The Design of a Phase 2 Study to Evaluate the Safety and Efficacy of Ropeginterferon Alfa-2b (P1101) in Chinese Patients with Polycythemia Vera Resistant or Intolerant to Hydroxyurea (HU)

Background: Polycythemia vera (PV) is the most common type of Philadelphia-negative myeloproliferative neoplasms (MPNs). PV is a long-term debilitating and life-threatening cancer that is associated with the risk of thrombosis, hemorrhage, and a long-term risk of developing myelofibrosis and acute myeloid leukemia. Early intervention with a disease-modifying treatment that can eradicate the mutated clones is needed to prevent disease progression and transformation. To date, therapeutic options for PV are limited and they only address the signs and symptoms. Most low-risk patients with PV are treated with phlebotomy and low-dose aspirin to manage increased blood viscosity and reduce the risk of vascular events, whereas high-risk and certain low-risk patients are treated with cytoreductive agents. Several cytoreductive agents are available such as hydroxyurea (HU) which is commonly used as a first-line therapy. Ruxolitinib, a JAK2 inhibitor, is also used. While interferon alfa agents have been used off label in clinical practice for more than three decades, their use has been limited due to the tolerability concerns. Ropeginterferon alfa-2b (P1101), a long-acting, mono-pegylated proline interferon, was developed for the treatment of MPNs, including PV. The novel formulation of P1101 improves its pharmacokinetic properties allowing treatment every 2 weeks with improved tolerability and convenience. P1101 was evaluated for the treatment of PV in the phase 3 PROUD-PV trial and its extension study CONTINUATION-PV. In the PROUD-PV study, due to the slow P1101 titration schedule, the maximum P1101 dose was not reached until week 28 and the primary analysis was done at 52 weeks. In CONTINUATION-PV, when patients were on their effective doses, a significantly higher proportion of patients treated with P1101 achieved a complete hematologic response (CHR) with improved disease burden compared to HU-treated patients. At 48 months there was a significant reduction in allelic burden from a baseline of 37.3% to 9.8% with 13.8% of patients achieving a complete molecular response (CMR). The molecular response rates (complete + partial) at 60 months was 69.1%. P1101 was approved by the European Medicines Agency in 2019 and the Taiwan Food and Drug Administration in 2020 as monotherapy in adults for the treatment of PV without symptomatic splenomegaly. Here, we describe a phase 2 study of P1101 in Chinese patients with PV utilizing an accelerated P1101 dose titration schedule. Study Design and Methods: This phase 2, multicenter, single-arm study is designed to evaluate safety and efficacy of P1101 in Chinese patients with PV utilizing a 250-350-500 ug P1101 dose titration schedule. The primary analysis will be conducted at 24 weeks. The study will recruit approximately 49 subjects in 15-20 sites in China. Key eligibility criteria include diagnosis of PV according to the 2016 WHO criteria, and resistance or intolerance to prior HU according to 2020 guidelines of CSCO. Patients who previously received interferon therapy have to be anti-P1101 binding antibody negative during the screening visit to be eligible. The study excludes patients with symptomatic splenomegaly. Eligible patients receive subcutaneous administration of P1101. Patients will receive an initial dose of 250 µg at Week 0, 350 µg at Week 2, and then 500 µg at Week 4. The dose is maintained at the highest dose that can be tolerated and delivers the best disease response. The maximum recommended dose is 500 μg every 2 weeks. Low-dose aspirin is administered during the 52 weeks of study treatment, unless contraindicated. The primary efficacy endpoint is the phlebotomy-free CHR rate at Week 24. Secondary endpoints include changes in hematocrit, white blood cell count, platelet count; time requiring no phlebotomy; time to first response; and duration of response. All patients will continue receiving treatment until week 52 to provide long-term follow-up information (blood parameters, molecular and cytogenetic data, safety parameters, and optional bone marrow data). This study has been granted IND approval by China CDE on Apr2021. Recruitment is expected to begin in early September 2021 with trial results expected in Q3 2022. Figure ： Study Design Figure 1 Figure 1. Disclosures Zagrijtschuk: PharmaEssentia U.S.A. Corp.: Current Employment. Urbanski: PharmaEssentia Corporation: Current Employment. Qin: PharmaEssentia Corp.: Current Employment.

Is Cenobamate the Breakthrough We Have Been Wishing for?

Close to one-third of patients with epilepsies are refractory to current anti-seizure medications; however, trials with cenobamate suggest effectiveness in such patients with focal onset seizures. We searched for data published or otherwise reported on cenobamate and outlined these here. Despite being marketed in the USA, few studies are yet published in full, and trials are ongoing. Nevertheless, cenobamate showed potential for a high degree of efficacy in reducing seizures with an unprecedented seizure-free rate of up to 28%. Rare cases of hypersensitivity reactions seen in early trials seem to be avoided by the current recommended titration schedule. Other adverse events were rated mild-to-moderate and most commonly included dizziness, drowsiness, and headache. If data are confirmed in further published trials, cenobamate will be a welcome new treatment and further analyses may identify those that will benefit the most.

Acute treatment of psychotic symptoms in a newly diagnosed Lewy body dementia patient with an accelerated titration schedule of rivastigmine and de-escalation of antipsychotics

A 76-year-old man presented with complaints of increased confusion, visual hallucinations and decline in memory. He was admitted to the hospital and started on quetiapine 50 mg daily for symptom management. Shortly after, he was diagnosed with Lewy body dementia and started on rivastigmine, a cholinesterase inhibitor (ChEI), at 1.5 mg two times per day. The patient’s symptoms continued to worsen and antipsychotics increased for aggressive behaviour. After he became physically aggressive, an extensive medication management review was conducted, prompting an alternative treatment strategy. The quetiapine dose was reduced from 150 mg daily to 12.5 mg daily, his rivastigmine was increased to 3 mg two times per day and all other antipsychotics were discontinued. The up-titration of his rivastigmine after 10 days of therapy was well tolerated with no adverse effects. He demonstrated a clear clinical response to optimised ChEI therapy and low dose quetiapine, showing improvements in alertness and functioning.

Dimethyl Fumarate

Background: Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is indicated for the treatment of relapsing multiple sclerosis. Flushing and gastrointestinal (GI) adverse events (AEs) are common within the first few months of starting DMF therapy. Although most symptoms are mild or moderate in severity, transient, and infrequently result in treatment discontinuation, they nevertheless present a challenge for patients to adhere to therapy and achieve an optimal treatment response. Methods: This review discusses management strategies for the prophylaxis and treatment of common DMF-associated AEs based on clinical trial evidence and real-world experience in clinical practice settings. Results: Before starting DMF therapy, patients should receive counseling on the importance of treatment adherence and the likely occurrence and severity of flushing and GI AEs (nausea, vomiting, diarrhea, and abdominal pain). Management strategies, such as administering DMF with food, using a slower-dose titration schedule, applying temporary dose reductions, and using symptomatic therapies, provide clinicians with several approaches to address DMF tolerability. In particular, DMF coadministration with certain foods (eg, sausage, peanut butter) may prevent or reduce the severity of GI AEs. Taking aspirin 325 mg/day 30 minutes before administering DMF in the first month of therapy can reduce the incidence and severity of flushing without negatively affecting GI-related events. Conclusions: Through continual patient education and support and management of treatment-related flushing and GI AEs, clinicians can help patients adhere to and persist with DMF therapy, thus maximizing treatment benefit.

An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial

Objective.Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.Methods.All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes.Results.Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged.Conclusion.Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD. Trial registration: ClinicalTrials.gov; www.clinicaltrials.govNCT01933334.