FDA Accepts Genentech's Biologics License Application for Fixed-dose Subcutaneous Combination of Perjeta and Herceptin for HER2-Positive Breast Cancer

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has accepted the company's Biologics License Application (BLA) for the fixed-dose combination (FDC) of Perjeta^® (pertuzumab) and Herceptin^® (trastuzumab) with hyaluronidase, administered by subcutaneous (SC) injection in combination with intravenous (IV) chemotherapy, for the treatment of eligible patients with HER2-positive breast cancer. The BLA for the FDC is based on results from the Phase III FeDeriCa study, which demonstrated non-inferior levels of Perjeta in the blood (pharmacokinetics) and comparable efficacy and safety to standard IV infusions of Perjeta plus Herceptin and chemotherapy.

"For more than two decades, our medicines have redefined the standard of care for people with HER2-positive breast cancer," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "Today's acceptance builds upon our commitment by potentially offering patients a faster way to administer Perjeta and Herceptin. We're working with the FDA to bring this treatment option to patients as quickly as possible."

SC administration of the FDC takes approximately eight minutes for the initial loading dose and approximately five minutes for each subsequent maintenance dose. This is compared to approximately 150 minutes for infusion of a loading dose of Perjeta and Herceptin using the standard IV formulations, and between 60-150 minutes for subsequent maintenance infusions of the two medicines.

The FeDeriCa study met its primary endpoint, with SC administration of the FDC showing non-inferior levels of Perjeta in the blood during a given dosing interval (C_trough) when compared to IV administration of Perjeta. A secondary endpoint of non-inferior C_trough of Herceptin was also met. A non-inferiority endpoint was chosen for the study to ensure that people were receiving sufficient dosing with Perjeta and Herceptin as compared to the established IV doses at the same treatment intervals. In addition, rates of total pathological complete response (pCR), another secondary endpoint, were comparable between the treatment arms. The safety profile of the FDC in combination with chemotherapy was comparable to that of IV administration of Perjeta plus Herceptin and chemotherapy, and no new safety signals were identified, including no meaningful difference in cardiac toxicity. The most common adverse events in both arms were alopecia, nausea, diarrhea and anemia.

In previous studies of other SC formulations, SC administration has been shown to be strongly preferred by the majority of patients compared to IV administration of the same medicine, with the most common reason being that administration required less time in the clinic. In the PHranceSCa study, Genentech is currently investigating patient preference for SC administration of the FDC compared to standard IV administration of Perjeta and Herceptin in people with HER2-positive early breast cancer (EBC). Interim results of this Phase II study will be presented at a future medical meeting.

About the FeDeriCa study

FeDeriCa is an international, multi-center, two-arm, randomized, open-label, Phase III study evaluating the pharmacokinetics, efficacy, and safety of SC injection of the FDC of Perjeta and Herceptin in combination with chemotherapy, compared with standard IV infusion of Perjeta and Herceptin in combination with chemotherapy, in 500 people with HER2-positive early breast cancer (EBC) who are being treated in the neoadjuvant (before surgery) and adjuvant (after surgery) settings. The primary endpoint of the study is minimum levels of Perjeta in the blood during a given dosing interval (C_trough). Secondary endpoints include safety; minimum levels of Herceptin in the blood during a given dosing interval (C_trough); and total pCR, meaning there is no tumor tissue detectable in the tissue removed at the time of surgery. The safety profile of Perjeta and Herceptin FDC was comparable with that of Perjeta and Herceptin administered intravenously.

About HER2-positive breast cancer

Breast cancer is one of the most common cancers among women worldwide. According to the American Cancer Society, close to 280,000 people in the United States will be diagnosed with breast cancer, and more than 42,000 will die from the disease in 2020. Breast cancer is not one, but many diseases based on the biology of each tumor. In HER2-positive breast cancer, there is excess HER2 protein on the surface of tumor cells. Approximately 15-20% of breast cancers are HER2-positive based on the result of a diagnostic test.

About the FDC of Perjeta and Herceptin

The FDC of Perjeta and Herceptin is a new SC formulation that combines Perjeta and Herceptin with Halozyme Therapeutics' Enhanze^® drug delivery technology.

Trastuzumab in the FDC is the same monoclonal antibody as in IV Herceptin and pertuzumab in the FDC is the same monoclonal antibody as in IV Perjeta. The mechanisms of action of Perjeta and Herceptin are believed to complement each other as both bind to the HER2 receptor, but in different locations. The combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of the HER signaling pathways.

Halozyme's Enhanze drug delivery technology may enable and optimize SC drug delivery for appropriate co-administered therapeutics. The technology is based on a proprietary recombinant human hyaluronidase PH20 (rHuPH20), an enzyme that temporarily degrades hyaluronan ? a glycosaminoglycan or chain of natural sugars in the body, to aid in the dispersion and absorption of other injected therapeutic drugs.

Current Perjeta and Herceptin IV Indication Statements and Important Safety Information

Perjeta U.S. Indication

Perjeta (pertuzumab) is approved for use in combination with Herceptin (trastuzumab) and docetaxel in people who have HER2-positive breast cancer that has spread to different parts of the body (metastatic) and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

Perjeta (pertuzumab) is approved for use in combination with Herceptin (trastuzumab) and chemotherapy for:

• Use prior to surgery (neoadjuvant treatment) in people with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (tumor is greater than two centimeters in diameter or node-positive). Perjeta should be used as part of a complete treatment regimen for early breast cancer.
• Use after surgery (adjuvant treatment) in people with HER2-positive early breast cancer that has a high likelihood of coming back.

Important Safety Information

Side effects with Perjeta

• Not all people have serious side effects; however, side effects with Perjeta therapy are common. It is important for patients to know what side effects may happen and what symptoms patients should watch for.
• A patient's doctor may stop treatment if serious side effects happen. Patients should be sure to contact their healthcare team right away if they have questions or are worried about any side effects.

Most serious side effects of Perjeta
Perjeta may cause heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure).

• A patient's doctor may run tests to monitor the patient's heart function before and during treatment with Perjeta.
• Based on test results, a patient's doctor may hold or discontinue treatment with Perjeta.
• Patients should contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than five pounds in 24 hours, dizziness or loss of consciousness.

Receiving Perjeta during pregnancy can result in the death of an unborn baby and birth defects.

• Birth control should be used while receiving Perjeta and for seven months after a patient's last dose of Perjeta.
• If a patient is a mother who is breastfeeding, she should talk with her doctor about either stopping breastfeeding or stopping Perjeta.
• If a patient thinks she may be pregnant, she should contact her healthcare provider immediately.
• If a patient is exposed to Perjeta during pregnancy, or becomes pregnant while receiving Perjeta or within seven months following her last dose of Perjeta in combination with Herceptin, she is encouraged to report Perjeta exposure to Genentech at (888) 835-2555.

Other possible serious side effects

• Perjeta should not be used in patients who are allergic to pertuzumab or to any of the ingredients in Perjeta.
• Infusion-related reactions: Perjeta is a medicine that is delivered into a vein through a needle. Perjeta has been associated with infusion-related reactions, some fatal. The most common infusion-related reactions when receiving Perjeta, Herceptin and docetaxel were feeling tired, abnormal or altered taste, allergic reactions, muscle pain and vomiting. The most common infusion-related reactions when receiving Perjeta alone were fever, chills, feeling tired, headache, weakness, allergic reactions and vomiting. The most common infusion-related reactions when receiving Perjeta alone were fever, chills, feeling tired, headache, weakness, allergic reactions and vomiting.
• Severe allergic reactions: Some people receiving Perjeta may have severe allergic reactions, called hypersensitivity reactions or anaphylaxis, which may happen quickly and may affect many areas of the body. Severe allergic reactions, some fatal, have been observed in patients treated with Perjeta.

Most common side effects
The most common side effects of Perjeta when given with Herceptin and docetaxel for treatment of breast cancer that has spread to other parts of the body (metastatic) are:

• Diarrhea
• Hair loss
• Low levels of white blood cells with or without fever
• Nausea
• Feeling tired
• Rash
• Damage to the nerves (numbness, tingling, pain in hands/feet)

The most common side effects of Perjeta when given with Herceptin and chemotherapy as part of an early breast cancer regimen before surgery are:

• Constipation
• Damage to the nerves (numbness, tingling, pain in hands/feet)
• Diarrhea
• Feeling tired
• Hair loss
• Headache
• Low levels of red blood cells
• Low levels of white blood cells with or without fever
• Low platelet count
• Mouth blisters or sores
• Nausea
• Pain in the muscles
• Vomiting
• Weakness

Side effects may vary based on chemotherapy regimen.

The most common side effects of Perjeta when given with Herceptin and chemotherapy as part of an early breast cancer regimen after surgery are:

• Diarrhea
• Nausea
• Hair loss
• Feeling tired
• Damage to the nerves (numbness, tingling, pain in hands/feet)
• Vomiting

Patients are encouraged to report side effects to Genentech and the FDA. Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please see the Perjeta full Prescribing Information for additional Important Safety Information, including most serious side effects, at http://www.perjeta.com.

Herceptin U.S. Indication
Adjuvant Breast Cancer
Herceptin is approved for the treatment of early stage breast cancer that is Human Epidermal growth factor Receptor 2-positive (HER2-positive) and has spread into the lymph nodes, or is HER2-positive and has not spread into the lymph nodes. If it has not spread into the lymph nodes, the cancer needs to be estrogen receptor/progesterone receptor (ER/PR)-negative or have one high-risk feature.* Herceptin can be used in several different ways:

• As part of a treatment course including the chemotherapy drugs doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. This treatment course is known as "AC?TH."
• With the chemotherapy drugs docetaxel and carboplatin. This treatment course is known as "TCH."
• Alone after treatment with multiple other therapies, including an anthracycline (doxorubicin)-based therapy (a type of chemotherapy).

Patients are selected for therapy based on an FDA-approved test for Herceptin.

*High risk is defined as ER/PR-positive with one of the following features: tumor size greater than 2 cm, age less than 35 years, or tumor grade 2 or 3.

Metastatic Breast Cancer

Herceptin has two approved uses in metastatic breast cancer:

• Herceptin in combination with the chemotherapy drug paclitaxel is approved for the first-line treatment of Human Epidermal growth factor Receptor 2-positive (HER2-positive) metastatic breast cancer.
• Herceptin alone is approved for the treatment of HER2-positive breast cancer in patients who have received one or more chemotherapy courses for metastatic disease.

Patients are selected for therapy based on an FDA-approved test for Herceptin.

Important Safety Information
Possible serious side effects with Herceptin
Not all people have serious side effects, but side effects with Herceptin therapy are common.
Although some people may have a life-threatening side effect, most do not. A patient's doctor will stop treatment if any serious side effects occur.
Herceptin is not for everyone. A patient should be sure to contact their doctor if they are experiencing any of the following:
HEART PROBLEMS

These include heart problems?such as congestive heart failure or reduced heart function?with or without symptoms. The risk for and seriousness of these heart problems were highest in people who received both Herceptin and a certain type of chemotherapy (anthracycline). In a study of adjuvant (early) breast cancer, one patient died of significantly weakened heart muscle. A patient's doctor will check for signs of heart problems before, during, and after treatment with Herceptin.

INFUSION REACTIONS, including:

• Fever and chills
• Feeling sick to your stomach (nausea)
• Throwing up (vomiting)
• Pain (in some cases at tumor sites)
• Headache
• Dizziness
• Shortness of breath

These signs usually happen within 24 hours after receiving Herceptin.

A patient should be sure to contact their doctor if they:
Are a woman who could become pregnant, or may be pregnant

Herceptin may result in the death of an unborn baby or birth defects. Contraception should be used while receiving Herceptin and for seven months after a patient's last dose of Herceptin. If a patient is or becomes pregnant while receiving Herceptin or within seven months after their last dose of Herceptin, the patient should immediately report Herceptin exposure to Genentech at (888) 835-2555.

Have any signs of SEVERE LUNG PROBLEMS, including:

• Severe shortness of breath
• Fluid in or around the lungs
• Weakening of the valve between the heart and the lungs
• Not enough oxygen in the body
• Swelling of the lungs
• Scarring of the lungs

A patient's doctor may check for signs of severe lung problems when he or she examines the patient.

Have LOW WHITE BLOOD CELL COUNTS

Low white blood cell counts can be life-threatening. Low white blood cell counts were seen more often in patients receiving Herceptin plus chemotherapy than in patients receiving chemotherapy alone.

A patient's doctor may check for signs of low white blood cell counts when he or she examines the patient.

Side effects seen most often with Herceptin
Some patients receiving Herceptin for breast cancer had the following side effects:

• Fever
• Feeling sick to your stomach (nausea)
• Throwing up (vomiting)
• Infusion reactions
• Diarrhea
• Infections
• Increased cough
• Headache
• Feeling tired
• Shortness of breath
• Rash
• Low white and red blood cell counts
• Muscle pain

A patient should contact their doctor immediately if they have any of the side effects listed above.

Patients are encouraged to report side effects to Genentech and the FDA. Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please see the Herceptin full Prescribing Information for additional Important Safety Information, including most serious side effects, at http://www.herceptin.com.

About Genentech in breast cancer

Genentech has been advancing breast cancer research for more than 30 years with the goal of helping as many people with the disease as possible. Our medicines, along with companion diagnostic tests, have substantially improved outcomes for HER2-positive breast cancer. As our understanding of breast cancer biology rapidly improves, we are working to identify new biomarkers and approaches to treatment for other subtypes of the disease, including triple-negative and hormone receptor-positive.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.