Innovation in the pharmaceutical industry in EU and USA: sources of new medicines over the period of 1996-2016

Arbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüftAbweichender Titel nach Übersetzung der Verfasserin/des VerfassersProductivity of pharmaceutical industry, calculated as the ratio of the number of new drugs introduced to the market (approved by the regulatory agencies) to the total R&D costs of the entire industry, then, declined since the 1950s (Lendrem et al, 2015). The number of approved innovative drugs has grown only insignificantly in recent decades globally, and R&D costs dramatically increased. This crisis has four main groups of reasons for such an adverse phenomenon in the industry (Scannell et al, 2012; Nosengo et al, 2016):1. strategy of research and selection of the target diseases: the “low-hanging” disease have been exhausted,2. high number of staff/FTEs specialists necessary for a full R&D and approval cycle of a single drug,3. increase of regulatory control and scrutiny, and4. imbalances in the management of pharmaceutical companies: huge amounts of money are spent on the development and introduction of new drugs, their increased cost does not always reflect the clinical benefits.The four above mentioned reasons formed the basis for a powerful innovation shift in the activities of pharmaceutical companies - the transition to the field of biotech research. More and more attention is paid to biotech drugs, drugs for cancer and rare diseases, the treatment of which is difficult or unavailable, and therefore the corresponding drugs are much less prone to the problem of "low clinical benefits", and regulators practice approach of much lower resistance for these drugs to get to the market. Higher risk taking by more complex research would be impossible without the underlying basic science research by Academia, a new emerging player in the field of pharmaceutical discovery. Large players have significantly less innovative potential and flexibility, prefer to focus on production, marketing and sales, therefore, to replenish their pipelines, they often do not invest in early discovery stages themselves, but buy innovative startups. The small companies are more efficient, they spend much less time and money on drug development, use capital and infrastructure more efficiently, and will be created under conditions of unmet medical need. For example, instead of purchasing equipment and reagents themselves, they conduct research - both preclinical (on biological models and laboratory animals) and clinical (testing the safety and efficacy of a new drug in patients), using the capabilities and resources of highly specialized contract research organizations. Innovative designs are more likely to be utilized in the comparable situations by SME rather than by big companies (Mesa, Zagrijtschuk et al, 2019).In the light of the fact that big pharma became essentially dependent on external novelty to maintain their pipelines while being unable to come up with own innovation, academia emerged in the past decade from its usual role of basic research to looking for applicable tools and interventions against disease targets to investigate their therapeutic relevance. The novel targets and drugs will be acquired from universities prior to this investment, either directly via the license agreement, or passing the stage of a start-up or SME intermediate. Project managers and meeting the timelines, the usual industry standard, were common components to projects success of universities, alongside with the ability to publish research result in good journals. Over the time, this path became the mainstream of the industry. Thus, the principle questions about the origin of pharmaceutical innovation turns to become not where does the invention happen and makes its early steps, but rather if the invention is going to be done and noticed/explored by the party, able to create drugs, and if the supportive conditions will be created. Funnily, both big and small pharma create innovation – the latter ones develop innovative models to operate more efficiently, while the genuine innovation by discovery happes esewhere. Knowing, understanding and positively influencing the factors is essential to positive guide and enhance the output of the whole pharmaceutical industry. USA based companies and universities used to be much more efficient in adopting and advancing the new model, as seen in faster market growth in the context of more competitive environment for faster research application. This work will focus on description of the differences between EU and USA in term of where does the innovation for novel drugs come from, and which stakeholder party was able to push the idea as a product to the market. The observation period covers the end of nineties (still, the golden age of a classic, big pharma dominated markets) through 2004, when the transformation occurred in form of market harmonization in the EU and the first wave of market consolidation in the USA until 2016 – a representative year for VC centric approach of early innovation funding, driven by the risk taking readiness and availability of early risk money as decisive factor for pharmaceutical success of academia and SMEs.5

Hematoxylin binds to mutant calreticulin and disrupts its abnormal interaction with thrombopoietin receptor.

Somatic mutations of calreticulin (CALR)have been identified as one of the main disease drivers of myeloproliferative neoplasms (MPNs), suggesting that developing drugs targeting mutant CALR is of great significance. Site-directed mutagenesis in the N-glycan binding domain (GBD)abolishes the ability of mutant CALRto oncogenically activate the thrombopoietin receptor (MPL).We thus hypothesized that a small molecule targeting the GBD might inhibit the oncogenicity of the mutant CALR. Using an in-silico molecular docking study, we identified candidate binders to the GBD of CALR. Further experimental validation of the hits identified a group of catechols inducing selective growth inhibitory effect on cells that depend on oncogenic CALRs for survival and proliferation. Apoptosis-inducing effects by the compound were significantly higher in the CALR mutated cells than in CALR wild type cells. Additionally, knockout or C-terminal truncation of CALR abolished the drug hypersensitivity in CALR mutated cells. We experimentally confirmed the direct binding of the selected compound to CALR, the disruption of the mutant CALR-MPL interaction, the inhibition of the JAK2-STAT5 pathway, and reduction of intracellular level of mutant CALR upon the drug treatment. Our data conclude that small molecules targeting the GBD of CALR can selectively kill CALR mutated cells by disrupting the CALR-MPL interaction and inhibiting the oncogenic signaling

A new dosing regimen of ropeginterferon alfa-2b is highly effective and tolerable: findings from a phase 2 study in Chinese patients with polycythemia vera

Abstract Ropeginterferon alfa-2b represents a new-generation pegylated interferon-based therapy and is administered every 2–4 weeks. It is approved for polycythemia vera (PV) treatment in the United States and Europe with a starting dose of 100 µg (50 µg for patients receiving hydoxyurea) and intra-patient dose titrations up to 500 µg at 50 µg increments, which took approximately 20 or more weeks to reach a plateau dose level. This study aimed to assess ropeginterferon alfa-2b at an alternative dosing regimen with a higher starting dose and quicker intra-patient dose titrations, i.e., the 250–350–500 μg schema, in 49 Chinese patients with PV with resistance or intolerance to hydroxyurea. The primary endpoint of the complete hematologic response rate at treatment weak 24 was 61.2%, which was notably higher than 43.1% at 12 months with the approved dosing schema. The JAK2 V617F allele burden decreased from baseline to week 24 (17.8% ± 18.0%), with one patient achieving a complete molecular response. Ropeginterferon alfa-2b was well-tolerated and most adverse events (AEs) were mild or moderate. Common AEs included alanine aminotransferase and aspartate aminotransferase increases mostly at grade 1 or 2 levels. Patients did not present with jaundice or significant bilirubin level increase. No grade 4 or 5 AEs occurred. Seven patients (14.3%) experienced reversible, drug-related grade 3 AEs. No AEs led to treatment discontinuation. Ropeginterferon alfa-2b at the 250–350–500 μg regimen is highly effective and well-tolerated and can help patients achieve greater and rapid complete hematologic and molecular responses. Clinical Trial Registration: This trial is registered at ClinicalTrials.gov (Identifier: NCT05485948) and in China (China National Medical Products Administration Registration Number: CTR20211664)

Secreted Mutant Calreticulins As Rogue Cytokines in Myeloproliferative Neoplasms

Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino-acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/ml, with a mean of 25.64 ng/ml. Plasma mutant CALR is found in complex with soluble Transferrin Receptor 1 (sTFRC) that acts as a carrier protein and increases CALR mutant half-life. Recombinant mutant CALR proteins bound and activated the TpoR on cell lines and primary megakaryocytic progenitors from CALR-mutated patients where they drive Tpo-independent colony formation. Importantly, the CALR-sTFRC complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in one cell can specifically interact in trans with the TpoR on a target cell. Cells that carry both TpoR and mutant CALR are hypersensitive to exogenous CALR mutant proteins in comparison to cells that only carry TpoR, and respond to levels of CALR mutant proteins similar to those in patient plasma. This is consistent with CALR mutated cells exposing at the cell-surface TpoR carrying immature Nlinked sugars. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gen