Successes and pitfalls in orphan drug development for sickle cell disease.

ABSTRACT: Sickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points.

Advancing rare disease treatment: EMA's decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation.

Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation.This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency's Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication.

Uptake of orphan drugs in the WHO essential medicines lists.

Objective: We evaluated the uptake of medicines licensed as orphan drugs by the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA) into the WHO Model list of essential medicines and the WHO Model list of essential medicines for children from 1977 to 2021. Methods: We collated and analysed data on drug characteristics, reasons for adding or rejecting medicines, and time between regulatory approval and inclusion in the lists. We compared trends in listing orphan drugs before and after revisions to the inclusion criteria of the essential medicines lists in 2001, as well as differences in trends for listing orphan and non-orphan drugs, respectively. Findings: The proportion of orphan drugs in the essential medicines lists increased from 1.9% (4/208) in 1977 to 14.6% (70/478) in 2021. While orphan drugs for communicable diseases have remained stable over time, we observed a considerable shift towards more orphan drugs for noncommunicable diseases, particularly for cancer. The median period for inclusion in the essential medicines lists after either FDA or EMA first approval was 13.5 years (range: 1-28 years). Limited clinical evidence base and uncertainty about the magnitude of net benefit were the most frequent reasons to reject proposals to add new orphan drugs to the essential medicines lists. Conclusion: Despite lack of a global definition of rare diseases, the essential medicines lists have broadened their scope to include medicines for rare conditions. However, the high costs of many listed orphan drugs pose accessibility and reimbursement challenges in resource-constrained settings.

The European landscape for gene therapies in orphan diseases: 6-year experience with the EMA Committee for Orphan Medicinal Products.

In 2000, the European Union (EU) introduced the orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products (COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as protocol assistance and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear.

Traits, trends and hits of orphan drug designations in cystic fibrosis.

BACKGROUND: In the United States (US) and in Europe, cystic fibrosis (CF) qualifies as a rare disease, thus positioning the field to benefit from regulatory incentives provided by orphan drug designation (ODD) to boost pharmaceutical research and development. In this study, we analyzed the pool of products for the treatment of CF that received such incentives from the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) over the past two decades. We describe the characteristics and trends in ODDs over time and explore factors that might be determinants of successful drug development. METHODS: We collected the products that received the ODD from the registries of the FDA and the EMA from 2000 to 2021, characterizing their nature, development stage, and type of sponsor. We categorized the study drugs according to the therapeutic target addressed and described trends of drug development over the study period. A logistic regression analysis was done to assess how ODD characteristics were associated with the approval for market authorization. RESULTS: From 2000-2021, 107 ODDs were collectively granted by the FDA and the EMA for products developed for the treatment of CF. Although the trends of the number of ODDs granted remained stable over time, those targeting the CF basic protein defect increased from 6 out of 54 (11.1%) in the first half of the study period up to 20 out of 54 (37.7%) in the second half, while those treating symptoms decreased from 48/54 (88.9%) to 33/53 (62.3%). Overall, 10 products obtained marketing approval: 7 in both the US and Europe, 3 only in Europe. All the approved ODDs were chemical products for chronic use. No statistically significant difference was found across the examinated variables, but we observed possible drivers of successful drug development for ODDs targeting CFTR, as well as for those with active substances previously marketed, and for those developed by large companies and companies with experience in developing orphan drugs. By contrast, our findings suggest that financial issues most hamper the development of ODDs sponsored by small-medium enterprises. CONCLUSIONS: Although ODDs for treating infection and other CF sequelae accounted for the majority, we observed a shift of ODDs toward mechanism-based products over the study period. In line with other rare diseases, we found that approximately 1/10 ODDs for CF reached the status of marketing approval. Advances in disease genetics paved the way for a shift in CF drug development; however, we described how the convergence of pharmaceutical technology, the financial environment, and the regulatory ecosystem played a crucial role in successful marketing authorization in CF.

X-ray polarization evidence for a 200-year-old flare of Sgr A.

The centre of the Milky Way Galaxy hosts a black hole with a solar mass of about 4 million (Sagittarius A* (Sgr A)) that is very quiescent at present with a luminosity many orders of magnitude below those of active galactic nuclei1. Reflection of X-rays from Sgr A* by dense gas in the Galactic Centre region offers a means to study its past flaring activity on timescales of hundreds and thousands of years2. The shape of the X-ray continuum and the strong fluorescent iron line observed from giant molecular clouds in the vicinity of Sgr A* are consistent with the reflection scenario3-5. If this interpretation is correct, the reflected continuum emission should be polarized6. Here we report observations of polarized X-ray emission in the direction of the molecular clouds in the Galactic Centre using the Imaging X-ray Polarimetry Explorer. We measure a polarization degree of 31% ± 11%, and a polarization angle of -48° ± 11°. The polarization angle is consistent with Sgr A* being the primary source of the emission, and the polarization degree implies that some 200 years ago, the X-ray luminosity of Sgr A* was briefly comparable to that of a Seyfert galaxy.

Vela pulsar wind nebula X-rays are polarized to near the synchrotron limit.

Pulsar wind nebulae are formed when outflows of relativistic electrons and positrons hit the surrounding supernova remnant or interstellar medium at a shock front. The Vela pulsar wind nebula is powered by a young pulsar (B0833-45, aged 11,000 years)1 and located inside an extended structure called Vela X, which is itself inside the supernova remnant2. Previous X-ray observations revealed two prominent arcs that are bisected by a jet and counter jet3,4. Radio maps have shown high linear polarization of 60% in the outer regions of the nebula5. Here we report an X-ray observation of the inner part of the nebula, where polarization can exceed 60% at the leading edge-approaching the theoretical limit of what can be produced by synchrotron emission. We infer that, in contrast with the case of the supernova remnant, the electrons in the pulsar wind nebula are accelerated with little or no turbulence in a highly uniform magnetic field.

Polarized x-rays from a magnetar.

Magnetars are neutron stars with ultrastrong magnetic fields, which can be observed in x-rays. Polarization measurements could provide information on their magnetic fields and surface properties. We observed polarized x-rays from the magnetar 4U 0142+61 using the Imaging X-ray Polarimetry Explorer and found a linear polarization degree of 13.5 ± 0.8% averaged over the 2- to 8-kilo-electron volt band. The polarization changes with energy: The degree is 15.0 ± 1.0% at 2 to 4 kilo-electron volts, drops below the instrumental sensitivity ~4 to 5 kilo-electron volts, and rises to 35.2 ± 7.1% at 5.5 to 8 kilo-electron volts. The polarization angle also changes by 90° at ~4 to 5 kilo-electron volts. These results are consistent with a model in which thermal radiation from the magnetar surface is reprocessed by scattering off charged particles in the magnetosphere.

Promoting engagement with quality communication in social media.

The COVID-19 pandemic made explicit the issues of communicating science in an information ecosystem dominated by social media platforms. One of the fundamental communication challenges of our time is to provide the public with reliable content and contrast misinformation. This paper investigates how social media can become an effective channel to promote engagement and (re)build trust. To measure the social response to quality communication, we conducted an experimental study to test a set of science communication recommendations on Facebook and Twitter. The experiment involved communication practitioners and social media managers from select countries in Europe, applying and testing such recommendations for five months. Here we analyse their feedback in terms of adoption and show that some differences emerge across platforms, topics, and recommendation categories. To evaluate these recommendations' effect on users, we measure their response to quality content, finding that the median engagement is generally higher, especially on Twitter. The results indicate that quality communication strategies may elicit positive feedback on social media. A data-driven and co-designed approach in developing counter-strategies is thus promising in tackling misinformation.

Trends and determinants of epinephrine prescriptions: a proxy of anaphylaxis epidemiology?

PURPOSE OF REVIEW: Epinephrine autoinjectors (EAIs) are recommended to all patients previously experiencing anaphylaxis reaction in order to prevent further reactions and fatalities. Under that perspective, EAI prescription could be considered as a proxy of anaphylaxis epidemiology. Nevertheless EAI prescription rates are still unacceptably low. RECENT FINDINGS: The review focuses on potential determinants, in addition to clinical indications, which might impact EAI prescription rates by exploring the scientific literature published within the past 18 months, wherever available. Although some controversial results, age, sex, ethnicity, geographical setting and socioeconomic conditions might influence both physician prescription behaviour and EAIs' accessibility from the patient's side, which hampers the accuracy of EAI prescription as a proxy of anaphylaxis. Low EAI prescription and refill rates have been recorded even in the absence of significant socioeconomic barriers, suggesting that economical limitations only partially account for the issue, and cultural restrictions have also to be considered and addressed. SUMMARY: In addition to providing the same opportunities in terms of EAI availability in all countries worldwide, implementing the resources for anaphylaxis management in terms of practical knowledge, education, and allergy specialist networks is an urgent need, even in the absence of socioeconomic barriers.

Emergent treatments for ß-thalassemia and orphan drug legislations.

In many countries, ß-thalassemia (ß-THAL) is not uncommon; however, it qualifies as a rare disease in the US and in European Union (EU), where thalassemia drugs are eligible for Orphan Drug Designation (ODD). In this paper, we evaluate all 28 ODDs for ß-THAL granted since 2001 in the US and the EU: of these, ten have since been discontinued, twelve are pending, and six have become licensed drugs available for clinical use. The prime mover for these advances has been the increasing depth of understanding of the pathophysiology of ß-THAL; at the same time, and even though only one-fifth of ß-THAL ODDs have become licensed drugs, the ODD legislation has clearly contributed substantially to the development of improved treatments for ß-THAL.

[Harmonizing development, approval and access of drugs for rare diseases in Europe.] / Verso un modello integrato di sviluppo, approvazione e accesso dei farmaci per malattie rare in Europa.

In the past few decades, the regulatory system has changed its approach to speed up the assessment and approval of drugs for the treatment of serious and orphan diseases. However, too early assessments may fail to provide solid evidence to define the therapeutic value of drugs and their fair price. As for rare diseases, patients' expectations amplify such criticalities due to the lack of therapeutic alternatives. The revision of the EU regulation on orphan medicinal products represents an opportunity to promote greater integration between the development and approval of drugs with their subsequent access. For this reason, we propose: 1) establishing a process for evaluating the comparative efficacy and quantification of the therapeutic benefit of a drug at a European level, while addressing incentives towards rarer diseases to support their development and marketing; 2) downsizing the impact of orphan drugs on general sustainability, considering that incentives supporting their development and marketing cannot transform them into new 'blockbusters'. In this perspective, a European procurement - initially intended for drugs for ultra-rare diseases - could improve access by all EU countries through simplifying the burdensome procedures for the pharmaceutical industry; 3) enhancing the contribution of post-authorization research from a public-private partnership perspective to steer the development of drugs already approved towards rarer pathologies or mutations of little commercial interest.

[Access to medicines for rare diseases: regulatory aspects and public health priorities.] / L'accesso ai farmaci per malattie rare tra aspetti regolatori e priorità di salute pubblica.

INTRODUCTION: In the last decades, the development of drugs for rare diseases has been supported by regulatory and financial incentives. On the other hand, public health policies have increasingly taken into account the person affected by a rare disease in their strategies. In this perspective, we examined the relation between the regulatory framework on rare diseases and the regulatory framework on drug approval. Technical proposals have been brought forward to protect the needs of individuals. RESULTS: The legislative framework on rare diseases has developed both at a European and national level with the aim to strengthen the network of centers for diagnosis and care by increasing the degree of social and health protection, as well as to accelerate the assessment, approval and access to new drugs. Since 2000, 210 orphan drugs have been approved by the European Medicines Agency (EMA) (compared to an estimated 7-8,000 rare diseases). Of the 118 orphan drugs active in the community register as of 2020, 97 (82.2%) were available in Italy: 17 (17.5%) in class A; 58 (59.8%) in class H; 12 (12.4%) in class C; 10 (10.3%) in class C-nn. In 2020, expenditure on drugs with an orphan indication accounted for 6% of the total pharmaceutical expenditure (+47% since 2016). These drugs have benefited from incentives at both European and national levels, as well as inclusion in national early access programs. However, the average duration of the assessment process is above the 100-day limit set by law. DISCUSSION: The legislation on rare diseases has developed in different directions, and drug legislation has undoubtedly played a major role in terms of the results achieved. However, orphan drugs enter the market with a high price, which increasingly represents a problem of sustainability for health systems but notwithstanding Italy shows a high ratio between the level of social protection and access times. In this perspective, it is necessary to be provided with tools for a better system balance with a view to optimize these timeframes. Introducing in Italy a system for tracking the negotiation process that considers the clock stops as the EMA does, would allow to know at what point the negotiation process is. In addition, once the 100-day period is over (net of any clock stops) and in case of failure to reach a negotiation agreement, a second 60-day negotiation round could be proposed and so on. In this way, all the parts involved the system would have a clear scope of action to conclude the process in a flexible but certain timeframe. In this regard, the joint clinical assessments foreseen by the new HTA Regulations provide an additional opportunity to harmonize central decisions with national requirements.

The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis.

BACKGROUND: Over the past decade, a new class of drugs called CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown to be able to improve clinical outcomes in patient with Cystic Fibrosis. In this analysis, we have extensively reviewed the regulatory pathways and decisions adopted by FDA and EMA to speed up the development, the review and the approval of these drugs, with the aim of identifying possible clinical and public health implications associated with differences. RESULTS: CFTR modulators have been developed towards addressing three main genetic domains: (1) F508del homozygous (F508del/F508del), (2) F508del heterozygous, and (3) genotypes not carrying F508del mutation; and expanded from adult to paediatric population. Programs to expedite the reviewing and licensing of CFTR modulators were extensively adopted by FDA and EMA. All CFTR modulators have been licensed in the US as orphan drugs, but in the EU the orphan status for LUM/IVA was not confirmed at the time of marketing authorization as results from the pivotal trial were not considered clinically significant. While FDA and EMA approved CFTR modulators on the basis of results from phase III double-blind RCTs, main differences were found on the extension of indications: FDA accepted non-clinical evidence considering a recovery of the CFTR function ≥ 10% based on chloride transport, a reliable indicator to correlate with improvement in clinical outcomes. By contrast, EMA did not deem preclinical data sufficient to expand the label of CFTR modulators without confirmatory clinical data. CONCLUSIONS: Regulators played an important role in fostering the development and approval of CFTR modulators. However, differences were found between FDA and EMA in the way of reviewing and licensing CFTR modulators, which extended beyond semantics affecting patients' eligibility and access: FDA's approach was more mechanistic/biology-driven while the EMA's one was more oriented by clinical evidence. This might refer to the connection between the EMA and the Member States, which tends to base decisions on pricing and reimbursement on clinical data rather than pre-clinical ones. Here we have proposed a two-step personalized-based model to merge the ethical commitment of ensuring larger access to all potential eligible patients (including those harboring very rare mutations) with the one of ensuring access to clinically assessed and effective medicines through Real World Data.

Can oral formulation increase the risk of lormetazepam abuse?

The slowness of dripping and the presence of alcohol have been offered/suggested as possible causes for the increased risk of developing dependence to the oral formulation of lormetazepam rather than to other anxiolytic and hypnotic drugs. We hence assessed the time of dripping of the most used benzodiazepines and z-drugs oral solution products under experimental conditions and the different employed excipients through a comparative analysis of the Summaries of Product Characteristics. A wide range of the median overall dispensing time was found across the eight products included in the analysis. Among the products containing LMZ, Minias® ranked in the fourth position, while LMZ Mylan Generics® and Noctamid® in the sixth and third, respectively. Our data suggest that the pace of dripping and the presence of alcohol cannot be considered themselves the cause that triggered the abuse of lormetazepam. More precisely, the quantity of alcohol per bottle has been found negligible at therapeutic doses; however, when these are exceeded, they may have clinical implications for patients. Further studies are needed to assess them. Meanwhile, the public-health problem remains and some improvements should be carried out at different levels, to guarantee the appropriate prescription and use of lormetazepam oral solution.

[Drugs for rare diseases: the blessing of being orphans.] / I farmaci per le malattie rare: la fortuna di essere orfani.

The incentives provided by Orphan Drugs Regulations have promoted the development of drugs that effectively ameliorate the course of serious conditions that had previously been neglected. However, the treatment of each individual patient with any of these drugs - the so-called 'orphan drugs' - is so expensive, that the total burden for publicly funded Health care Service is enormous and may become unsustainable. Italy is no exception, if it is to abide by its basic tenet of providing access to essential medicines - free of charge - to the entire population. We do not see any glimpses of improvement on the horizon: therefore we suggest that radical change must be introduced. First, price negotiation ought to take place at the European level, not at the member state level. Second, pricing should take into account not only value for patients, but also costs of research and development (R&D) plus production. Italian Medicines Agency (AIFA) should also support research focused on optimizing the effective use of orphan drugs in clinical practice. The challenges are complex: but AIFA is recognized as an authoritative body, and may be able to coagulate the agreement of other regulatory agencies for the ultimate purpose of achieving, for each of the orphan drugs a more reasonable 'European price'.