On July 24, 2015 Molecular Partners AG (ticker: MOLN) reiterated its commitment to its un-partnered pipeline. This includes advancing the clinical and preclinical development pipeline and ramping up the activities in immuno-oncology (Press release, Molecular Partners, JUL 24, 2015, View Source [SID:1234506696]).

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Following Molecular Partners’ expansion of its strategic ophthalmology partnership with Allergan, the company confirmed the discontinuation of the DARPin-toxin alliance with Roche.

Molecular Partners had entered into an oncology alliance with Roche in December 2013. Under this partnership, Roche and Molecular Partners generated DARPin-toxin fusion candidates. Roche is currently terminating its Pseudomonas exotoxin conjugate programs, including antibody and DARPin-based projects. The agreement put in place between Molecular Partners and Roche was specific for the use of DARPins in combination with Pseudomonas exotoxin.

"The DARPin platform generated highly differentiated binders in short time, and it is unfortunate that Roche decided to discontinue these programs for reasons related to the toxin," said Christian Zahnd, Chief Executive Officer of Molecular Partners and continued: "We discussed other areas of mutual interest, but given our own proprietary focus on immuno-oncology, it made no sense to amend the current collaboration. This way, we can avoid working on potentially competing pathways."

Molecular Partners will evaluate if DARPins from the collaboration will be added to its proprietary pipeline directly or repurposed in other programs.

Molecular Partners is advancing a growing proprietary pipeline of DARPin therapies in oncology. The most advanced systemic DARPin is MP0250 is in Phase 1 clinical studies in solid tumors. MP0250 inhibits both VEGF and HGF from binding to their receptors, thereby blocking tumor growth and tumor spreading. The second most advanced oncology DARPin is MP0274 and has broad anti-HER activity inhibiting both downstream HER2 and HER3-mediated signaling and leading to induction of apoptosis. MP0274 is currently in preclinical development. The current focus of Molecular Partners in research is immuno-oncology.

On July 24, 2015 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for Ad-RTS-hIL-12 + veledimex in the treatment of patients with malignant glioma (Press release, Ziopharm, JUL 24, 2015, View Source [SID:1234506625]). Ad-RTS-hIL-12 is a novel gene therapy candidate for the controlled expression of IL-12, a critical protein for stimulating an anti-cancer T cell immune response.

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The FDA’s Office of Orphan Products grants orphan drug status to support development of medicines for underserved patient populations or rare disorders affecting fewer than 200,000 people in the U.S. Orphan Drug Designation provides eligibility for a seven-year period of market exclusivity in the United States after product approval, an accelerated review process, accelerated approval where appropriate, grant funding, tax benefits and an exemption from user fees.

"Malignant glioma is an aggressive cancer with few treatment options," said Laurence J. N. Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "This designation supports our effort to advance Ad-RTS-IL-12, a novel immuno-oncology therapy which has demonstrated promising preclinical efficacy in brain cancer, as a potential treatment for this indication. Enrollment in our Phase 1 study is progressing well, and we look forward to early results from this clinical trial later in the year."

Ad-RTS-hIL-12 + veledimex is currently being studied in a Phase 1 trial designed to examine a gene therapy treatment strategy for high grade gliomas, with the goal of generating an anti-tumor T cell immune response. The primary objective of the study is to determine the safety and tolerability of a single intra-tumoral Ad-RTS-hIL-12 injection plus escalating oral veledimex doses. Secondary objectives are to determine the veledimex maximum tolerated dose, the immune responses elicited by Ad-RTS-hIL-12 and veledimex, and investigator assessment of response, including the tumor objective response rate and progression-free survival, and determine overall survival, among other measures. The study is expected to enroll up to 72 subjects at up to 12 leading treatment centers.

On July 24, 2015 Novartis reported the US Food and Drug Administration (FDA) has approved Odomzo (sonidegib, formerly LDE225) 200 mg capsules for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy (Press release, Novartis, JUL 24, 2015, View Source [SID:1234506624]).

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"The FDA approval of Odomzo offers a new and non-invasive treatment option for a potentially devastating disease that is hard to treat and can be disfiguring," said Bruno Strigini, President, Novartis Oncology. "Odomzo is an important addition to our growing portfolio of targeted treatments for advanced skin cancers and underscores our commitment to developing and bringing to market new options for patients."

The Odomzo approval was based on the demonstration of a durable objective response rate (ORR) in an international, multi-center, double-blind, randomized, two-arm, non-comparative trial in patients with laBCC not amenable to local therapy or metastatic basal cell carcinoma (mBCC) [1].

Patients with laBCC treated with Odomzo 200 mg (n=66) were followed for at least 12 months unless discontinued earlier. The ORR was 58% (95% confidence interval: 45, 70), consisting of 5% (n=3) complete responses (CR) and 53% (n=35) partial responses (PR). A pre-specified sensitivity analysis using an alternative definition for CR, defined as at least a PR according to MRI and/or photography and no evidence of tumor on biopsy of residual lesion, yielded a CR rate of 20%[1]. Among the 38 patients with an objective response, 31 patients (82%) have ongoing responses ranging from at least 1.9 to 18.6 months and the median duration of response has not been reached [1].

The most serious risks of Odomzo are embryofetal toxicity and musculoskeletal adverse reactions including rhabdomyolysis. Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, may occur with Odomzo and other drugs which inhibit the hedgehog pathway. The incidence of musculoskeletal adverse reactions in patients with laBCC treated with Odomzo 200 mg was 68%, with 9% reported as grade 3 or 4. Adverse reactions occurring in more than 10% of patients treated with Odomzo 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus. The most frequent grade 3 and 4 laboratory abnormalities occurring in at least 5% of patients were serum creatine kinase (CK) elevation and lipase elevation[1].

About the BOLT Clinical Trial
Data from the Phase II, randomized, double-blind multicenter BOLT (Basal cell carcinoma Outcomes in LDE225 Trial) formed the basis of the FDA’s approval. The primary endpoint was ORR of patients treated with Odomzo 200 mg and 800 mg, defined as the proportion of patients with confirmed complete or partial tumor response, or shrinkage, as measured by a central review committee. There was no evidence of better ORR among patients with laBCC randomized to receive Odomzo 800 mg daily[1].

The evaluation of tumor response was based on a composite assessment of modified Response Evaluation Criteria in Solid Tumors (mRECIST) that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography (World Health Organization (WHO) adapted criteria), and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of CR[1].

About Basal Cell Carcinoma
BCC consists of abnormal, uncontrolled growths or lesions that arise in the skin’s basal cells, which line the deepest layer of the epidermis (the outermost layer of the skin)[6] and accounts for more than 80% of non-melanoma skin cancers[7]. It occurs most frequently on the head and neck, with the nose being the most common site[7]. BCC that spreads from where it started to nearby tissue is called locally advanced[8] and can be highly disfiguring[2]. Advanced BCC is thought to represent roughly 1-10% of all cases of BCC[9]-[11]. While BCC is generally diagnosed and treated early, it may recur in an estimated 3% of patients after five years[12]. Although BCC rarely becomes advanced, there have been few treatment options at this stage of the disease. Worldwide incidence of BCC is rising by 10% each year due to factors such as an aging population and increased ultraviolet exposure. Incidence rates are estimated to be between 0.003% and 0.55% worldwide[13].

About Odomzo
Odomzo (sonidegib, formerly LDE225) is an oral, selective smoothened (SMO) inhibitor approved by the FDA for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy[1]. SMO is a molecule that regulates the hedgehog (Hh) signaling pathway, which plays a critical role in stem cell maintenance and tissue repair, as well as in advanced basal cell carcinoma[3]-[5]. Odomzo is currently in clinical development in other diseases.

Odomzo was approved in Switzerland for the treatment of advanced BCC that is not amenable to curative surgery or radiotherapy on June 30, 2015. The CHMP granted a positive opinion on June 25, 2015. Additional regulatory submissions are being reviewed by health authorities worldwide.

IMPORTANT SAFETY INFORMATION
Important note: Before prescribing, consult the full prescribing information.

Presentation: Hard gelatin capsules containing 200 mg sonidegib.

Indications: Odomzo is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) who are not amenable to curative surgery or radiation therapy.

Dosage and administration: Adults: One 200 mg dose taken orally once daily on an empty stomach, at the same time each day. Children: Safety and effectiveness has not been established in pediatric patients with BCC.

Patients with renal impairment: Sonidegib has not been studied in patients with renal impairment. Based on available data, sonidegib elimination via the kidney is negligible. A population pharmacokinetic analysis did not find significant influence of renal function on the apparent clearance (CL/F) of sonidegib suggesting that dose adjustment is not necessary in patients with renal impairment.

Patients with hepatic impairment: No dose adjustment necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Sonidegib has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Caution should therefore be used in patients with severe hepatic impairment.

Contraindications: Women who are pregnant or breast-feeding.

Warnings and precautions:
Muscle related adverse events: Creatine phosphokinase (CK) levels should be checked prior to starting treatment and as clinically indicated thereafter, for example, if muscle related symptoms are reported. If clinically notable elevation of CK is detected, renal function should be assessed. Dose modification or interruption guidelines should be followed. Patients should be closely monitored for muscle related symptoms if Odomzo is used in combination with certain medications that may increase the potential risk of developing muscle toxicity (e.g. CYP3A4 inhibitors, chloroquine, hydroxychloroquine, fibric acid derivatives, penicillamine, zidovudine, niacin, HMG-CoA reductase inhibitors).

Closely monitor patients with neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) due to an increased risk of muscle toxicity.

Blood donation: Patients should be instructed not to donate blood while taking Odomzo and for at least 20 months after ending treatment.

Women of child-bearing potential:
Women of childbearing potential must use a highly effective method of contraception while receiving Odomzo. Contraception must be continued for 20 months after ending treatment.

Pregnancy: Negative pregnancy status must be confirmed by a test performed by a health care provider prior to initiation of Odomzo treatment. Odomzo must not be used during pregnancy.

Breast-feeding: Women must not breast feed while taking Odomzo and for at least 20 months after ending treatment.

Sexually active males: Men should not father a child or donate semen while taking Odomzo and for at least 6 months after ending treatment. Sexually active males must use a condom, regardless of vasectomy status, during intercourse and for at least 6 months after ending treatment to prevent exposure of female partners to the drug via seminal fluid.

Fertility: Male and female fertility may be compromised with Odomzo. Fertility preservation strategies should be discussed prior to starting treatment with Odomzo.

Adverse drug reactions:
Very common (>=10%): amenorrhea, decreased appetite, dysgeusia, headache, nausea, diarrhea, vomiting, abdominal pain, alopecia, pruritus, muscle spasms, myalgia, musculoskeletal pain, fatigue, pain, weight decreased.
Common (between 1 to 10%): constipation, dyspepsia, gastroesophageal reflux disorder, rash, abnormal hair growth, myopathy (muscular fatigue and muscular weakness), dehydration.

Laboratory abnormalities: Very common (>=10%): hemoglobin decreased, lymphocyte count decreased, amylase increased, blood glucose increased, lipase increase, serum creatine phosphokinase increase, serum creatinine increased, alanine amino transaminase (ALT) increased, aspartate amino transaminase (AST) increased.

Interactions: Avoid concomitant use of strong CYP3A inhibitors, including but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone.

Avoid concomitant use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin and St John’s Wort (Hypericum perforatum). If a strong CYP3A inducer must be used concomitantly with sonidegib, consideration should be given to increasing the dose of sonidegib by 200 mg increments to a maximum daily dose of 800 mg.

Monitor patients carefully for adverse drug reactions with concomitant use of substrates of CYP2B6 and CYP2C9 enzymes or BCRP transporter, especially those with a narrow therapeutic range.

Due to overlapping toxicities, patients taking Odomzo who are also taking medications known to increase the risk of muscle-related toxicity may be at increased risk of developing muscle-related adverse events. Patients should be closely monitored and dose adjustments should be considered if muscle symptoms develop.

On July 24, 2015 Amgen (NASDAQ:AMGN) reported that the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) for Kyprolis (carfilzomib) for Injection in combination with Revlimid (lenalidomide) and dexamethasone (KRd) for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy (Press release, Amgen, JUL 24, 2015, View Source [SID:1234506622]).

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"The expanded indication of Kyprolis provides patients with relapsed multiple myeloma a new therapeutic option, helping to address a real unmet need for this common blood cancer," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The approval of a second indication for Kyprolis in just three years demonstrates that it is becoming a critical component in the treatment of multiple myeloma, and underscores our commitment to advancing care for patients with this challenging disease."

The FDA approved the expanded indication for Kyprolis based on data from the ASPIRE study. The study showed that patients treated in the KRd arm lived 50 percent longer (8.7 months) without their disease worsening compared to patients treated with Revlimid and low-dose dexamethasone (Rd) alone. The median progression-free survival (PFS) was 26.3 months (95 percent CI, 23.3 to 30.5 months) in the KRd arm compared to 17.6 months (95 percent CI, 15.0 to 20.6 months) in the Rd arm. The most common adverse events in the Kyprolis arm included pneumonia (1 percent), myocardial infarction (0.8 percent) and upper respiratory tract infection (0.8 percent).

"The ability of this Kyprolis treatment regimen to produce deep and durable responses is critical towards extending the time patients live without their disease progressing," said ASPIRE principal investigator Keith Stewart, M.D., Ch.B.

Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.

Multiple myeloma is the second most common hematologic cancer.1 In the U.S., there are nearly 96,000 people living with, or in remission from, multiple myeloma.2 The estimated number of new cases of multiple myeloma in 2014 was more than 24,000 and the estimated number of deaths was 11,090.2

About ASPIRE
The international, randomized Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial evaluated Kyprolis in combination with lenalidomide and low-dose dexamethasone, versus lenalidomide and low-dose dexamethasone alone, in patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were randomized to receive Kyprolis (20 mg/m2 on days 1 and 2 of cycle one only, escalating to 27 mg/m2 on days 8, 9, 15 and 16 of cycle one and continuing on days 1, 2, 8, 9, 15 and 16 of subsequent cycles), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in four-week cycles), versus lenalidomide and low-dose dexamethasone alone. The study randomized 792 patients at sites in North America, Europe and Israel.

The OS results did not cross the pre-specified early stopping boundary for the interim analysis. At the time of the interim analysis, there were 143 deaths (36.1 percent) in the KRd group, compared to 162 deaths (40.9 percent) in the Rd group. The ORR was 87 percent with KRd and 67 percent with Rd. In the KRd and Rd groups, 14 percent versus 4 percent of patients achieved a stringent complete response, a measurement indicating depth of response. Median DOR was 28.6 months for patients receiving KRd (95 percent CI, 24.9 to 31.3 months) and 21.2 months for patients receiving Rd (95 percent CI, 16.7 to 25.8 months).

The rate of deaths due to adverse events (AEs) within 30 days of the last dose was balanced between the KRd arm and the Rd arm. The most common causes of death occurring in patients in the KRd arm compared to the Rd arm included cardiac disorders (3 percent versus 2 percent), infection (2 percent versus 3 percent), renal (0 percent versus less than 1 percent), and other AEs (2 percent versus 3 percent). Serious AEs were reported in 60 percent of the patients in the KRd arm and 54 percent of the patients in the Rd arm. The most common serious AEs reported in the KRd arm compared to the Rd arm were pneumonia (14 percent versus 11 percent), respiratory tract infection (4 percent versus 1.5 percent), pyrexia (4 percent versus 2 percent), and pulmonary embolism (3 percent versus 2 percent). Discontinuation due to any AE occurred in 26 percent of patients in the KRd arm versus 25 percent of patients in the Rd arm. Adverse events leading to discontinuation of Kyprolis occurred in 12 percent of patients.

The ASPIRE data were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) and published in The New England Journal of Medicine in December 2014.

About Kyprolis (carfilzomib) for Injection
Kyprolis (carfilzomib) for Injection is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy.

Kyprolis is also indicated under FDA accelerated approval as a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx Pharmaceuticals is a subsidiary of Amgen and holds development and commercialization rights to Kyprolis globally, excluding Japan. Kyprolis is also approved for use in Argentina, Israel, Mexico and Thailand. For more information about Kyprolis, visit www.kyprolis.com.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection

WARNINGS AND PRECAUTIONS

Cardiac Toxicities:
New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. In clinical studies with Kyprolis, these events typically occurred early in the course of Kyprolis therapy (< 5 cycles). Death due to cardiac arrest has occurred within a day of Kyprolis administration. Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment. While adequate hydration is required prior to each dose in Cycle 1, all patients should also be monitored for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure. In patients > 75 years of age, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications.

Acute Renal Failure:
Cases of acute renal failure have occurred in patients receiving Kyprolis. Renal insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred with an incidence of approximately 8% in a randomized controlled trial. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft and Gault equation). Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome:
Cases of tumor lysis syndrome (TLS), including fatal outcomes, have been reported in patients who received Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Ensure that patients are well hydrated before administration of Kyprolis in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly including interruption of Kyprolis until TLS is resolved.

Pulmonary Toxicity:
Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in less than 1% of patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension:
Pulmonary arterial hypertension (PAH) was reported in approximately 1% of patients treated with Kyprolis and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for pulmonary 11 hypertension until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.

Dyspnea:
Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of patients. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Hypertension:
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Venous Thrombosis:
Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In the combination study, the incidence of venous thromboembolic events in the first 12 cycles was 13% in the Kyprolis combination arm versus 6% in the control arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%. Thromboprophylaxis is recommended and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Infusion Reactions:
Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Administer dexamethasone prior to Kyprolis to reduce the incidence and severity 12 of infusion reactions. Inform patients of the risk and of symptoms and to contact a physician immediately if symptoms of an infusion reaction occur.

Thrombocytopenia:
Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day cycle with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in approximately 40% of patients in clinical trials with Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure:
Cases of hepatic failure, including fatal cases, have been reported (< 1%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic Syndrome:
Cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) including fatal outcome have been reported in patients who received Kyprolis. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES):
Cases of PRES have been reported in patients receiving Kyprolis. Posterior reversible encephalopathy syndrome (PRES), formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI). Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

Embryo-fetal Toxicity:
Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using Kyprolis. Kyprolis caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

ADVERSE REACTIONS
The most common adverse events occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, decreased platelets, dyspnea, diarrhea, decreased lymphocyte, headache, decreased hemoglobin, cough, edema peripheral.

The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.

USE IN SPECIFIC POPULATIONS
Patients on dialysis: Administer Kyprolis after the dialysis procedure.

POST-MARKETING EXPERIENCE
The following adverse reactions were reported in the post-marketing experience: dehydration, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), tumor lysis syndrome including fatal outcomes, and posterior reversible encephalopathy syndrome (PRES). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Full prescribing information is available at www.kyprolis.com.

On July 24, 2015 Novartis reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (Press release, Novartis, JUL 24, 2015, View Source [SID:1234506618]). The Company also announced that the US Food and Drug Administration (FDA) has granted priority review for the same patient population.

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"The CHMP positive opinion and FDA priority review of Tafinlar and Mekinist validate the importance of this targeted therapy combination for patients with the most serious form of skin cancer," said Bruno Strigini, President, Novartis Oncology. "This good news for the combination of Tafinlar and Mekinist in metastatic melanoma follows on the FDA’s recent Breakthrough Therapy designation for the combination in BRAF V600 mutation-positive non-small cell lung cancer. We look forward to working with the US and EU regulatory authorities to help bring this targeted therapy combination to more patients who may benefit."

The CHMP positive opinion is based on results from the Phase III COMBI-d and COMBI-v studies. The COMBI-d study showed that the combination of Tafinlar and Mekinist achieved a statistically significant overall survival (OS) benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; Hazard Ratio [HR] 0.71 [95% Confidence Interval (CI), 0.55-0.92], p=0.011). In those who received Tafinlar in combination with Mekinist, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for those who received Tafinlar only, respectively[1]. The COMBI-v study showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to vemurafenib monotherapy (median for the combination not reached vs 17.2 months; HR 0.69 [95% CI, 0.53-0.89], p=0.005). In the COMBI-v study, the rate of OS at 1 year was 72% with the combination of Tafinlar and Mekinist and 65% for those receiving vemurafenib only[2]. The safety results from these studies were consistent with the profile observed to date for the combination; no new safety concerns were observed[1],[2]. The most common adverse reactions seen for combination therapy in both studies at >=20% include pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, arthralgia, vomiting, hypertension, and cough[1]. Adverse events or toxicities were generally manageable with appropriate intervention, as described in the product labelling submitted with the application.

The European Commission will review the CHMP recommendation and is expected to deliver its final decision within three months. The decision will be applicable to all 28 EU member states plus Iceland, Norway and Liechtenstein.

The US FDA granted Priority Review in metastatic melanoma for the supplemental New Drug Application (sNDA) for the combination of Tafinlar and Mekinist, which included data from the COMBI-d and COMBI-v studies. Since January 2014, the combination of Tafinlar and Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was approved through the FDA’s Accelerated Approval program and reviewed under a Priority Review designation. The approval was contingent on the results of the COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600 mutation. A PDUFA date is in November 2015.

Metastatic melanoma is the most serious and life-threatening type of skin cancer[3] and is associated with low survival rates with a five-year survival of about 20% for those with late-stage disease[4]. There are about 200,000 new cases of melanoma diagnosed worldwide each year[5], approximately half of which have BRAF mutations[4],[6]. Gene tests can determine whether a tumor has a BRAF mutation, and results can play a key role in prognosis and determining appropriate treatment[4].

The FDA Breakthrough Therapy designation in BRAF V600 mutation-positive non-small cell lung cancer (NSCLC) is based on interim analysis results from an ongoing single-arm, two-stage, Phase II trial investigating the Tafinlar and Mekinist combination in patients with metastatic NSCLC who had the BRAF V600E mutation and failed at least one line of chemotherapy. The data, which were presented at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), showed an overall response rate (ORR) of 63% [95% CI: 40.6, 81.2%] based on investigator assessment; the analysis by independent review was consistent with an ORR of 68% [95% CI: 45.1, 86.1%]. The most common adverse events (incidence >=20%) among patients included in this analysis were pyrexia, diarrhea, nausea, vomiting, decreased appetite, asthenia, cough, peripheral edema, and rash[7].

Breakthrough Therapy designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint. The designation includes all of the fast track program features, as well as more intensive FDA guidance. It is a distinct status from both Accelerated Approval and Priority Review, which can also be granted to the same drug if relevant criteria are met[8].

Tafinlar and Mekinist in combination for NSCLC is the sixth Breakthrough Therapy designation for Novartis, continuing the company’s trajectory as a leader in developing innovative therapies to help treat diseases in which there remains significant unmet medical need.

About the COMBI-d Study
COMBI-d is a pivotal Phase III, randomized, double-blinded study comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK inhibitor, Mekinist, to single agent therapy with Tafinlar and placebo in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study randomized 423 patients at investigative sites in Australia, Europe and North and South America. The primary endpoint of this study was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), and safety. There was no crossover between treatment arms[1].

Updated results from the COMBI-d study showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; HR 0.71 [95% CI, 0.55-0.92], p=0.011). In those who received the Tafinlar and Mekinist combination, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for those who received Tafinlar only, respectively. The analysis for the combination also showed median PFS of 11.0 months, ORR of 69%, and median DoR of 12.9 months. The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for Tafinlar monotherapy; no new safety concerns were observed. The most common adverse events (>=20%) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, joint pain (arthralgia), hypertension, vomiting, cough, and peripheral edema. More patients had AEs leading to dose modifications in the combination arm compared to Tafinlar monotherapy. Increased incidence (57% vs 33%) and severity (grade 3, 7% (n=15) vs 2% (n=4)) of pyrexia occurred with combination treatment as compared to Tafinlar monotherapy. There was a lower incidence of cutaneous squamous cell carcinoma (cuSCC) (link is external) including keratoacanthoma with the combination arm (3% (n=6)) compared to the Tafinlar monotherapy arm (10% (n=22)). Discontinuation of treatment due to adverse events occurred in 11% (n=24) vs 7% (n=14) of patients in the combination group and the monotherapy group, respectively[1].

About the COMBI-v Study
COMBI-v was a two-arm, open-label, Phase III study comparing the combination of Tafinlar and Mekinist combination therapy with vemurafenib monotherapy in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was OS[2].

Results from the COMBI-v study showed a 31% decrease in the risk of death for patients treated with Tafinlar and Mekinist combination therapy compared to vemurafenib monotherapy (HR 0.69 [95% CI, 0.53-0.89], p=0.005). At 12 months, the rate of OS was 72% for the combination of Tafinlar and Mekinist and 65% for vemurafenib monotherapy. The analysis for the combination also showed median PFS of 11.4 months, ORR of 64%, and median DoR of 13.8 months. The most frequent adverse events in the Tafinlar and Mekinist combination arm (>=30%) were pyrexia, nausea, diarrhea, and chills. More patients had AEs leading to dose modifications in the combination arm compared to the vemurafenib monotherapy arm. For the combination group compared to the vemurafenib group, there was a lower incidence of rash, 22% (n=76) vs 43% (n=149); photosensitivity reaction, 4% (n=13) vs 22% (n=78); hand-foot syndrome, 4% (n=14) vs 25% (n=87); skin papillomas, 2% (n=6) vs 23% (n=80); squamous-cell carcinomas and keratoacanthomas, 1% (n=5) vs 18% (n=63); and hyperkeratosis, 4% (n=15) vs 25% (n=86). Adverse events occurring more frequently in the combination arm compared with the vemurafenib arm included pyrexia, 53% (n=184) vs 21% (n=73), respectively, and bleeding events, 18% (n=62) vs 7% (n=25), respectively. Discontinuation of treatment due to adverse events was similar between the treatment groups: 13% (n=44) for the combination group compared to 12% (n=41) for the monotherapy group[2].