pertuzumab - Perjeta; Omnitarg; 2C4
Status: marketed in U.S.; EU approval in March 2013
Organizations involved:
Genentech/Roche – Manuf.; R&D; Tech.; World mark.
Cross ref.: See the entry for Herceptin, with this product a similar monoclonal antibody.
Description: Perjeta is a formulation of pertuzumab, a recombinant humanized monoclonal antibody (MAb) that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein
(HER2 receptor). Pertuzumab is expressed by Chinese hamster ovary (CHO) cell culture containing the antibiotic, gentamicin (not detectable in the final product). Pertuzumab has an approximate molecular weight of 148 kDa. Perjeta represents a personalized
medicine to treat patients who are determined
through a genetic test to have HER2 positive
breast cancer.
Perjeta is a sterile, clear to slightly opalescent, colorless to pale brown liquid for intravenous
infusion packaged in 420 mg/14 mL (30 mg/mL) single-use vials.. Each single use vial contains 420 mg of pertuzumab at a concentration of 30 mg/mL in 20 mM L-histidine acetate (pH 6.0), 120 mM sucrose and 0.02% polysorbate 20. Perjeta is stored refrigerated [2°C to 8°C (36°F to 46°F)].
Like Herceptin, Perjeta is considered a personalized medicine. As with Herceptin, detection of HER2 protein overexpression is necessary for selection of patients appropriate for ERJETA therapy, because these are the only patients studied and for whom benefit has been
shown.
Nomenclature: HER2 receptor Mab, rDNA/2C4 [BIO]; Omnitarg [TR former]; Perjeta [TR; upon FDA approval]; pertuzumab [USAN INN]; pertuzumab (genetical recombination) [JAN]; Immunoglobulin G1, anti-(human v (receptor)) (human-mouse monoclonal 2C4 heavy chain), disulfide with human-mouse monoclonal 2C4 kappa-chain, dimer [CAS]; 380610-27-5 [CAS RN]; 2C4 [SY]; rhuMAb 2C4 [SY]; UNII-K16AIQ8CTM [SY]
Biological.: Perjeta is a personalized medicine that targets the HER2 receptor, a protein found in high quantities on the outside of cells in HER2-positive cancers. Perjeta is believed to work in a way that is complementary to Herceptin, as the two medicines target different regions on the HER2 receptor. Like trastuzumab (Herceptin), pertuzumab also targets the HER2 receptor, but as a HER dimerization inhibitor, or HDI, it inhibits the dimerization or 'pairing' of the HER2 protein with other members of the HER family of receptors: HER1/EGFR, HER3 and HER4 on the surface of cells, a process that is believed to play a role in tumor growth and survival. The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different regions. The combination of Perjeta, Herceptin and chemotherapy is thought to provide a more comprehensive blockade of HER signaling pathways.
Companies.: Perjeta was developed, is manufactured and worldwide marketing rights are held by Genentech/Roche.
FDA class: Biologics BLA
Approvals: Date = 20120608, full BLA
Date = 20130930, sBLA, accelerated approval of a Perjeta regimen (Perjeta, Herceptin and docetaxel); Indication = for neoadjuvant treatment (use before surgery) in people with high-risk, HER2-positive early stage breast cancer.
Indications: {Full text of the "INDICATIONS AND USAGE" section of the product insert/labeling, Oct, 2013];
PERJETA is a HER2/neu receptor antagonist indicated for:
Status: A BLA was filed in Feb. 2012 and granted priority review. The PDUFA (target decision) date was June 8, 2012. Omnitarg was developed and tested for use in patients with advanced HER2-positive breast cancer who have not received prior treatment or who have suffered a relapse following surgery, i.e., as first- and second-line therapy.
The U.S. product insert includes a black box warning regarding embryo-fetal toxicity:
"Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception."
With FDA approval, Genentech agreed to post-marketing commitments related to the manufacturing process for Perjeta. These included FDA review of data from the next several production runs.
In Dec. 2012, the European Union’s Committee for Medicinal Products for Human Use (CHMP) gave a positive opinion for the use of Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and docetaxel in patients with HER2-positive metastatic or locally recurrent unresectable breast cancer (mBC). The recommendation supported an indication for people with this specific type of cancer who have not received prior anti-HER2 therapy or chemotherapy for their metastatic disease. The CHMP opinion was based on positive overall survival and progression-free survival data from the Phase III CLEOPATRA study. Updated overall survival results showed the risk of death was reduced by 34 percent for people who received the Perjeta combination.
The EU granted approval to Perjeta on March 4 2013
Medical:
The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion,
followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion
over 30 to 60 minutes.
The most common side effects
observed in patients receiving Perjeta in
combination with trastuzumab and docetaxel
were diarrhea, hair loss, a decrease in
infection-fighting white blood cells, nausea,
fatigue, rash, and nerve damage (peripheral
sensory neuropathy). Perjeta is being
approved with a Boxed Warning alerting
patients and health care professionals to the
potential risk of death or severe effects to a
fetus. Pregnancy status must be verified prior
to the start of Perjeta treatment.
Trials: In its pivotal clinical trial, CLEOPATrA, patients previously untreated HER2-positive metastatic breast cancer (mBC) who received the combination of Perjeta, Herceptin and docetaxel chemotherapy lived a median of 6.1 months longer without their cancer getting worse (progression-free survival, or PFS) compared to Herceptin plus docetaxel chemotherapy (median PFS 18.5 vs. 12.4 months).
Overall survival data from the trial were not expected to be available until 2013, but the FDA apparently found the available progression-free survival data compelling enough to approve the BLA.
The FDA approval of Perjeta was based on results from CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab), an international, Phase III, randomized, double-blind, placebo-controlled study. CLEOPATRA evaluated the efficacy and safety profile of Perjeta combined with Herceptin and docetaxel chemotherapy compared to Herceptin and chemotherapy plus placebo in 808 people with previously untreated HER2-positive mBC or that had recurred after prior therapy in the adjuvant or neoadjuvant setting. The study showed people who received Perjeta in combination with Herceptin and chemotherapy experienced a 38% reduction in the risk of their disease worsening or death compared to people who received Herceptin and chemotherapy plus placebo (HR=0.62; p-value less than 0.0001, according to independent review). The study demonstrated a 6.1 month improvement in median PFS for people who received Perjeta compared to those who received Herceptin and chemotherapy plus placebo (median PFS 18.5 vs. 12.4 months).
Medical: The initial dose is 840 mg administered as a 60-minute intravenous
infusion, followed every 3 weeks thereafter by 420 mg administered as a
30 to 60 minute intravenous infusion.
In CLEOPATRA, the most common adverse reactions (rate greater than 30 percent) seen with Perjeta in combination with Herceptin and docetaxel were diarrhea, hair loss, low white blood cell count, nausea, fatigue, rash and peripheral neuropathy (numbness, tingling or burning sensation in the arms or legs). The most common Grade 3-4 adverse reactions (rate greater than 2 percent) were low white blood cell count, low white blood cell count with fever, decrease in a certain type of white blood cell, diarrhea, peripheral neuropathy, decrease in red blood cell count, weakness and fatigue.
As of FDA apprroval, "The combination of Perjeta, Herceptin and chemotherapy is the only regimen to have shown a significant improvement in PFS compared to Herceptin plus chemotherapy in people with previously untreated HER2-positive mBC."
Medical: The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion,
followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion
over 30 to 60 minutes.
In the randomized CLEOPATRA trial,
patients with breast cancer were required to have evidence of HER2 overexpression defined as
3+ IHC by Dako Herceptest™ or FISH amplification ratio 2.0 by Dako HER2 FISH
PharmDx™ test kit. Only limited data were available for patients whose breast cancer was
positive by FISH, but did not demonstrate protein overexpression by IHC.
Market: A typical 18-month course of Perjeta plus Herceptin costs approximately $188,000.
The combination course of treatment approved by FDA in fall 2013 will vary between 9 and 18 weeks and the costs from $27K to $49K depending on the duration of course. This bundling will help Roche to sustain its revenue from Herceptin biosimilar threats.
Roche reported total 2012 sales of $$61.2 million, with all but $2.2 million of this in the U.S.
In Aug. 2013, National Institute for Health and Care Excellence (NICE) jrejected Perjeta, stating that its ability to extend patients' lives is unclear and that it's far more costly than currently available treatments. [Recall: In studies in patients with advanced HER2-positive disease, the Perjeta combination with Herceptin and docetaxel stalled cancer growth 6 months longer than the two-drug combination did. But the evidence couldn't confirm how long Perjeta could extend patients' lives]. The The U.K. listed price is £2,395 per 420 mg vial, and the dosing schedule calls for an 840mg initial dose, with 420mg a week after that, NICE says. Total is about $190,000. Even Roche admitted the tripl combination was likely not cost-effective for the NHS.
Companies involvement:
Full monograph
179.2 HER2 receptor Mab, rDNA/2C4
Use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival.
Limitations of Use:
The safety of PERJETA as part of a doxorubicin-containing regimen has not been established.
The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established.
Nomenclature:
HER2 receptor Mab, rDNA/2C4 [BIO]
Omnitarg [TR prior to approval]
Perjeta [TR]
pertuzumab [USAN INN]
Pertuzumab (genetical recombination) [JAN]
Immunoglobulin G1, anti-(human v (receptor)) (human-mouse
monoclonal 2C4 heavy chain), disulfide with human-mouse
monoclonal 2C4 kappa-chain, dimer [CAS]
380610-27-5 [CAS RN]
2C4 [SY]
rhuMAb 2C4 [SY]
UNII-K16AIQ8CTM [SY]
NDC 50242-145-01 [NDC]
molecular weight (kDa) = 148
FDA Class: Biologic BLA
Year of approval (FDA) = 2012
Date of 1st FDA approval = 20120608
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
exempt from CBER lot release requirements
hamster source materials
monoclonal antibodies
monoclonal antibodies, recombinant
periplastic E. coli proteins (PECP)
recombinant DNA
Chinese hamster ovary (CHO) cells
genital warts
mammalian cell culture
gentamicin (gentamycin)
HER-2/neu (c-erbB2) proto-oncogene
histidine
polysorbate 20 (Tween 20)
receptors, epidermal growth factor
Absorbable Gelatin Sponge, USP
priority review status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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