Peptidradiorezeptor-Therapie (PRRT)

ZusammenfassungNeuroendokrine Neoplasien (NEN) stellen ein komplexes, heterogenes Krankheitsbild dar, wobei der Primärtumorlokation meist im Gastrointestinaltrakt lokalisiert ist. Als „Orphan Disease“ sind NEN zwar selten, werden aber primär durch eine verbesserte bildgebende Diagnostik in den letzten Jahren verstärkt diagnostiziert. Hierbei spielt die Somatostatinrezeptor (SSTR)-gerichtete molekulare Bildgebung eine große Rolle, insbesondere die Einzelphotonen-Emissions-Computertomografie (SPECT) sowie die Positronen-Emissions-Tomografie (PET). Neben einer exakten Ausbreitungsdiagnostik generiert die SSTR-gerichtete Bildgebung auch eine Therapierationale für eine Peptidradiorezeptortherapie (PRRT) in einem sog. „theranostischen“ Ansatz. Hierbei wird ein β-Strahler mit dem identischen Peptid des diagnostischen SPECT-/PET-Gegenstücks gekoppelt, um somit eine gezielte, SSTR-gerichtete Bestrahlung von NEN und metastatischer Läsionen zu ermöglichen. Das daraus resultierende „heiße“ Somatostatinanalogon kann als hocheffektives Radiotherapeutikum mit akzeptablem Nebenwirkungsprofil eingesetzt werden, was bereits in einer randomisierten, prospektiven, multizentrischen Studie belegt wurde. Die PRRT erfolgt in Deutschland stationär auf einer nuklearmedizinischen Isotopenstation, wobei Indikation, Durchführung und Nachsorge dieser zielgerichteten Therapie in einem interdisziplinären Ansatz in enger Absprache mit Kolleg*innen der Inneren Medizin, der Medizinphysik und Nuklearmedizin erfolgen sollte. Mit Lutathera (177Lu-Oxodotreotid) steht seit Kurzem ein in Deutschland zugelassenes Arzneimittel zur SSTR-gerichteten Therapie zur Verfügung, womit die PRRT verstärkt Anwendung finden dürfte.

A neurologist’s rhombencephalitis after comirnaty vaccination. A change of perspective

Rhombencephalitis is an orphan disease of multiple causes that may manifest with facial palsy, limb ataxia and reduced consciousness. Up to now it is described after COVID-19 infection and in this (personal) case was found up to 8 weeks after Comirnaty vaccination. So far, we do not fully understand the pathophysiological characteristics of encephalitis associated with SARS-CoV-2. In rare cases, vaccination may cause an immunological reaction and delayed inflammation, the consequences of which we have not yet deciphered. Rhombencephalitis should be considered as a rare potential mRNA-associated vaccination side effect.

A Desk Top Allusion to The Rare Orphan Diseases and Orphan Drugs: Possessions to Discern by Every Healthcare Professional

This article gives a brief knowledge about orphan diseases and drugs. An orphan disease is a rare illness lack market and resource data for the treatment and the drugs used for their treatment are called orphan drugs. The pharmaceutical firms show less interest in the development of drugs to treat them, and lack profit without government assistance. The authors reviewed published scientific literature and grouped a broad list of Orphan diseases and orphan drugs. The article summarizes the entire list of orphan diseases and drugs with their description.

Prospects of off-label (OL) drug use in oncology: Identifying predicting variables for registration and universal healthcare reimbursement.

e18842 Background: Many cancer drugs used OL, eventually complete clinical development and are registered and reimbursed, while others are not. We aimed to describe OL indications' registration and reimbursement prospects in a universal healthcare system and identify groups of treatments that remain OL longer. Methods: We studied 612 OL oncology prescription requests for 115 unique indications and 29 drugs. All requests were approved by the Institutional Drug Committee in Rabin Medical Center, a tertiary center in Israel, between January 2016 and December 2018. OL indications were not registered by the Israeli Ministry of Health (MOH) and were not included in the Israeli National List of Health Services (NLHS) for reimbursement at the time of prescription. Additionally, 459 requests for 100 indications were not approved by the FDA at the time of prescription. We explored the subsequent regulatory and reimbursement milestones in the timeline following each prescription. We identified three temporal events: FDA indication approval, MOH indication registration, and NLHS indication inclusion of reimbursement. We then defined three time-to-event variables from the OL prescription to each of the three milestones. We applied Kaplan-Meier analysis and multivariable Cox regression to identify drug and indication properties, which are predictors for registration and reimbursement. Results: With a median follow-up of 34.5 months, 10.4% of indications were eventually registered in Israel, and 6% were included in the NLHS. 7% of non-FDA approved indications were subsequently approved. For MOH registration, positive predictors were immunotherapy, sufficient evidence (ESMO-MCBS A-B, 5-4), and a patient access program at the time of prescription (HR = 21.99; p< .0005, HR = 3.4; p= .02 and HR = 2.73; p< .0005, respectively). Negative predictors were metastatic setting and lung and gastrointestinal (GI) cancers (HR = 0.42; p= .002, HR = 0.17; p= .001, and HR = 0.24; p= .043, respectively). For NLHS inclusion, positive predictors were immunotherapy, sufficient evidence, and an access program (HR = 9.03, HR = 6.24, and HR = 2.56, respectively, all p< .0005). Negative predictors were lung and GI cancers and orphan disease designation (HR = 0.07; p= .002, HR = 0.14; p= .021, and HR = 0.13; p= .009, respectively). For FDA approval, positive predictors were immunotherapy, sufficient evidence, and a patient access program (HR = 12.11; p< .0005, HR = 4.34; p= .002, and HR = 2.25; p= .001, respectively). Negative predictors were metastatic setting, lung cancer, and orphan disease (HR = 0.43; p= .003, HR = 0.25; p= .006, and HR = 0.08; p= .018, respectively). Conclusions: Few OL indications are subsequently approved and reimbursed, usually due to clinical futility and insufficient evidence. However, we identified factors related to lack of initiative for further clinical development and registration.

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid–based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood–brain barrier, neurological diseases are significantly represented among the first targets for NBTs. As orphan disease NBTs are now entering the clinical stage, substantial efforts are required to develop the scientific background and infrastructure for NBT design and mechanistic studies, genetic testing, understanding natural history of orphan disorders, data sharing, NBT manufacturing, and regulatory support. The outcomes of these efforts will also benefit patients with “common” diseases by improving diagnostics, developing the widely applicable NBT technology platforms, and promoting deeper understanding of biological mechanisms that underlie disease pathogenesis. Furthermore, with successes in genetic research, a growing proportion of “common” disease cases can now be attributed to mutations in particular genes, essentially extending the orphan disease field. Together, the developments occurring in orphan diseases are building the foundation for the future of personalized medicine. In this review, we will focus on recent achievements in developing therapies for orphan neurological disorders.