marzeptacog alfa (CB 813d) / GC Biopharma - LARVOL DELTA

Advances in Development of Drug Treatment for Hemophilia with Inhibitors. (PubMed, ACS Pharmacol Transl Sci) - "More recently, emicizumab, a bispecific antibody that mimics the function of activated clotting factor VIII, has demonstrated favorable efficacy for prophylaxis in patients with hemophilia A and inhibitors, representing a promising new therapeutic strategy...This review summarizes the current understanding of the pathophysiology of inhibitor development in hemophilia, outlines existing treatment options, and discusses advancements in novel therapeutic biologics, including a recombinant activated clotting factor VII variant (marzeptacog alfa), a new bispecific antibody (Mim8), antitissue factor pathway inhibitor antibodies (concizumab and marstacimab), and small interfering RNA targeting antithrombin (fitusiran). All of these agents are administered subcutaneously, with some offering the convenience of less frequent dosing (e.g., weekly or monthly). These potential drug candidates may provide significant benefits for the prophylaxis or treatment of bleeding disorders in..."

Journal • Review • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Rare Diseases

Subcutaneous marzeptacog alfa (activated) for on-demand treatment of bleeding events in subjects with haemophilia A or B with inhibitors. (PubMed, Clin Pharmacol Ther) - "A statistically significant relationship between MarzAA zero-order absorption and improvement of bleedings (p< 0.05) were identified albeit with low precision. No statistically significant difference in treatment response between MarzAA and intravenous SoC was identified, indicating the potential of MarzAA for treatment of episodic bleeding events with a favorable subcutaneous administration route."

Journal • Hematological Disorders • Hemophilia • Rare Diseases

Model-informed pediatric dose selection of marzeptacog alfa (activated): an exposure matching strategy. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Moreover, the probability of trial success evaluations given a plausible design confirmed the potential of a 60 μg/kg dose level. Taken together, this work demonstrates the utility of model-informed drug development and could be helpful for other pediatric development programs for rare diseases."

Journal • Hematological Disorders • Hemophilia • Pediatrics • Rare Diseases

Phase-3 Dose Selection of Marzeptacog Alfa (Activated) Informed by Population Pharmacokinetic Modeling: A Novel Hemostatic Drug. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "According to the Phase-3 protocol, if a second dose was required after three hours due to lack of efficacy, 90% of the population was observed to be above target six hours after the initial dose. The model-informed drug development approach integrated information from several trials and guided dose selection in the pivotal Phase-3 clinical trial for episodic treatment of an acute bleeding event in individuals with HA or HB with inhibitors, without the execution of a Phase-2 trial for that indication."

Journal • P3 data • PK/PD data • Hematological Disorders • Hemophilia • Rare Diseases

Crimson 1: A Phase 3 study to evaluate the efficacy and safety of subcutaneous marzeptocog alfa (activated) for on-demand treatment of bleed events in subjects with hemophilia A or B, with inhibitors (ISTH 2022) - "Aims: To evaluate the efficacy and safety of MarzAA versus standard of care (SOC; i.e., NovoSeven®, recombinant FVIIa [rFVIIa], or activated prothrombin complex concentrate) for treatment of bleeds in PwHA/PwHB with inhibitors. Due to changes in business strategy, the Sponsor terminated enrollment and dosing early on 15 November 2021. At that time, 18 subjects had been randomized and enrolled, with observation of 74 eligible bleeds (30 and 44 bleeds in 8 and 11 subjects treated with MarzAA and SOC, respectively). The proportion of effective treatment at 24 hours post-initial dose was 86.2% versus 86.5% for subjects treated with MarzAA versus SOC, respectively."

Clinical • P3 data • Cardiovascular • Hematological Disorders • Hemophilia • Rare Diseases

"Addendum: 1 subject (n=11) developed a transient cross-reactive antibody in study for on-demand subcutaneous FVIIa variant (MarzAA) #isth2022" (@DrSamelsonJones)

Phase 1/2 study to evaluate the pharmacokinetics, pharmacodynamics, safety, and efficacy of marzeptacog alfa (activated) for the treatment of bleeds in subjects with inherited bleeding disorders (ISTH 2022) - No abstract available

Clinical • P1/2 data • PK/PD data • Hematological Disorders

Study of Coagulation Factor VIIa Marzeptacog Alfa (Activated) in Subjects With Inherited Bleeding Disorders (clinicaltrials.gov) - P1/2; N=19; Terminated; Sponsor: Catalyst Biosciences; Recruiting ➔ Terminated; Company decision (not a safety issue)

Clinical • Trial termination • Hematological Disorders • Hemophilia • Rare Diseases

Subcutaneous Marzeptacog Alfa (Activated) Versus Intravenous rFVIIa for Treatment of Episodic Bleeding in FVIII Deficient Hemophilia a Rats (ASH 2021) - " Animals were allocated to treatment with either SQ vehicle, SQ MarzAA (60, 180 or 385 µg/kg) or IV rFVIIa (NovoSeven ® ) (580 µg/kg) immediately after the bleeding was diagnosed. Single doses of SQ MarzAA w ere effective in treating episodic bleeding in HA rats and statistically distinguishable from vehicle at all dose levels tested . When clinically relevant doses were compared directly to rFVIIa , SQ MarzAA compared favorably to IV rFVIIa. Taken together, these data provide robust nonclinical evidence that a single dose of SQ MarzAA may be successful in treat ing episodic bleeding when administered after bleeding has started."

Preclinical • Hematological Disorders • Hemophilia • Rare Diseases

Catalyst granted FDA’s orphan drug designation for hemophilia drug (SeekingAlpha) - "The FDA has granted the orphan drug designation to Catalyst Biosciences...for its lead candidate marzeptacog alfa as a treatment for bleeding in patients with hemophilia A or B."

Orphan drug • Genetic Disorders • Hemophilia

Study of Coagulation Factor VIIa Marzeptacog Alfa (Activated) in Subjects With Hemophilia A or B (clinicaltrials.gov) - P3; N=18; Terminated; Sponsor: Catalyst Biosciences; N=60 ➔ 18; Trial completion date: Mar 2022 ➔ Dec 2021; Recruiting ➔ Terminated; Sponsor decision (not a safety decision)

Clinical • Enrollment change • Trial completion date • Trial termination • Hematological Disorders • Hemophilia • Rare Diseases

Catalyst Biosciences Announces Change in Corporate Strategy (GlobeNewswire) - "Catalyst Biosciences, Inc...today announced a strategic decision to halt the clinical development of MarzAA, report data to date, and seek a buyer for its hemophilia assets. Catalyst plans to focus its resources on its complement therapeutics and protease medicines platform."

Discontinued • Genetic Disorders • Hemophilia

Marzeptacog alfa: DSMB meeting related to P3 trial in subjects with hemophilia A or B in Q1 2022 (Catalyst Biosciences) - Corporate Presentation:

DSMB • Hemophilia

Marzeptacog alfa: PK data from P1 portion of P1/2 trial (NCT04548791) in subjects with inherited bleeding disorders in 2022 (Catalyst Biosciences) - Corporate Presentation: Data from P2 portion of P1/2 trial (NCT04548791) in subjects with inherited bleeding disorders in 2022

P1 data • P2 data • Hemophilia

FDA Grants Catalyst Biosciences Orphan Drug Designation for MarzAA for the Treatment of Factor VII Deficiency (GlobeNewswire) - "Catalyst Biosciences, Inc...announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Disease Designation (ODD) for its lead product candidate, subcutaneous Marzeptacog alfa (activated), or MarzAA, for the treatment of Factor VII Deficiency (FVIID). MarzAA was previously granted ODD and Fast Track Designation (FTD) for treatment of Hemophilia A/B with inhibitors and FTD for the treatment of FVIID."

Orphan drug • Genetic Disorders • Hemophilia

"$CBIO FDA Grants Catalyst Biosciences Orphan Drug Designation for MarzAA for the Treatment of Factor VII Deficiency https://t.co/euhlRtBzsy" (@stock_titan)

FDA event • Orphan drug

Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety. (PubMed, Res Pract Thromb Haemost) - P2 | "One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. The data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes."

Clinical • Journal • P2 data • PK/PD data • Cerebral Hemorrhage • Hematological Disorders • Hemophilia • Hypertension • Rare Diseases

Catalyst Biosciences Reports Second Quarter 2021 Operating & Financial Results and Provides a Corporate Update (GlobeNewswire) - "Expected Milestones....Present PK data from the Phase 1/2 trial."

P1/2 data • Genetic Disorders • Hemophilia

CATALYST BIOSCIENCES : Management’s Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q) (Market Screener) - "Recent Development Program Updates....The Phase 3 registration trial - MAA-304 ('Crimson 1')...We plan to submit our first report to the Data and Safety Monitoring Board ('DSMB') in 2021. We are also enrolling patients in a Phase 1/2 trial ('MAA-202') of MarzAA for treatment of bleeding in Factor VII Deficiency, Glanzmann Thrombasthenia, and in individuals with HA with inhibitors treated with Hemlibra...DalcA...We are planning to meet with the FDA to discuss the design of a registrational Phase 3 clinical trial and the necessary data to support its initiation and are actively seeking a partner for this program."

DSMB • FDA event • Genetic Disorders • Hemophilia

[VIRTUAL] Subcutaneous Marzeptacog Alfa (Activated) is Effective Treatment of Bleeding in FVII Deficient Rats (ISTH 2021) - "Methods : Sprague Dawley rats were treated with intravenous (IV) vehicle or warfarin 0.3 mg/kg to induce FVIID...Rats were placed under isoflurane anesthesia for the TVT procedure...Conclusions : SQ MarzAA successfully treated induced bleeding in FVIID rats. These results provide robust nonclinical evidence that SQ MarzAA has the potential for prophylaxis or on-demand treatment of bleeding in patients with FVIID."

Preclinical • Anesthesia • Hematological Disorders

[VIRTUAL] Dose Selection for Subcutaneous Marzeptacog Alfa (Activated) in Subjects with Factor Vll Deficiency Using Population Pharmacometric Clinical Trial Simulations (ISTH 2021) - P1/2 | "Conclusions : The clinical trial simulations indicated that hemostasis may be achieved with the proposed doses and that good exposure levels may be sustained for 24 hours even in the 20 ug/kg dose group. The Phase 1/2 trial (NCT04548791) is currently enrolling participants."

Clinical • Hematological Disorders • Hemophilia • Rare Diseases

[VIRTUAL] Dose Selection of Marzeptacog Alfa (Activated) in Children with Hemophilia: A Population Pharmacokinetic Exposure Matching Strategy (ISTH 2021) - "Results : The relationship between MarzAA CL and BW was found to be non-linear with higher CL/kg at lower BW (Figure 1), with most of the non-linear trend below 14 kg, corresponding to the median BW in children of 2 years of age as described in The National Health and Nutrition Examination Survey (NHANES) database.Across all age groups using a single 60 μg/kg dose, the lower bound of the 95% PI of AUC0-24h in pediatrics was only slightly lower compared to that of adults, and a similar pattern was observed for Cmax (Figure 2), indicating comparable exposure across pediatric age groups compared to adults. Conclusions : The simulations support selecting a SQ dose of 60 μg/kg MarzAA in a clinical trial with pediatric subjects with HA/HB with inhibitors."

Clinical • PK/PD data • Hematological Disorders • Hemophilia • Pediatrics • Rare Diseases

Catalyst Biosciences Presents Four Posters at the International Society for Thrombosis and Haemostasis (ISTH) 2021 Virtual Congress (GlobeNewswire) - "Catalyst Biosciences, Inc...presented four posters at the International Society for Thrombosis and Haemostasis (ISTH) 2021 Virtual Congress, being held July 17-21, 2021...The population pharmacokinetics simulation supported selecting a 60 µg/kg SQ dose of MarzAA in a pediatric clinical trial, similar to the dose in the ongoing clinical trial in adult and adolescent subjects...The data demonstrated that formulation buffer composition affects DalcA MRGPRX2 (Mas-related Gprotein coupled receptor X2)-mediated cell activation in vitro...'The data support our approach in our ongoing trials of MarzAA in hemostasis, where we are enrolling patients in the Crimson 1 Phase 3 registrational study as well as in a Phase 1/2 trial.'"

Clinical data • Enrollment status • Preclinical • Genetic Disorders • Hemophilia

Catalyst Biosciences Announces Presentations at the International Society on Thrombosis and Haemostasis (GlobeNewswire) - "Catalyst Biosciences...announced four poster presentations on marzaptacog alfa (activated) (MarzAA) and dalcinanonog alfa (DalcA) at the upcoming International Society on Thrombosis and Haemostatis (ISTH) Virtual Congress being held from July 17-21, 2021."

Clinical protocol • Preclinical • Hemophilia

Catalyst Biosciences Receives FDA Fast Track Designation for Subcutaneous MarzAA for the Treatment of Episodic Bleeding in Factor VII Deficiency (GlobeNewswire) - "Catalyst Biosciences...announced the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation for Marzeptacog alfa (activated), MarzAA, the Company’s subcutaneously (SQ) administered next-generation engineered coagulation Factor VIIa (FVIIa) for the treatment of episodic bleeding in subjects with Factor VII deficiency."

Fast track designation • Hemophilia