closely with the observed variability based on comparison of the interquartile range. Limitations, reasons for caution The computational model currently describes follicle development during treatment with follitropin delta. We envision extending the model to encompass other treatment outcomes and additional preparations of exogenous gonadotrophins. While the model incorporates our current understanding of mechanisms important for follicle development, ongoing research in the field will likely drive improvements. Wider implications of the findings The computational model is hypothesis-generating and can improve the design of future clinical trials through in silico trial simulation. For instance, the effects of changing subject inclusion/exclusion criteria or of novel dosing regimens can be investigated. Trial registration number NCT01426386, NCT03809429

[This corrects the article DOI: 10.3389/fendo.2022.1004596.].

Radium-223 and taxane chemotherapy each improve survival of patients with metastatic castration-resistant prostate cancer (mCRPC). Whether the radium-223-taxane sequence could extend survival without cumulative toxicity was explored. The global, prospective, observational REASSURE study (NCT02141438) assessed real-world safety and effectiveness of radium-223 in patients with mCRPC. Using data from the prespecified second interim analysis (data cutoff, March 20, 2019), hematologic events and overall survival (OS) were evaluated in patients who were chemotherapy-naive at radium-223 initiation and subsequently received taxane chemotherapy starting ≤90days ("immediate") or >90days ("delayed") after the last radium-223 dose. Following radium-223 therapy, 182 patients received docetaxel (172 [95%]) and/or cabazitaxel (44 [24%]); 34 patients (19%) received both. Seventy-three patients (40%) received immediate chemotherapy and 109 patients (60%) received delayed chemotherapy. Median time from last radium-223 dose to first taxane cycle was 3.6months (range, 0.3-28.4). Median duration of first taxane was 3.7months (range, 0-22.0). Fourteen patients (10 in the immediate and four in the delayed subgroup) had grade 3/4 hematologic events during taxane chemotherapy, including neutropenia in two patients in the delayed subgroup and thrombocytopenia in one patient in each subgroup. Median OS was 24.3months from radium-223 initiation and 11.8months from start of taxane therapy. In real-world clinical practice settings, a heterogeneous population of patients who received sequential radium-223-taxane therapy had a low incidence of hematologic events, with a median survival of 1year from taxane initiation. Thus, taxane chemotherapy is a feasible option for those who progress after radium-223. ClinicalTrials.gov identifier NCT02141438. Radium-223 and chemotherapy are treatment options for metastatic prostate cancer, which increase survival but may affect production of blood cells as a side effect. We wanted to know what would happen if patients received chemotherapy after radium-223. Among the 182 men treated with radium-223 who went on to receive chemotherapy, only two men had severe side effects affecting white blood cell production (neutropenia) during chemotherapy. On average, the 182 men lived for 2years after starting radium-223 and 1year after starting chemotherapy. In conclusion, patients may benefit from chemotherapy after radium-223 treatment without increasing the risk of side effects.