Aphexda

APHEXDA is indicated in combination with filgrastim (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma.

For injection: 62 mg as a white to off-white lyophilized powder in a single-dose vial for reconstitution.

The following clinically significant adverse reactions are discussed in other sections of the labeling:

• Anaphylactic Shock and Hypersensitivity Reactions [see
  
  5.1 Anaphylactic Shock and Hypersensitivity Reactions

  Anaphylactic shock occurred in 0.7% of APHEXDA-treated patients in clinical studies (n=407). The time to anaphylactic shock was between 5 minutes and 30 minutes after drug administration. Hypersensitivity reactions occurred in 7.6% of APHEXDA-treated patients in the GENESIS study. In addition, pruritus, flushing, urticaria, rash, erythema, vomiting, nausea and chills have been reported.

  Premedicate all patients prior to each dose of APHEXDA 30-60 minutes prior to administration with a triple-drug premedication regimen that includes an H1-antihistamine, an H2 blocker, and a leukotriene inhibitor [see

  Dosage and Administration (2.1)

  ]. Patients receiving concomitant negative chronotropic drugs (e.g., beta blockers) may be more at risk for hypotension in case of hypersensitivity reaction. When appropriate, beta blockers should be replaced with non-chronotropic drugs.

  Administer APHEXDA only in a setting where personnel and therapies are immediately available for the treatment of anaphylaxis and other systemic reactions. Monitor patients for signs or symptoms of hypersensitivity reactions for one hour following administration of APHEXDA and manage reactions promptly.
  ]
  
• Injection Site Reactions [see
  
  5.2 Injection Site Reactions

  Injection site reactions were reported in 73% of patients receiving APHEXDA in the GENESIS trial. Symptoms of injection site reactions included pain, erythema, pruritus, bruising, discomfort, induration, mass, nodule, rash, swelling, and urticaria. Among 92 patients treated with APHEXDA, the highest severity of the reactions was severe in 9%.

  Premedicate with an analgesic medication (e.g., acetaminophen) prior to each APHEXDA dose. Use analgesic medication and local treatments postdose, as needed.
  ]
  
• Potential for Tumor Cell Mobilization in Patients in Leukemia [see
  
  5.3 Tumor Cell Mobilization in Patients with Leukemia

  For the purpose of hematopoietic stem cell (HSC) mobilization, APHEXDA may cause mobilization of leukemic cells and subsequent contamination of the apheresis product. Therefore, APHEXDA is not intended for HSC mobilization and harvest in patients with leukemia.
  ]
  
• Leukocytosis [see
  
  5.4 Leukocytosis

  Administration of APHEXDA in conjunction with filgrastim increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during APHEXDA use.
  ]
  
• Potential for Tumor Cell Mobilization [see
  
  5.5 Potential for Tumor Cell Mobilization

  When APHEXDA is used in combination with filgrastim for HSC mobilization, tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumor cells has not been well-studied.
  ]
  

APHEXDA for injection contains motixafortide, which is a hematopoietic stem cell mobilizer. The chemical name of the synthetic motixafortide acetate, the active pharmaceutical ingredient is N-(4-Fluoro-benzoyl)-L-arginyl-L-arginyl-[L-3-naphthyl)alanyl]-L-cysteinyl-L-tyrosyl
⁵-L-citrullinyl-L-lysyl-D-lysyl-L-prolyl-L-tyrosyl
¹⁰-L‑arginyl-L-citrullinyl-L-cysteinyl-L-arginineamide, cyclic (4-13)-disulfide, acetate salt. Motixafortide acetate is a synthetic, cyclic peptide composed of a sequence of amino acids with the following structure:

APHEXDA is supplied as a sterile white to off-white, preservative-free lyophilized powder in single-dose vials. Each vial contains 73 mg of motixafortide (provided as motixafortide acetate) for reconstitution with 2 mL 0.45% saline, delivering 62 mg motixfortide per 1.7 mL. Motixafortide is present as a salt with 4 to 8.5 molar equivalents of acetate. The inactive ingredients include 26 mg of mannitol and hydrochloric acid for pH adjustment.

Reconstitution with 2 mL of 0.45% sodium chloride for injection (or 1 mL water for injection + 1 mL 0.9% sodium chloride for injection) yields a clear solution of 36.5 mg/mL motixafortide, pH 5.8 to 7.5.

The efficacy of APHEXDA in combination with filgrastim was evaluated in the GENESIS study (NCT 03246529). In this randomized, double-blind, placebo-controlled study, 122 patients with multiple myeloma were randomized in a 2:1 ratio to receive APHEXDA 1.25 mg/kg subcutaneously (N=80) or placebo (N=42). Prior to receiving APHEXDA or placebo, patients received daily morning doses of filgrastim 10-15 mcg/kg for 4 days. On the evening of Day 4, patients received APHEXDA or placebo. On Day 5, patients received a fifth morning dose of filgrastim within 1 hour prior to their first apheresis (12 hours ± 2 hours from the APHEXDA/placebo administration). The apheresis cell collection goal for the study was ≥ 6 × 10
⁶ CD34+ cells/kg. The assessment of CD34+ cells was performed by central and local laboratories. Central laboratory assessments were used for the efficacy results. Local laboratory results were used for clinical treatment decisions.

In the event that the cell collection goal was not achieved with the first apheresis on Day 5, patients received another morning dose of filgrastim on Day 6 within 1 hour prior to their second apheresis. In the event that the cell collection goal was still not achieved, patients received a second administration of APHEXDA or placebo on the evening of Day 6 and a seventh dose of filgrastim in the morning of Day 7 within 1 hour prior to a third apheresis. If the collection goal was not achieved, patients received an eighth dose of filgrastim in the morning of Day 8 within 1 hour prior to a fourth apheresis.

The median age of the study population was 63 years (range 34-75); 65% were males, 86% Caucasian, 8% African American, 2% Asian and 10% were of Hispanic or Latino ethnicity. Seventy percent of patients were previously treated with lenalidomide.

The efficacy of APHEXDA was based upon the proportion of patients who achieved a cell collection goal of ≥ 6 × 10
⁶ CD34+ cells/kg in up to 2 aphereses after administration of filgrastim and a single administration of APHEXDA or placebo.

Efficacy results showed that 67.5% of patients in the APHEXDA treatment arm versus 9.5% in the placebo arm achieved the cell collection goal of ≥ 6 × 10
⁶ CD34+ cells/kg in up to 2 aphereses after a single administration of APHEXDA or placebo, resulting in an adjusted difference between treatment arms of 56.8% (p < 0.0001) (Table 3).

*The reported p values are two sided based on the Cochran-Mantel-Haenszel common proportion difference method stratifying for response status (CR or PR) at baseline and to baseline platelet count (<200 × 10
⁹/L or ≥ 200 × 10
⁹/L).

Multiple factors can influence time to engraftment and graft durability following stem cell transplantation. In the GENESIS study, time to neutrophil and platelet engraftment and graft durability following transplantation were similar across treatment groups.