On June 26, 2015 Novartis reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for Farydak (panobinostat, previously known as LBH589) capsules, in combination with bortezomib[*] and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD) (Press release, Novartis, JUN 26, 2015, View Source [SID:1234505809]). If approved in the EU, panobinostat will be first in its class of anticancer agents available to these patients[1].

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Multiple myeloma is a cancer of the plasma cells, a type of white blood cell present in the bone marrow, and affects approximately 84,000 people in Europe[4],[5]. Panobinostat is the first histone deacetylase (HDAC) inhibitor to show efficacy in multiple myeloma[2]. As an HDAC inhibitor, its epigenetic activity may help restore cell function in patients with multiple myeloma[3].

"Panobinostat is the first and only HDAC inhibitor recommended by the CHMP for the treatment of patients living with multiple myeloma who have progressed after standard-of-care therapy with bortezomib and an IMiD," said Alessandro Riva, MD, Global Head of Oncology Development and Medical Affairs, Novartis Oncology. "We are pleased with the positive CHMP opinion on panobinostat for previously treated patients because it brings us one step closer to providing a new treatment option for patients in need in Europe."

The CHMP recommendation is based on efficacy and safety data in a subgroup analysis of 147 patients who had received at least two prior regimens, including bortezomib and an IMiD, during the Phase III, randomized, double-blind, placebo-controlled, multicenter global registration trial, called PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA), evaluating panobinostat in combination with bortezomib and dexamethasone against bortezomib and dexamethasone alone in patients with relapsed and/or relapsed and refractory multiple myeloma. The trial found that the median progression-free survival (PFS) benefit increased in panobinostat patients who had received prior treatment with both bortezomib and an IMiD (12.5 months; n=73), as compared to the placebo arm (4.7 months; n=74) (hazard ratio=0.47 [95% confidence interval (CI): 0.31, 0.72])[6].

The most common non hematological adverse reactions included diarrhea, fatigue, nausea and vomiting. Treatment-emergent hematological toxicities included thrombocytopenia, anemia, neutropenia and lymphopenia. QTc prolongation of >480 and <500 msec was recorded in 1.3% of patients and change from baseline of >60 msec was observed in 0.8% of patients. No patients had an absolute QTc prolongation of >500 msec. Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation and sinus tachycardia) were reported in 17.6% of the panobinostat-treated patients versus 9.8% of placebo-treated patients and syncope events were reported in 6.0% versus 2.4%. Discontinuation due to adverse events (AEs), regardless of causality, was observed in 36.2% of patients. The most common AEs leading to treatment discontinuation were diarrhea (4.5%), asthenia and fatigue (2.9% each) and pneumonia (1.3%). On treatment deaths not due to the study indication (multiple myeloma) were reported in 6.8% of panobinostat-treated patients versus 3.2% of placebo-treated patients[6].

In the EU, the European Commission generally follows the recommendation of the CHMP and delivers its final decision within three months of the CHMP recommendation. The decision will be applicable to all 28 EU member states plus Iceland, Norway and Liechtenstein. Additional regulatory submissions for panobinostat are being reviewed by health authorities worldwide. Panobinostat in combination with bortezomib and dexamethasone was approved in the US in February 2015 and Chile in May 2015 under brand name Farydak for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an IMiD. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials[7].

About multiple myeloma
Multiple myeloma impacts approximately 84,000 people in Europe[5]. Multiple myeloma is a cancer of the plasma cells, a kind of white blood cell present in bone marrow-the soft, blood-producing tissue that fills the center of most bones. The cancer is caused by the production and growth of abnormal cells within the plasma, which multiply and build up in the bone marrow, pushing out healthy cells and preventing them from functioning normally[4]. Multiple myeloma is an incurable disease with a high rate of relapse (when the cancer returns) and resistance (when the therapy stops working)[8]. Standard-of-care regimens of proteasome inhibitors and IMiDs are often used to treat multiple myeloma, but most patients will stop responding to these treatments creating an unmet need for new options with novel mechanisms of action[8],[9],[10]. Multiple myeloma typically occurs in individuals 60 years of age or older, with few cases in individuals younger than 40[11].

About the PANORAMA Clinical Trial Program
PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) is a Phase III randomized, double-blind, placebo-controlled, multicenter global registration trial to evaluate panobinostat in combination with bortezomib and dexamethasone against bortezomib and dexamethasone alone in patients with relapsed or relapsed and refractory multiple myeloma who failed on at least one prior treatment. The study of 768 patients took place in 215 clinical trial sites worldwide making it the largest global registration trial for multiple myeloma to date. The primary endpoint of the trial was PFS. Data for overall survival, the key secondary endpoint of the trial, are not yet mature. Other secondary endpoints include overall response rate, duration of response and safety[12].

About Farydak
Panobinostat is approved as Farydak in the US and Chile in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an IMiD[7]. Farydak, an HDAC inhibitor, has an impact on epigenetics and may help restore cell function in patients with multiple myeloma.
Additional regulatory submissions for Farydak are being reviewed by health authorities worldwide. The safety and efficacy profile of panobinostat has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that panobinostat will become commercially available for additional indications anywhere else in the world.

On June 26, 2015 Roche reported that the EU Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission approves the use of Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and chemotherapy for the neoadjuvant treatment (use before surgery) of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence (Press release, Hoffmann-La Roche , JUN 26, 2015, View Source [SID:1234505808]).

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The EU filing was based primarily on data from the Phase II NeoSphere study, which showed that nearly 40% of people receiving the Perjeta regimen had no evidence of tumour tissue detectable at the time of surgery in the affected breast and local lymph nodes (known as a pathological complete response, or pCR) compared to 21.5% of people who received Herceptin and taxane chemotherapy alone. 1 This is the first CHMP recommendation in the neoadjuvant setting based on pCR.

Every year, approximately 100,000 people in Europe are diagnosed with HER2-positive breast cancer, an aggressive type of the disease that is likely to progress more quickly than cancer that is HER2-negative. 2,3 The majority of breast cancer cases are diagnosed at an early stage of the disease, before the cancer has spread to other parts of the body. 4,5

"Breast cancer treatment has the greatest impact in the early stage, where it can potentially prevent the disease from returning and spreading. Consequently, there is a need to bring promising treatments to patients with early breast cancer," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are very pleased that the use of pCR as a novel clinical trial endpoint may hopefully soon allow us to make the Perjeta regimen available to patients with early breast cancer in Europe."

The CHMP opinion was provided in the context of the totality of Perjeta data available to date, including the biological rationale for the combination of Perjeta, Herceptin and taxane chemotherapy, its established safety profile and the efficacy results in the advanced breast cancer (aBC) setting. The submission was supported by efficacy and safety data from two neoadjuvant studies, NeoSphere and TRYPHAENA, as well as long-term safety results from the CLEOPATRA trial in people with previously untreated HER2-positive aBC. Data from the ongoing Phase III APHINITY study in the adjuvant (post-surgery) setting will provide additional insights into the broader role of Perjeta in the treatment of HER2-positive early breast cancer (eBC).

Perjeta is already approved as a neoadjuvant treatment for people with HER2-positive eBC in the U.S. and 20 other countries.

Follow-up data from the NeoSphere study were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2015 Annual Meeting. 6 These data suggest that, at three years, people who received the Perjeta regimen prior to surgery were 31% less likely to experience disease worsening, recurrence or death (progression-free survival, PFS HR=0.69; 95% CI, 0.34–1.40) compared to those who received Herceptin and chemotherapy.6 People treated with the Perjeta regimen were also 40% less likely to experience disease recurrence or death (disease-free survival, DFS HR=0.60; 95% CI, 0.28–1.27). 6

About the NeoSphere trial
The NeoSphere trial1 (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomised, multicentre, international Phase II study in 417 people with newly diagnosed HER2-positive, operable, locally advanced or inflammatory eBC. Participants were randomised to one of four study arms and received four cycles (12 weeks) of neoadjuvant treatment followed by surgery and a year of adjuvant treatment with Herceptin plus chemotherapy. The primary endpoint was pCR. Secondary endpoints included clinical response, time to clinical response, safety profile, DFS, PFS, breast-conserving surgery rate and biomarker assessment. Study data showed the following:

Treatment with Perjeta, Herceptin and docetaxel chemotherapy significantly improved the rate of pCR in the breast and local lymph nodes by 17.8% compared to Herceptin and chemotherapy alone (39.3% vs. 21.5%, p=0.0063).
pCR of 21.5% for Herceptin and chemotherapy

pCR of 39.3% for Perjeta, Herceptin and chemotherapy

pCR of 11.2% for Perjeta and Herceptin

pCR of 17.7% for Perjeta and chemotherapy

The Perjeta regimen was not associated with a significant increase in adverse events (AEs), compared to Herceptin and chemotherapy alone.

The most common severe (Grade 3 or higher) AEs for the Perjeta regimen were neutropenia (decrease in a certain type of white blood cell, 44.9%), febrile neutropenia (fever associated with decrease in a certain type of white blood cell, 8.4%), leukopenia (decrease in overall white blood cells, 4.7%) and diarrhoea (5.6%).

pCR means that there is no tumour tissue detectable at the time of surgery either in the affected breast or in the affected breast and local lymph nodes following completion of neoadjuvant treatment.

About the TRYPHAENA trial
The TRYPHAENA trial7 (ToleRabilitY of Pertuzumab, Herceptin and AnthracyclinEs in NeoAdjuvant breast cancer) is a randomised, multicentre Phase II study that was conducted in 225 people with HER2-positive, operable, locally advanced or inflammatory eBC with tumours greater than two centimetres. Participants were randomised to one of three neoadjuvant Perjeta regimens. The primary endpoint was cardiac safety. Secondary endpoints included pCR, clinical response, breast-conserving surgery rate, DFS, PFS, overall survival (OS) and biomarker assessment. Study data showed the following:

The study was not powered to compare the three study arms. The rates of total pCR in the breast and local lymph nodes in the three arms were as follows:

pCR of 56.2% for Perjeta, Herceptin and anthracycline-based chemotherapy, followed by Perjeta, Herceptin and chemotherapy

pCR of 54.7% for anthracycline-based chemotherapy, followed by Perjeta, Herceptin and chemotherapy

pCR of 63.6% for the anthracycline-free arm (Perjeta, Herceptin, chemotherapy and carboplatin chemotherapy)

No new or unexpected cardiac AEs, or other AEs, were observed in any of the study arms. AEs observed were consistent with those seen in previous studies of Perjeta, Herceptin and chemotherapy, either in combination or alone.

The most common severe (Grade 3 or higher) AEs in any of the three study arms were:
In the concurrent arm: neutropenia (47.2%), leukopenia (19.4%) and febrile neutropenia (18.1%)

In the sequential arm: neutropenia (42.7%), leukopenia (12.0%), febrile neutropenia (9.3%), diarrhoea (5.3%) and left ventricular dysfunction (4.0%)

In the anthracycline-free arm: neutropenia (46.1%), febrile neutropenia (17.1%), anaemia (decrease in red blood cells, 17.1%); the AEs of diarrhoea, leukopenia, anaemia and thrombocytopenia (decrease in platelets) all had an incidence of 11.8%

About Roche’s medicines for HER2-positive breast cancer

Roche has been leading research into the HER2 pathway for over 30 years and is committed to improving the health, quality of life and survival for people with both early and advanced HER2-positive disease.

Roche has developed three innovative medicines that have helped transform the treatment of HER2-positive breast cancer:
Herceptin, Perjeta and Kadcyla. HER2-positive breast cancer is a particularly aggressive form of the disease that affects approximately 20% of patients.3 Over the past 15 years, the outlook for people with HER2-positive disease has improved to the extent that those with this form of the disease treated with these innovative medicines now typically experience better outcomes than people with less aggressive HER2-negative disease. 8

Eligibility for treatment with Roche’s HER2-targeted medicines is determined via a diagnostic test, saving time from the outset by identifying patients who will likely benefit from these medicines at the onset of their disease.

On June 26, 2015 Cantargia reported that it has acquired a non-exclusive license to the POTELLIGENT Technology platform for the production of the proprietary product candidate CAN04 (Press release, Kyowa Hakko Kirin, JUN 26, 2015, View Source [SID:1234505807]). The POTELLIGENT Technology platform has been designed for research and development of antibody dependent cellular cytotoxicity (ADCC) enhanced antibodies. Commercial details of the agreement were not disclosed.

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The POTELLIGENT Technology platform will be used to produce Cantargia’s lead product candidate, the monoclonal antibody CAN04 directed against the target molecule IL1RAP. The molecule IL1RAP is expressed on both cancer stem cells and mature cancer cells. CAN04 has a mode of action combining the blocking of IL-1 signaling in the cancer cell and ADCC. By using the POTELLIGENT Technology platform, a significantly enhanced ADCC activity can be obtained leading to increased efficacy.

"By utilizing BioWa’s POTELLIGENT Technology, CAN04 can be produced with significantly higher potency than normally obtained in a standard production system", says Göran Forsberg, CEO of Cantargia. "This will be a very important tool to augment the antitumor activity of CAN04 that enables state-of-the-art production technology".

"We are extremely pleased that the value of our POTELLIGENT Technology continues to be recognized by innovative companies such as Cantargia for their antibody programs in oncology," said Yasunori Yamaguchi, President and CEO of BioWa." We are very excited to work together with Cantargia on their promising antibody program".