Roxadustat for the Treatment of Anemia in Patients with Lower‐Risk Myelodysplastic Syndrome: Open‐label, Dose‐selection, Lead‐in Stage of a Phase 3 Study

2021 ◽  
Author(s):  
David H. Henry ◽  
John Glaspy ◽  
Rosemary Harrup ◽  
Moshe Mittelman ◽  
Amy Zhou ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Lower Risk ◽  
Dose Selection ◽  
Open Label ◽  
Phase 3 ◽  
Label Dose

scholarly journals Scaling Approaches for Pediatric Dose Selection: The Fremanezumab (AJOVY®) Journey to Select a Phase 3 Dose Using Pharmacokinetic Data from a Phase 1 Study

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 785
Author(s):  
Aksana Jones ◽  
Orit Cohen-Barak ◽  
Andrijana Radivojevic ◽  
Jill Fiedler-Kelly
Keyword(s):  
Pediatric Population ◽  
Phase 1 ◽  
Adult Population ◽  
Predictive Performance ◽  
Pharmacokinetic Data ◽  
Dose Selection ◽  
Open Label ◽  
Phase 3 ◽  
Pediatric Dose ◽  
Population Pk

Fremanezumab, a fully humanized IgG2Δa/kappa monoclonal antibody, selectively targets the calcitonin-gene-related peptide (CGRP) and prevents it from binding to the CGRP receptor. The safety, tolerability, pharmacokinetics (PK), and efficacy of fremanezumab for treating migraines administered as a once monthly 225 mg dose or a once quarterly 675 mg dose have been well characterized in adults. The fremanezumab exposure and body weight relationship supported the use of the approved 225 mg monthly adult dose for pediatric patients weighing ≥45 kg. In the pediatric Phase 3 program, a 120 mg dose for patients weighing <45 kg was determined using the results of an open-label study and a population PK modeling and simulation strategy. A thorough evaluation was conducted to further characterize the population PK of fremanezumab and assess the predictive performance of the adult population PK model when applied to the Phase 1 pediatric data, the predictive performance of alternative pediatric population PK models, and the predictive performance of the selected pediatric population PK model via a noncompartmental-based approach. This latter comparison to noncompartmental results provided additional evidence that the pediatric population PK model predicts the observed data well and supports the 120 mg monthly dose in patients weighing <45 kg.

Luspatercept Response in ESA-NaïVe/RS+ Patients and RS- Patients with Low-Intermediate Risk Myelodysplastic Syndromes (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5551-5551
Author(s):  
Uwe Platzbecker ◽  
Ulrich Germing ◽  
Katharina Götze ◽  
Philipp Kiewe ◽  
Thomas Wolff ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Erythroid Differentiation ◽  
Intermediate Risk ◽  
Phase 2 ◽  
Open Label ◽  
Employment Equity ◽  
Phase 3 ◽  
Erythroid Response ◽  
Equity Ownership

Abstract Background: Management of anemia is a common therapeutic challenge in patients with myelodysplastic syndromes (MDS). Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label study to evaluate the effects of luspatercept in patient (pts) with low-intermediate risk MDS. Endpoints included erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, safety, and pt-reported QoL. Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), no prior HMA, and no current lenalidomide or erythropoiesis-stimulating agent (ESA). An expansion cohort of up to 56 patients was added to this phase 2 study to evaluate response to luspatercept in pts who do not qualify for the phase 3 MEDALIST trial (for RS+ positive patients with baseline EPO ≥ 200 U/L and ≥ 2U RBC/8 weeks). These include pts with low transfusion burden (< 4U RBC/8 weeks) who are either 1) ring sideroblast (RS)+ (≥ 15% RS in bone marrow) with baseline EPO ≤ 200 U/L and no prior ESA use, or 2) RS- with any baseline EPO level and any prior ESA use. Patients are treated with 1.0 mg/kg of luspatercept every 3 weeks for up to 5 doses, with titration up to 1.75 mg/kg. Patients may rollover to an open-label extension study for up to an additional 2 years of treatment. Results: Results for the initial patient cohorts have demonstrated a high proportion of HI-E and RBC-TI responses in RS+ patients. Data for the additional ESA-naïve RS+ patients with low EPO levels and RS- patients with 3 months of treatment will be presented at the meeting. Conclusions: Erythroid response to luspatercept has been demonstrated in RS+ patients with lower-risk MDS and is being explored in ESA-naïve RS+ patients with low EPO levels and RS- patients. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). Disclosures Donovan: Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.

A phase Ib, open-label, dose-finding study of ruxolitinib in patients (pts) with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF) and baseline platelets (PLTs) 50 to <100 x 109/l.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS6642-TPS6642 ◽  
Author(s):  
Heinz Gisslinger ◽  
Mary Frances McMullin ◽  
Nadja Jaekel ◽  
Carole Brennan Miller ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Primary Myelofibrosis ◽  
Dose Finding ◽  
Open Label ◽  
Phase 3 ◽  
Starting Dose ◽  
Finding Study ◽  
Label Dose ◽  
Dose Finding Study ◽  
Pm 10

TPS6642^ Background: Ruxolitinib, a potent and selective oral JAK1/2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 studies in pts with PMF, PPV-MF, or PET-MF. There is considerable experience in pts who develop thrombocytopenia on study, and ruxolitinib is well-tolerated with dose adjustment. However, there is limited experience in pts with baseline thrombocytopenia as those with low PLTs (< 100 x 109/L) were excluded from the phase 3 protocols. EXPAND (Evaluating RuXolitinib in Patients with Low Baseline PlAtelet CouNts Diagnosed With Myelofibrosis) will evaluate the safety of ruxolitinib and establish the maximum safe starting dose (MSSD) in thrombocytopenic pts with MF. Methods: This is a phase 1b, open-label, dose-finding study (NCT01317875) in pts with PMF, PPV-MF, or PET-MF and baseline PLT 50-100 x 109/L. A Bayesian logistic regression model with escalation with overdose control will be used to guide dose-escalation decisions. The study consists of 2 phases: dose-escalation and safety-expansion. The starting dose is ruxolitinib 5 mg twice daily (BID) with a maximum of 15 mg BID. In the dose-escalation phase, cohorts will be: 5 mg BID, 5 mg am/10 mg pm, 10 mg BID, 10 mg am/15 mg pm, and 15 mg BID; only pts with PLT 75-100 x 109/L (1st stratum) will initially be enrolled. Once safety is established at the first 2 dose levels (5 mg BID; 5 mg am/10 mg pm), pts with PLT 50-75 x 109/L will be included (2nd stratum). Each dose level in the 2nd stratum will be open only if both that dose and the following one are deemed safe in the 1st stratum. In the safety-expansion phase, 20 pts (10 from each stratum) additional to those treated at the MSSD during dose escalation will be treated at the respective MSSD for their stratum. In cohort 1 (n = 4), 3 pts were evaluable as they completed > 28 days of treatment; 1/4 pts discontinued after 6 doses due to disease progression. No dose-limiting toxicities were observed. The second cohort (5 mg am/10 mg pm) has completed enrollment (n = 3) and is ongoing.

Sign in / Sign up

Export Citation Format

Share Document