FDA Approval Summary: Margetuximab plus Chemotherapy for Advanced or Metastatic HER2-Positive Breast Cancer.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.

Factor VIII associated with lipidic nanoparticles retains efficacy in the presence of anti-factor VIII antibodies in hemophilia A mice.

The development of inhibitory antibodies against factor VIII (FVIII) is a major challenge in hemophilia A (HA) therapy. Such antibodies develop in nearly 30% of patients receiving replacement FVIII, abrogating therapeutic efficacy. This work evaluated whether B-domain deleted FVIII encapsulated in phosphatidylinositol containing lipid nanoparticles (PI-BDD FVIII) could serve as an efficacious FVIII replacement therapy in the presence of inhibitors. The HA mice were given clinically relevant doses of FVIII to develop inhibitors. The efficacy of free and PI-BDD FVIII was studied in inhibitor-positive HA mice using a tail clip assay. Mathematical modeling of these data was conducted to evaluate the hypothesis that lipid association sterically shields the protein from inhibitor binding. The immunization protocol resulted in a mean inhibitory titer level of 198 ± 52 BU/ml. Free BDD FVIII was ineffective at controlling blood loss in inhibitor-positive HA mice as early as 2 h post dose. In contrast, PI-BDD FVIII treated animals retained partial hemostatic efficacy as long as 18 h post dose. Mathematical modeling supports the hypotheses that a greater fraction of lipid-associated FVIII remains unbound to inhibitors and that PI-BDD FVIII has lower binding affinity to inhibitors than does the free protein. In addition, the modeling approaches extend current efforts to model the impact of immunogenicity on PK and the therapeutically meaningful endpoint of efficacy, thereby addressing an important knowledge gap, particularly in the FVIII scientific literature. Clinical translation of these findings could result in a significant improvement in the quality of care of inhibitor-positive HA patients. Copyright © 2016 John Wiley & Sons, Ltd.

Soy Phosphatidylinositol-Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain-Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs.

Soy phosphatidylinositol (PI)-containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain-deleted factor VIII (BDD FVIII) in hemophilia A (HA) mice. We hypothesize that PI-associated BDD FVIII is more potent than the free protein and, using mathematical modeling, have projected that PI-associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI-associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. Two HA dogs were administered a 50-U/kg intravenous dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses such as whole blood clotting time and thromboelastography were conducted on recovered plasma and whole blood samples. PI association decreased clearance (∼25%) and increased plasma exposure (∼1.4-fold) of rcFVIII. PI-rcFVIII-treated animals had prolonged improvements in whole blood clotting time and thromboelastography parameters compared to free rcFVIII-treated animals. Because rcFVIII is a BDD form of FVIII, these studies provide proof of principle that observations with human BDD FVIII in mice translate to higher animal species. In addition, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients.

Soy phosphatidylinositol containing nanoparticle prolongs hemostatic activity of B-domain deleted factor VIII in hemophilia A mice.

Factor VIII (FVIII) replacement therapy in hemophilia A (HA) is complicated by a short half-life and high incidence of inhibitory antibody response against the protein. Phosphatidylinositol (PI) containing lipidic nanoparticles have previously been shown to reduce the immunogenicity and prolong the half-life of full length FVIII. It has not been established whether this prolongation in half-life improves hemostatic efficacy and whether this approach could be extended to the B-domain deleted form of FVIII (BDD FVIII). In the current study, we evaluated the pharmacokinetics (PK), hemostatic efficacy, and immunogenicity of BDD FVIII associated with PI nanoparticles (PI-BDD FVIII) in HA mice. Comparative human PK was predicted using an "informed scaling" approach. PI-BDD FVIII showed an approximate 1.5-fold increase in terminal half-life compared with free BDD FVIII following i.v. bolus doses of 40 IU/kg. PI-BDD FVIII-treated animals retained hemostatic efficacy longer than the free FVIII-treated group in a tail vein transection model of hemostasis. PI association reduced the development of inhibitory and binding antibodies against BDD FVIII after a series of i.v. injections. The combined improvements in circulating half-life and hemostatic efficacy could significantly prolong the time above clinically established therapeutic thresholds of prophylactic FVIII replacement therapy in humans.

Effects of replacement of factor VIII amino acids Asp519 and Glu665 with Val on plasma survival and efficacy in vivo.

Proteolytic cleavage of factor VIII (FVIII) to activated FVIIIa is required for participation in the coagulation cascade. The A2 domain is no longer covalently bound in the resulting activated heterotrimer and is highly unstable. Aspartic acid (D) 519 and glutamic acid (E) 665 at the A1-A2 and A2-A3 domain interfaces were identified as acidic residues in local hydrophobic pockets. Replacement with hydrophobic valine (V; D519V/E665V) improved the stability and activity of the mutant FVIII over the wild-type (WT) protein in several in vitro assays. In the current study, we examined the impact of mutations on secondary and tertiary structure as well as in vivo stability, pharmacokinetics (PK), efficacy, and immunogenicity in a murine model of Hemophilia A (HA). Biophysical characterization was performed with far-UV circular dichroism (CD) and fluorescence emission studies. PK and efficacy of FVIII was studied following i.v. bolus doses of 4, 10 and 40 IU/kg with chromogenic and tail clip assays. Immunogenicity was measured with the Bethesda assay and ELISA after a series of i.v. injections. Native secondary and tertiary structure was unaltered between variants. PK profiles were similar at higher doses, but at 4 IU/kg plasma survival of D519V/E665V was improved. Hemostasis at low concentrations was improved for the mutant. Immune response was similar between variants. Overall, these results demonstrate that stabilizing mutations in the A2 domain of FVIII can improve HA therapy in vivo.