On February 26, 2016 Novartis reported that the United States Food and Drug Administration (FDA) approved Afinitor (everolimus) tablets for the treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic (Press release, Novartis, FEB 26, 2016, View Source [SID:1234509242]).

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Afinitor received a priority review designation providing a shortened review period for drugs that treat serious conditions and offer a significant improvement in safety or effectiveness.

"Afinitor is the first treatment approved for progressive, nonfunctional NET of lung origin, and one of very few options available for progressive, nonfunctional GI NET, representing a shift in the treatment paradigm for these cancers," said Bruno Strigini, President, Novartis Oncology. "We are proud of our Afinitor development program, which has translated to meaningful benefits for patients with several different cancers and rare diseases."

Neuroendocrine tumors are a rare type of cancer that originate in neuroendocrine cells throughout the body, and are most often found in the GI tract, lungs or pancreas[1],[4]. NET can be defined as functional or nonfunctional. Functional NET are characterized by symptoms caused by the oversecretion of hormones and other substances. Nonfunctional NET may be characterized by symptoms caused by tumor growth, such as intestinal obstruction, pain and bleeding for GI NET, and asthma, chronic obstructive pulmonary disease and pneumonia for lung NET[5],[6],[7],[8]. More than 70% of patients with NET have nonfunctional tumors[9]. At the time of diagnosis, 5%-44% (depending on site of tumor origin) of patients with NET in the GI tract and 28% of patients with lung NET have advanced disease, meaning the cancer has spread to other areas of the body, making it difficult to treat[1],[4]. Progression, or the continued growth or spread of the tumor, is typically associated with poor outcomes[10].

The approval of Afinitor was based on efficacy and safety data from a pivotal study (RADIANT-4) showing Afinitor reduced the risk of progression in patients with progressive, well-differentiated, nonfunctional NET of GI or lung origin by 52% (hazard ratio [HR] = 0.48; 95% confidence interval [CI], 0.35-0.67; p<0.001) vs placebo. Additionally, the data showed Afinitor increased median progression-free survival (PFS) by 7.1 months: median PFS by central review was 11.0 months (95% CI, 9.2-13.3) in the Afinitor arm and 3.9 months (95% CI, 3.6-7.4) in the placebo arm[3].

In the pivotal trial, the most common treatment-related grade 3/4 adverse events (AEs) (>=5%) for Afinitor and placebo, respectively, were infections (11.0% vs 2.0%), diarrhea (9.0% vs 2.0%), stomatitis (9.0% vs 0.0%), fatigue (5.0% vs 1.0%) and hyperglycemia (5.0% vs 0.0%)[3].

Additional worldwide regulatory filings for this indication are underway, with a decision in the EU anticipated in 2016.

RADIANT-4 Study: Part of the largest clinical trial program in advanced NET
RADIANT-4 (RAD001 In Advanced Neuroendocrine Tumors) is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. It examined the efficacy and safety of Afinitor plus best supportive care (BSC) vs placebo plus BSC in 302 patients with unresectable, progressive, well-differentiated, nonfunctional, locally advanced or metastatic NET of GI (excluding pancreatic) or lung origin. The major efficacy outcome measure of RADIANT-4 was PFS based on independent radiological assessment evaluated by Response Evaluation Criteria in Solid Tumors. Additional efficacy outcome measures were overall survival and best overall response rate (defined as complete response plus partial response)[3].

Patients were randomized 2:1 to receive daily Afinitor 10 mg or daily placebo orally. All patients received BSC during treatment, which excluded somatostatin analogues (SSAs). Patients had low or intermediate grade histology, no history or active symptoms of carcinoid syndrome, had documented disease progression within the previous 6 months and were required to have ceased treatment with SSAs for 4 weeks before study entry[3],[11].

The safety profile of Afinitor was consistent with what has been observed in previous studies of this drug. The most common treatment-related, all-grade AEs (incidence >=30%) were stomatitis (63%), infections (58%), diarrhea (41%), peripheral edema (39%), fatigue (37%) and rash (30%). Afinitor was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of Afinitor-treated patients[3].

About Afinitor (everolimus) tablets
Afinitor (everolimus) tablets is now approved by the United States (US) Food and Drug Administration (FDA) for the treatment of adult patients with progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Additionally, Afinitor is approved in 99 countries, including the US and throughout the European Union, for locally advanced, metastatic or unresectable progressive NET of pancreatic origin. It is also approved in >120 countries including the US and European Union for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy (in the US, specifically following sunitinib and sorafenib).

Afinitor is also approved in 102 countries including the US and European Union for advanced HR+/HER2- breast cancer in combination with exemestane, after prior endocrine therapy.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor or Votubia, Certican and Zortress and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets
Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors may be at an increased risk for angioedema. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, infections (including upper respiratory tract infection, sore throat and runny nose, sinusitis, middle ear infection and pneumonia), absence of menstrual periods, high levels of cholesterol, nausea, decreased appetite, low level of red blood cells, acne, abnormal taste, irregular menstrual periods, inflammation of lung tissue, swelling of extremities or other parts of the body, high level of blood sugar, itching, weight loss, nose bleeds, cough and headache. The most common grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, infections (including pneumonia), low level of red blood cells, absence of menstrual periods, high level of blood sugar, feeling tired or weak, diarrhea, low white blood cells, inflammation of lung tissue and spontaneous bleeding or bruising. Cases of hepatitis B reactivation, blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

On February 26, 2016 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that the U.S. Food and Drug Administration (FDA) approved Gazyva(obinutuzumab) plus bendamustine chemotherapy followed by Gazyva alone as a new treatment for people with follicular lymphoma who did not respond to a Rituxan (rituximab)-containing regimen, or whose follicular lymphoma returned after such treatment (Press release, Genentech, FEB 26, 2016, View Source [SID:1234509241]).

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Follicular lymphoma is the most common type of indolent (slow-growing) non-Hodgkin’s lymphoma (NHL) and accounts for approximately one in five cases of NHL.

"People with follicular lymphoma whose disease returns or worsens despite treatment with a Rituxan-containing regimen need more options because the disease becomes more difficult to treat each time it comes back," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Gazyva plus bendamustine provides a new treatment option that can be used after relapse to significantly reduce the risk of progression or death."

The approval is based on results from the Phase III GADOLIN study, which showed that, in people with follicular lymphoma whose disease progressed during or within six months of prior Rituxan-based therapy, Gazyva plus bendamustine followed by Gazyva alone demonstrated a 52 percent reduction (HR=0.48, 95 percent CI 0.34-0.68, p<0.0001) in the risk of disease worsening or death (progression-free survival, PFS), compared to bendamustine alone, as assessed by an independent review committee (IRC). The supplemental Biologics License Application based on these data was granted Priority Review, a designation granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.

The safety of Gazyva was evaluated based on 392 people in the GADOLIN study with indolent NHL of whom 81 percent had follicular lymphoma. The most common Grade 3-4 side effects of this Gazyva regimen were low white blood cell counts, infusion reactions and low platelet counts. The most common side effects of this Gazyva regimen were infusion reactions, low white blood cell counts, nausea, fatigue, cough, diarrhea, constipation, fever, low platelet counts, vomiting, upper respiratory tract infection, decreased appetite, joint or muscle pain, sinusitis, low red blood cell counts, general weakness and urinary tract infection.

With this approval, Gazyva is approved in the United States to treat two common types of blood cancer. Gazyva is also approved in combination with chlorambucil for people with previously untreated chronic lymphocytic leukemia (CLL) based on data from the pivotal CLL11 study, which compared Gazyva plus chlorambucil head-to-head with Rituxan plus chlorambucil.

Marketing applications for Gazyva based on the GADOLIN study results have also been submitted to other regulatory authorities, including the European Medicines Agency (EMA), for approval consideration.

For those who qualify, Genentech offers patient assistance programs for people taking Gazyva through Genentech Access Solutions.

About the GADOLIN Study

GADOLIN (NCT01059630; GA04753g) is a Phase III open-label, multicenter, randomized two-arm study evaluating Gazyva plus bendamustine followed by Gazyva alone until disease progression or for up to two years compared to bendamustine alone. GADOLIN included 413 patients with indolent (slow-growing) non-Hodgkin’s lymphoma (NHL), including 321 patients with follicular lymphoma, whose disease progressed during or within six months of prior Rituxan-based therapy. The primary endpoint of the study is progression-free survival (PFS) as assessed by an independent review committee (IRC), with secondary endpoints including PFS as assessed by investigator review, best overall response (BOR), complete response (CR), partial response (PR), duration of response, overall survival (OS) and safety profile. Results in follicular lymphoma showed:

The Gazyva regimen improved PFS compared to bendamustine alone, as assessed by IRC (HR=0.48, 95 percent CI 0.34-0.68, p<0.0001). Median PFS was not reached in those receiving the Gazyva regimen versus 13.8 months in those receiving bendamustine alone.

Investigator-assessed PFS was consistent with IRC-assessed PFS. As assessed by investigator review, median PFS with the Gazyva regimen was more than double that with bendamustine alone (29.2 months vs. 13.7 months; HR=0.48, 95 percent CI 0.35-0.67, p<0.0001).

In addition, BOR for those receiving the Gazyva regimen was 78.7 percent (15.5 percent CR, 63.2 percent PR) compared to 74.7 percent for those receiving bendamustine alone (18.7 percent CR, 56 percent PR), as assessed by IRC.

The median duration of response was not reached for those receiving the Gazyva regimen and was 11.6 months for those receiving bendamustine alone.

The Gazyva regimen reduced the risk of death (OS) by 38 percent compared to bendamustine alone based on a post-hoc analysis with 24.1 months of median observation time (HR=0.62, 95 percent CI 0.39-0.98). The median OS has not yet been reached in either study arm.

The most common Grade 3-4 side effects observed in those receiving the Gazyva regimen were low white blood cell counts (33 percent), infusion reactions (11 percent) and low platelet counts (10 percent). The most common side effects were infusion reactions (69 percent), low white blood cell counts (35 percent), nausea (54 percent), fatigue (39 percent), cough (26 percent), diarrhea (27 percent), constipation (19 percent), fever (18 percent), low platelet counts (15 percent), vomiting (22 percent), upper respiratory tract infection (13 percent), decreased appetite (18 percent), joint or muscle pain (12 percent), sinusitis (12 percent), low red blood cell counts (12 percent), general weakness (11 percent) and urinary tract infection (10 percent).
About Follicular Lymphoma

Follicular lymphoma is the most common indolent (slow-growing) form of non-Hodgkin’s lymphoma (NHL), accounting for about one in five cases of NHL. It is considered incurable and relapse is common. In the United States, it was estimated that more than 14,000 new cases of follicular lymphoma would be diagnosed in 2015.

About Genentech Access Solutions

Access Solutions is part of Genentech’s commitment to helping people access the Genentech medicines they are prescribed, regardless of their ability to pay. The team of 350 in-house specialists at Access Solutions is dedicated to helping people navigate the access and reimbursement process, and to providing assistance to eligible patients in the United States who are uninsured or cannot afford the out-of-pocket costs for their medicine. To date, the team has helped more than 1.2 million patients access the medicines they need. Please contact Access Solutions (866) 4ACCESS/(866) 422-2377 or visit View Source for more information.

About Gazyva

Gazyva is an engineered monoclonal antibody designed to attach to CD20, a protein found only on B-cells. It attacks targeted cells both directly and together with the body’s immune system. Gazyva was discovered by Roche Glycart AG, a wholly owned, independent research unit of Roche. In the United States, Gazyva is part of a collaboration between Genentech and Biogen.

Gazyva is being studied in a large clinical program, including the Phase III GOYA and GALLIUM studies. GOYA is comparing Gazyva head-to-head with Rituxan plus CHOP chemotherapy in first line diffuse large B-cell lymphoma (DLBCL) and GALLIUM is comparing Gazyva plus chemotherapy head-to-head with Rituxan plus chemotherapy in first line indolent non-Hodgkin’s lymphoma (NHL). Additional combination studies investigating Gazyva with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are planned or underway across a range of blood cancers.

Gazyva U.S. Indications

Gazyva (obinutuzumab) is a prescription medicine used:

With the chemotherapy drug, chlorambucil, to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment.

With the chemotherapy drug, bendamustine, followed by Gazyva alone for follicular lymphoma (FL) in adults who did not respond to a rituximab-containing regimen, or whose FL returned after such treatment.

Important Safety Information

Patients must tell their doctor right away about any side effects they experience. Gazyva can cause side effects that can become serious or life threatening, including:

Hepatitis B Virus (HBV): Hepatitis B can cause liver failure and death. If a patient has had history of hepatitis B infection, Gazyva could cause it to return. Patients should not receive Gazyva if they have active hepatitis B liver disease. The patient’s doctor or healthcare team will need to screen for hepatitis B before, and monitor the patient for hepatitis during and after, treatment with Gazyva. Sometimes this will require treatment for hepatitis B. Symptoms of hepatitis include: worsening of fatigue and yellow discoloration of skin or eyes.

Progressive Multifocal Leukoencephalopathy (PML): PML is a rare and serious brain infection caused by a virus. PML can be fatal. A patient’s weakened immune system could put the patient at risk. The patient’s doctor will watch for symptoms. Symptoms of PML include: confusion, difficulty talking or walking, dizziness or loss of balance, and vision problems.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effects they experience. Gazyva can cause side effects that may become severe or life threatening, including:

Infusion Reactions: These side effects may occur during or within 24 hours of any Gazyva infusion. Some infusion reactions can be serious, including, but not limited to, severe allergic reactions (anaphylaxis), acute life-threatening breathing problems, or other life-threatening infusion reactions. If a patient has a reaction, the infusion is either slowed or stopped until the patient’s symptoms are resolved. Most patients are able to complete infusions and receive medication again. However, if the infusion reaction is serious, the infusion of Gazyva will be permanently stopped. The patient’s healthcare team will take steps to help lessen any side effects the patient may have to the infusion process. The patient may be given medicines to take before each Gazyva treatment. Signs of infusion reactions may include: tiredness, dizziness, headache, redness of the face, nausea, chills, fever, vomiting, diarrhea, breathing problems, and chest pain

Tumor Lysis Syndrome (TLS): Tumor lysis syndrome, including fatal cases, has been reported in patients receiving Gazyva. Gazyva works to break down cancer cells quickly. As cancer cells break apart, their contents are released into the blood. These contents may cause damage to organs and the heart, and may lead to kidney failure requiring the need for dialysis treatment. The patient’s doctor may prescribe medication to help prevent TLS. The patient’s doctor will also conduct regular blood tests to check for TLS. Symptoms of TLS may include nausea, vomiting, diarrhea, and tiredness

Infections: While a patient is taking Gazyva, the patient may develop infections. Some of these infections may be severe. Fatal infections have been reported, so the patient should be sure to talk to the doctor if the patient thinks the patient has one. Patients with active infection should not be treated with Gazyva. The patient’s risk for infections may continue even after the patient stops taking Gazyva. The patient’s doctor may prescribe medications to help prevent infections. Symptoms of infection include fever and cough

Low White Blood Cell Count: When a patient has an abnormally low count of infection-fighting white blood cells, it is called neutropenia. While the patient is taking Gazyva, the patient’s doctor will do blood work to check the patient’s white blood cell counts. Severe and life-threatening neutropenia can develop during or after treatment with Gazyva. Some cases of neutropenia can last for more than one month. If a patient’s white blood cell count is low, the patient’s doctor may prescribe medication to help prevent infections

Low Platelet Count: Platelets help stop bleeding or blood loss. Gazyva may reduce the number of platelets the patient has in the blood; having low platelet count is called thrombocytopenia. This may affect the clotting process. While the patient is taking Gazyva, the patient’s doctor will do blood work to check the patient’s platelet count. Severe and life-threatening thrombocytopenia can develop during or after treatment with Gazyva. If the patient’s platelet count gets too low, the treatment may be delayed or reduced
Most common side effects of Gazyva

The most common side effects of Gazyva in CLL are infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

The safety of Gazyva was evaluated based on 392 patients with indolent NHL (iNHL) of whom 81 percent had follicular lymphoma. In patients with follicular lymphoma, the most common side effects that were seen were consistent with the overall population who had iNHL. The most common side effects of Gazyva are infusion reactions, low white blood cell counts, nausea, fatigue, cough, diarrhea, constipation, fever, low platelet counts, vomiting, upper respiratory tract infection, decreased appetite, joint or muscle pain, sinusitis, low red blood cell counts, general weakness, and urinary tract infection.

Before receiving Gazyva, patients should talk to their doctor about:

Immunizations: Before receiving Gazyva therapy, the patient should tell the patient’s healthcare provider if the patient has recently received or is scheduled to receive a vaccine. Patients who are treated with Gazyva should not receive live vaccines.

Pregnancy: A patient should tell the doctor if the patient is pregnant, plans to become pregnant, or is breastfeeding. Gazyva may harm the unborn baby. Mothers who have been exposed to Gazyva during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers. It is not known if Gazyva may pass into the patient’s breast milk. The patient should speak to the doctor about using Gazyva if the patient is breastfeeding.

Patients must tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the Gazyva full Prescribing Information, including Boxed WARNINGS, for additional Important Safety Information.

Rituxan Indications

Rituxan (rituximab) is indicated for the treatment of patients with:

Low-grade or follicular CD20-positive non-Hodgkin’s lymphoma as a single-agent therapy in patients whose disease recurred or did not respond to initial treatment

Follicular CD20-positive non-Hodgkin’s lymphoma as an initial treatment with chemotherapy, and in patients whose initial treatment was successful, as a single-agent follow-up therapy

Low-grade or follicular CD20-positive non-Hodgkin’s lymphoma as a single-agent follow-up therapy for patients who responded to initial treatment with CVP chemotherapy

CD20-positive diffuse large B-cell non-Hodgkin’s lymphoma as an initial treatment in combination with CHOP chemotherapy

CD20-positive chronic lymphocytic leukemia in combination with FC chemotherapy as an initial treatment or as a treatment after disease has recurred

People with serious infections should not receive Rituxan.

Important Safety Information:

Patients must tell their doctor right away about any side effects they experience. Rituxan can cause serious side effects that can lead to death, including:

Infusion Reactions: may occur during or within 24 hours of the infusion. The patient’s doctor should give the patient medicines before their treatment. Symptoms can include hives, rash, itching, facial or oral swelling, sudden cough, shortness of breath, difficulty breathing, weakness, dizziness, feeling faint, racing heart or chest pain.

Severe Skin and Mouth Reactions: symptoms can include painful sores, ulcers, or blisters on the skin, lips or mouth; peeling skin; rash; or pustules.

Hepatitis B Virus (HBV) Reactivation: may cause serious liver problems including liver failure and death. If patients have had hepatitis B or are carriers of HBV, receiving Rituxan could cause the virus to become an active infection again. Patients should not receive Rituxan if they have active HBV liver disease. The patient’s doctor will do blood tests to check for HBV infection prior to treatment and will monitor the patient during and for several months following their treatment.

Progressive Multifocal Leukoencephalopathy (PML): a rare, serious brain infection that can lead to severe disability and death and for which there is no known prevention, treatment or cure. Symptoms can include difficulty thinking, loss of balance, changes in speech or walking, weakness on one side of the body or blurred or lost vision.

What are the additional possible serious side effects of Rituxan?

Patients must tell their doctor right away about any side effects they experience. Rituxan can cause serious side effects that can lead to death, including:

Tumor Lysis Syndrome (TLS): may cause kidney failure and the need for dialysis treatment, abnormal heart rhythm and can lead to death. The patient’s doctor may give the patient medicines before their treatment to help prevent TLS.

Serious Infections: can happen during and after treatment and can lead to death. These infections may be bacterial, fungal or viral. Symptoms can include fever; cold or flu symptoms; earache or headache; pain during urination; white patches in the mouth or throat; cuts or scrapes that are red, warm, swollen or painful.

Heart Problems: symptoms can include chest pain and irregular heartbeats that may require treatment. The patient’s doctor may need to stop their treatment.

Kidney Problems: the patient’s doctor should do blood tests to check how well the patient’s kidneys are working.
Stomach and Serious Bowel Problems: can include blockage or tears in the bowel that can lead to death. Stomach area pain during treatment can be a symptom.

Low Blood Cell Counts: the patient’s blood cell counts may be monitored during treatment.
The most common side effects of Rituxan are infusion reactions, chills, infections, body aches, tiredness and low white blood cells.

Patients must tell their doctor if they are pregnant, plan to become pregnant or are breastfeeding. It is not known if Rituxan may harm the patient’s unborn baby or pass into the patient’s breast milk. Women should use birth control while using Rituxan and for 12 months after treatment.

Patients must tell their doctor about any side effect that bothers them or that does not go away.

These are not all of the possible side effects of Rituxan. For more information, patients should ask their doctor or pharmacist.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the Rituxan full Prescribing Information, including Boxed WARNINGS and Medication Guide, for additional Important Safety Information.

On February 26, 2016 Takeda Pharmaceutical Company Limited (TSE: 4502) reported that the Japanese Ministry of Health, Labour and Welfare has granted Orphan Drug designation* to ixazomib (generic name, development code: MLN9708), an investigational oral proteasome inhibitor for the treatment of patients with relapsed and/or refractory multiple myeloma (Press release, Takeda, FEB 26, 2016, View Source [SID:1234509221]). The Orphan Drug designation is a system for supporting and promoting the development of drugs that are not sufficiently researched and developed due to a small number of patients, regardless of high medical need.

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Ixazomib’s phase 3 trials for patients with multiple myeloma are now being conducted in Japan. The drug became available in the U.S., under the brand name NINLARO, in December, 2015 after the U.S. Food and Drug Administration (FDA) approval as a treatment for patients with relapsed and/or refractory multiple myeloma who have received at least one prior therapy. The drug is currently under review in the European Union. The European Medicines Agency (EMA) granted ixazomib an accelerated assessment in July 2015 and accepted its Marketing Authorization Application (MAA) in August 2015 for the treatment of patients with relapsed and/or refractory multiple myeloma.

This Orphan Drug designation reflects the high medical need for oral proteasome inhibitor ixazomib as a potential new treatment option for patients with multiple myeloma in Japan, and further demonstrates Takeda’s commitment to putting the patient at the center. Takeda will continue its development activities so that this innovative drug can be delivered to Japanese patients as soon as possible.

* The designation is granted by the Minister of Health, Labour and Welfare for drugs that meet the designation criteria, which include the following: the number of patients who may use the drug is less than 50,000 in Japan; there is no alternative appropriate drug or treatment; high efficacy or safety is expected compared to existing products; there is a theoretical rationale for using the product for the target disease and the development plan is appropriate. If a product is designated as an orphan drug, support such as subsidies, guidance and consultation on research and development activities by the Minister of Health, Labour and Welfare, preferential tax treatment, priority review, and extension of re-examination period will become available.

About ixazomib and the TOURMALINE Trials
Ixazomib (MLN9708) is an investigational oral proteasome inhibitor which is being studied in multiple myeloma, systemic light-chain (AL) amyloidosis, and other malignancies. It is the first oral proteasome inhibitor to enter Phase 3 clinical trials.

Ixazomib was granted orphan drug designation in multiple myeloma in both the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014. Ixazomib was launched in the U.S. in December, 2015 under the brand name NINLARO, and is also currently under review by the European Medicines Agency for the treatment of patients with relapsed and/or refractory multiple myeloma.

The comprehensive ixazomib clinical development program, TOURMALINE, further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. TOURMALINE includes a total of five ongoing pivotal trials – four investigating every major multiple myeloma patient population and one in light-chain amyloidosis:

ž TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. This trial is currently ongoing, and patients continue to be treated to progression and will be evaluated for long-term outcomes.

ž TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma

ž TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)

ž TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT

ž TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis

About Multiple Myeloma
Multiple myeloma is a cancer of the plasma cells, which are found in the bone marrow. In multiple myeloma, a group of monoclonal plasma cells, or myeloma cells, becomes cancerous and multiplies. These malignant plasma cells have the potential to affect many bones in the body, possibly resulting in compression fractures, lytic bone lesions and related pain. Multiple myeloma can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count, with some of the more common symptoms including bone pain and fatigue, a symptom of anemia. Multiple myeloma is a rare form of cancer, with 114,000 new cases globally per year. It is reported that there are approximately 14,000 patients with multiple myeloma in Japan.

On February 26, 2016 PharmaMar (MSE:PHM) reported the start of an open-label multi-centre two-stage Phase II trial with the anti-tumour drug PM184. The trial will be conducted in 10 European clinical centres and will include 106 patients (Press release, PharmaMar, FEB 26, 2016, View Source [SID:1234509220]). The trial will focus on patients with hormone-receptor positive, HER2-negative, locally advanced and/or metastatic breast cancer, who have experienced progression following earlier treatment with anthracyclines and taxanes. The second stage of this Phase II trial will be randomised vs. investigator’s best choice, to assess the efficacy and safety of PM184.

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The primary endpoint is to evaluate the efficacy of PM184 with regard to fourmonth progression free survival (PFS). Secondary endpoints include analysing a more convenient administration pattern for PM184, overall survival, median PFS, overall response, and response duration measured in accordance with RECIST (Response Evaluation Criteria In Solid Tumors) Guideline Version 1.1. The trial will also assess safety and pharmacological profiles in the target population, and perform pharmacogenetic analyses to examine inter-patient variations in the transformation and elimination of PM184, together with pharmacogenomic studies that will contribute to identifying predictors of the response to the drug.

"We are encouraged that PM184 is now progressing into Phase II clinical trial which represents a significant step forward by PharmaMar in addressing breast cancer, one of the most common cancers," said Arturo Soto, Director of Clinical Development at PharmaMar’s Oncology Unit. "PM184 is a compound of marine origin that inhibits the microtubular function and targets a protein called tubulin in a novel way, and we are very looking forward to the results," he added.

PM184

PM184 is a marine-derive drug found in a sponge called Lithoplocamia lithistoides. This drug candidate is a microtubule inhibitor that targets a protein called tubulin in a novel way. It blocks cancer growth by impairing cell division of tumor cells through the inhibition of a crucial process called mitosis. It is in early-stage development and is currently being investigated in phase I studies in various solid tumors.

Breast cancer

Breast cancer is the most frequent form of cancer among women in the Western countriesi . Approximately 232,340 new cases were detected in the US in 2013, and it caused 39,620 deaths in that 2 year.ii The number of cases is expected to increase by 50% by 2030. Despite progress with treatment, close to 30% of women who are diagnosed in the early stages of breast cancer experience progression to a recurrent or advanced form of the disease. Average survival for patients with metastatic or advanced breast cancer is 18-30 months.