Development of medicines for rare diseases and inborn errors of metabolism: Toward novel public-private partnerships.

Medicine development for rare diseases, including inborn errors of metabolism (IEMs) is challenging. Many academic innovations fail to reach the patient, either by stranding in the translational stage or due to suboptimal patient access related to pricing or uncertain effectiveness. Expanding and solidifying the role of the academic in public-private partnerships (PPPs) may present an innovative solution to help overcome these complexities. This narrative review explores the literature on traditional and novel collaborative approaches to medicine development for rare diseases and analyzes examples of PPPs, with a specific focus on IEMs. Several academic institutions have introduced guidelines for socially responsible licensing of innovations for private development. The PPP model offers a more integrative approach toward academic involvement of medicine development. By sharing risks and rewards, failures in the translational stage can be mutually absorbed. If socially responsible terms are not included, however, high pricing can impede patient access. Therefore, we propose a framework for socially responsible PPPs aimed at medicine development for metabolic disorders. This socially responsible PPP framework could stimulate successful and accessible medicine development for IEMs as well as other rare diseases if the establishment of such collaborations includes terms securing joint data ownership and evidence generation, fast access, and socially responsible pricing.

Effectiveness and safety of mexiletine in patients at risk for (recurrent) ventricular arrhythmias: a systematic review.

AIMS: While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically endangered. Here we aim to demonstrate the effectiveness and safety of mexiletine in the treatment of patients with (recurrent) ventricular arrhythmias, emphasizing the absolute necessity of its accessibility. METHODS AND RESULTS: Studies were included in this systematic review (PROSPERO, CRD42020213434) if the efficacy or safety of mexiletine in any dose was evaluated in patients at risk for (recurrent) ventricular arrhythmias with or without comparison with alternative treatments (e.g. placebo). A systematic search was performed in Ovid MEDLINE, Embase, and in the clinical trial registry databases ClinicalTrials.gov and ICTRP. Risk of bias were assessed and tailored to the different study designs. Large heterogeneity in study designs and outcome measures prompted a narrative synthesis approach. In total, 221 studies were included reporting on 8970 patients treated with mexiletine. Age ranged from 0 to 88 years. A decrease in ventricular arrhythmias of >50% was observed in 72% of the studies for pre-mature ventricular complexes, 64% for ventricular tachycardia, and 33% for ventricular fibrillation. Electrocardiographic effects of mexiletine were small; only in a subset of patients with primary arrhythmia syndromes, a relative (desired) QTc decrease was reproducibly observed. As for adverse events, gastrointestinal complaints were most frequently observed (33% of the patients). CONCLUSIONS: In this systematic review, we present all the currently available knowledge of mexiletine in patients at risk for (recurrent) ventricular arrhythmias and show that mexiletine is both effective and safe.

Cost-Based Price Calculation of Mexiletine for Nondystrophic Myotonia.

OBJECTIVES: Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs. METHODS: We calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative. RESULTS: The calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily. CONCLUSIONS: The current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions.

A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon® (immediate-release) and Procysbi® (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM® . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi® . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18).

Registries for orphan drugs: generating evidence or marketing tools?

Independent disease registries for pre-and post-approval of novel treatments for rare diseases are increasingly important for healthcare professionals, patients, regulators and the pharmaceutical industry. Current registries for rare diseases to evaluate orphan drugs are mainly set up and owned by the pharmaceutical industry which leads to unacceptable conflicts of interest. To ensure independence from commercial interests, disease registries should be set up and maintained by healthcare professionals and patients. Public funding should be directed towards an early establishment of international registries for orphan diseases, ideally well before novel treatments are introduced. Regulatory bodies should insist on the use of data from independent disease registries rather than company driven, drug-oriented registries.