On February 21, 2017 Pfizer Inc. (NYSE:PFE) reported that a Biologics License Application (BLA) for inotuzumab ozogamicin has been accepted for filing and granted Priority Review by the U.S. Food and Drug Administration (FDA) (Press release, Pfizer, FEB 21, 2017, View Source [SID1234517774]). Inotuzumab ozogamicin is being evaluated for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

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Inotuzumab ozogamicin received Breakthrough Therapy designation from the FDA in October 2015 for ALL. Priority Review status accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing, and is given to drugs that may offer major advances in treatment or may provide a treatment for which no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in August 2017.

"ALL that has recurred after, or is refractory to, first-line therapy is a rapidly progressing and deadly disease," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development. "Based on the positive results of the INO-VATE 1022 Phase 3 trial, we believe inotuzumab ozogamicin, if approved, represents a new treatment option for adult patients with relapsed or refractory B-cell precursor ALL."

In addition, a Marketing Authorization Application (MAA) for inotuzumab ozogamicin in the same patient population is currently under review by the European Medicines Agency (EMA).

The submissions are based on results from the Phase 3 INO-VATE 1022 trial, which enrolled 326 adult patients with relapsed or refractory B-cell ALL and compared inotuzumab ozogamicin to standard of care chemotherapy. The INO-VATE 1022 study had two independent primary endpoints, complete response with or without hematologic remission (CR/CRi) and overall survival (OS). Results from the trial were published in The New England Journal of Medicine in June 2016.

About Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia with a poor prognosis in adults.1 The current foundational treatment is intensive, long-term chemotherapy.2 In 2017, it is estimated that 5,970 cases of ALL will be diagnosed in the United States, with about 2 in 5 cases occurring in adults.3 Approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens.4 For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.5

About Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen expressed on approximately 90 percent of B-cell malignancies, linked to a cytotoxic agent.6 When inotuzumab ozogamicin binds to the CD22 antigen on B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.7 The most common adverse events (AEs) observed in clinical trials for inotuzumab ozogamicin were cytopenias, including febrile neutropenia. Common nonhematologic treatment-emergent AEs with inotuzumab ozogamicin included nausea, headache and pyrexia. Additionally, veno-occlusive liver disease (VOD) was observed more frequently in patients treated with inotuzumab ozogamicin, especially those who went on to receive hematopoietic stem cell transplantation.

Inotuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing and clinical development activities for this molecule.

On February 21, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the European Commission has granted a conditional marketing authorisation for Alecensa (alectinib) as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib (Press release, Hoffmann-La Roche, FEB 21, 2017, View Source [SID1234517773]). Most people with ALK-positive NSCLC develop resistance to the current standard of care within one year of treatment, and approximately 60% will develop metastases in the central nervous system (CNS).1,2

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"Every year, an estimated 75,000 people are diagnosed with ALK-positive NSCLC worldwide," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "Development of resistance to the current standard of care underlines the need for alternative treatments. Today’s approval provides the promise of a new treatment option for people in Europe with this devastating disease."

The conditional approval is based primarily on data from the pivotal phase II NP28673 and NP28761 studies, which showed that Alecensa shrank tumours in up to 52.2% (95% CI: 39.7%, 64.6%) of people with advanced ALK-positive NSCLC whose disease had progressed following treatment with crizotinib (overall response rate; ORR).2,3 The studies also showed that Alecensa extended the time that people lived without their disease worsening or death (progression-free survival, PFS) by up to 8.9 months (95% CI: 5.6, 12.8).2,3 In addition, a pooled analysis of the two studies showed that Alecensa shrank CNS tumours that were measurable in 64% of patients (95% CI: 49.2%, 77.1%), and 22% (n=-29) achieved a complete response of their measurable and non-measurable CNS tumours.4

Conditional approval is granted to a medicinal product that fulfils an unmet medical need where the benefit of immediate availability outweighs the risk of less comprehensive data than normally required. Under the provisions of the conditional approval, Roche will provide additional data on first-line Alecensa in ALK inhibitor naïve ALK-positive NSCLC patients from an ongoing phase III study ALEX, comparing Alecensa to crizotinib.5 The ALEX study is expected to report data in the first half of 2017.

Alecensa is already approved for ALK-positive NSCLC in eight countries in the crizotinib failure setting, and also in Japan for people whose tumours were advanced, recurrent or could not be removed completely through surgery (unresectable).6 In addition to ALEX, Alecensa is also being explored as a first-line treatment option with the phase III J-ALEX study comparing Alecensa to crizotinib in Japanese patients.5,7 Results from the J-ALEX study were presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and showed that Alecensa reduced the risk of disease worsening or death (PFS) by 66% (hazard ratio [HR]=0.34, 99% CI: 0.17-0.70, p<0.0001) compared to crizotinib in this specific form of lung cancer.7

Each year lung cancer causes 1.59 million deaths worldwide, more than any other cancer.8 NSCLC is the most common type of lung cancer, and is the leading cause of cancer-related deaths in Europe and across the world, accounting for approximately 85% of lung cancer cases.9 ALK-positive NSCLC occurs in approximately 5% of patients with advanced NSCLC, translating to about 75,000 patients being diagnosed with the disease annually.9,10 It is almost always found in people with a specific type of NSCLC called adenocarcinoma, and is more common in light or non-smokers.11

About the NP28673 study2
NP28673 is a phase I/II global, single arm, open-label, multicentre trial evaluating the safety and efficacy of Alecensa in 138 people with ALK-positive NSCLC whose disease progressed on crizotinib.
The study showed by assessment of an independent review committee an ORR of 50.8% (95% CI: 41.6%, 60.0%), as measured by RECIST criteria.
An investigator assessment also showed tumours shrank in 51.4% of people who received Alecensa (95% CI: 42.8%, 60.0%)

In addition, the people whose tumours shrank in response to Alecensa continued to respond for a median of 15.2 months (95% CI: 11.2, 24.9) (duration of response, DOR)

The median PFS for people who received Alecensa was 8.9 months (95% CI: 5.6, 12.8)
Alecensa demonstrated a safety profile consistent with that observed in previous studies.
The following events were reported in ≥2% of patients: dyspnoea (4%); anaemia (3%); fatigue, INR increased, pulmonary embolism and hyperbilirubinemia (each 2%).

About the NP28761 study3
NP28761 is a phase I/II North American, single arm, open-label, multicentre trial evaluating the safety and efficacy of Alecensa in 87 people with ALK-positive NSCLC whose disease progressed on crizotinib.
The study showed by assessment of an independent review committee an ORR of 52.2% (95% CI: 39.7%, 64.6%) as measured by RECIST criteria.
An investigator assessment showed tumours shrank in 52.9% of people who received Alecensa (95% CI: 41.9%, 63.7%).

In addition, the people whose tumours shrank in response to Alecensa continued to respond for a median of 14.9 months (95% CI: 6.9, NE) (DOR).

The median PFS for people who received Alecensa was 8.0 months (95% CI: 6.3, 12.6).
Alecensa demonstrated a safety profile consistent with that observed in previous studies.
The most common (occurring in at least 2% of people) Grade 3 or higher adverse events were an increase in muscle enzymes (increased blood levels of creatine phosphokinase; 8%), increased liver enzymes (alanine aminotransferase; 6%, and aspartate aminotransferase; 5%), shortness of breath (dyspnoea; 3%), elevated levels of triglyceride (hypertriglyceridaemia), decreased potassium level (hypokalaemia) low levels of phosphate in the blood (hypophosphatemia; 3%), partial blood thickening (thromboplastin; 2%) time prolonged.

About Alecensa
Alecensa (RG7853/AF-802/RO5424802/CH5424802) is an oral medicine created at Chugai Kamakura
Research Laboratories and is being developed for people with NSCLC whose tumours are identified as ALK-positive. ALK-positive NSCLC is often found in younger people who have a light or non-smoking history.11 It is almost always found in people with a specific type of NSCLC called adenocarcinoma.11 Alecensa is currently approved in the United States, Kuwait, Israel, Hong Kong, Canada, South Korea, Switzerland and India for the treatment of advanced (metastatic) ALK-positive NSCLC whose disease has worsened after, or who could not tolerate treatment with, crizotinib and in Japan for ALK positive NSCLC patients.5

In a pooled analysis of CNS endpoints from studies NP28673 and NP28761, Alecensa demonstrated activity in brain metastases, indicating that the drug may be taken up in the brain.4 The brain is protected by the blood-brain barrier, a network of tightly joined cells that line the inside of the blood vessels in the brain and spinal cord.12 One of the ways the blood-brain barrier prevents molecules from affecting the brain is to actively eject them from the barrier through a process known as ‘active efflux’.13 The active efflux system does not recognise Alecensa, which means that it may travel into and throughout brain tissue.2,3

The global phase III ALEX study of Alecensa includes a companion test developed by Roche Diagnostics. Alecensa is marketed in Japan by Chugai Pharmaceutical, a member of the Roche Group.

February 20, 2017: Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) today announces that a Phase II study of savolitinib has been initiated in locally advanced or metastatic pulmonary sarcomatoid carcinoma ("PSC") in China. Savolitinib is a highly selective and potent oral c-Met inhibitor with global first-in-class potential. The first drug dose was administered on February 10, 2017.

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This Phase II study is a multi-center, single-arm, open-label study to evaluate the efficacy and safety of savolitinib as a monotherapy in treating locally advanced or metastatic PSC patients harboring mesenchymal epithelial transition ("Met") gene alterations. The primary endpoint is objective response rate (ORR), with secondary endpoints including progression free survival (PFS), disease control rate (DCR), duration of response (DoR), overall survival (OS) and safety. Additional details about this study can be found at clinicaltrials.gov, using identifier NCT02897479.

About PSC and Met gene alterations

PSC is a rare subset of poorly differentiated non-small cell lung cancer ("NSCLC"). Containing a component with sarcoma-like (spindle and/or giant cell) features, PSC accounts for approximately 0.4% of all cases of lung cancer in the US, according to the Surveillance, Epidemiology and End Results database. These tumors are highly aggressive with outcomes significantly worse than other forms of NSCLC, and are more resistant to conventional chemotherapies[1],[2]. There is no approved targeted therapy for this fatal disease.

The sarcomatoid component of some PSC tumors is believed to derive from carcinoma cells through the activation of Met. Met gene exon 14 skipping has been reported as one of the major genetic alterations in PSC, acting as a negative control in Met signaling. This genetic alteration has been found in approximately 20-30% of PSC patients[3]. As such, a highly selective c-Met inhibitor may provide clinically meaningful benefit to patients with PSC.

About Savolitinib

Savolitinib is a potential global first-in-class inhibitor of c-Met (also known as mesenchymal epithelial transition factor) receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumors. It was developed as a potent and highly selective oral inhibitor specifically designed to address issues observed in the clinic with first-generation c-Met inhibitors, including renal toxicity.

On February 20, 2017 AstraZeneca reported that it has entered into an agreement with TerSera Therapeutics LLC (TerSera) for the commercial rights to Zoladex (goserelin acetate implant) in the US and Canada (Press release, AstraZeneca, FEB 20, 2017, View Source [SID1234517765]). Zoladex is an injectable luteinising hormone-releasing hormone agonist, used to treat prostate cancer, breast cancer and certain benign gynaecological disorders. It was first approved in the US and Canada in 1989.

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TerSera will pay AstraZeneca $250 million upon completion. AstraZeneca will also receive sales-related income through milestones totalling up to $70 million, as well as recurring quarterly sales-based payments at mid-teen percent of Product Sales. AstraZeneca will also manufacture and supply Zoladex to TerSera, providing a further source of ongoing income from Zoladex in the US and Canada.

Mark Mallon, Executive Vice President, Global Product & Portfolio Strategy at AstraZeneca said: "This agreement allows us to retain a significant share of the value of Zoladex in the US and Canada, while concentrating our resources on our innovative New Oncology medicines. It also ensures patients have continued access to Zoladex, with TerSera’s dedicated focus helping to expand the potential of this important medicine."

Ed Fiorentino, Chairman and CEO of TerSera Therapeutics, said: "We are very pleased to be partnering with AstraZeneca, and investing in the future growth of Zoladex, which continues to be a mainstay of treatment for its indicated uses."

Financial considerations
In 2016, Product Sales for Zoladex were $69 million in the US and Canada, and $816 million globally. AstraZeneca will continue to commercialise Zoladex in all markets outside the US and Canada. The transaction is expected to complete in the first quarter of 2017, subject to customary closing conditions. AstraZeneca will maintain a significant ongoing interest in Zoladex in the US and Canada through the sustainable and ongoing income from the upfront, milestone, quarterly sales-based and supply payments received from TerSera. The $250 million upfront, $70 million milestone payments and double-digit percentage quarterly sales-based payments received from TerSera will be reported as Externalisation Revenue in the Company’s financial statements.

The agreement does not include the transfer of any AstraZeneca employees or facilities and does not impact AstraZeneca’s financial guidance for 2017.