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Fda's Rocket Docket WEEK OF APRIL 20, 2015 8 STRATEGY: METAMORPHOSES OF OVID Newco Ovid is working with patients and families to develop failed drugs for rare and Orphan brain diseases, starting with Angelman syndrome FDA’S ROCKET DOCKET 11 EMERGING COMPANY PROFILE: EAST BY SOUTH BY STEVE USDIN, WASHINGTON EDITOR China’s Nuance hopes to draw in-licensing partners by using South Africa to add patient diversity FDA is approving more cancer drugs, more rapidly than and speed to global development programs. ever, and the trend is likely to continue, according to Richard Pazdur, director of the Office of Hematology and Oncology Drug Products at FDA’s Center for Drug Evaluation and Research. 12 REGULATION: GETTING PERSONAL IN BREAST CANCER In an interview with BioCentury TV, Pazdur said Breast cancer patients tell FDA they want unprecedented efficacy in early stage trials is prompting a more personalized approach to collecting the agency to review cancer drug applications as and applying risk-benefit data. quickly as possible, to approve cancer drugs based on single-arm and early stage trials, and to streamline review procedures for supplemental indications. Pazdur’s comments, and the reality on the ground, 15 REGULATION: JAPAN EMBARKS ON SAKIGAKE represent a complete reversal of the messages he and Japan is rolling out its sakigake early access pathway, which FDA were sending drug sponsors five and 10 years could cut approval times for innovative therapies in half. ago. Pazdur attributes the turnaround to advances in the scientific understanding of cancer that have made the development of drugs targeting molecular and immunological pathways possible. In addition to scientific advances, Pazdur highlighted 17 EBB & FLOW: LIKING JAPAN’S RETAIL EXODUS the role of patients in helping to shape cancer drug development. Beyond the bull run in Japan. Plus: Why Biocartis picked Euronext; X is for Atlas; and He also pointed to areas where he feels FDA should Sofinnova Ventures’ diagnostic play. improve its policies, such as creating regulations to compel sponsors to start Phase I trials in pediatric indications of targeted cancer therapies when companies start a Phase II trial in an adult indication. Pazdur also noted that broad dissemination of early data “touted as major breakthroughs” is fueling demand for access to experimental drugs. As a result, he said FDA and drug sponsors should make it easier for patients to understand whether and how they can get access to unapproved cancer drugs outside of clinical trials. Biosimilars are another area where FDA needs to focus attention, Pazdur said. EMERGING STRATEGY REGULATION FINANCE COMPANIES “WHAT IT REPRESENTS IS THE FRUITION OF A LOT OF INVESTIGATION AND BASIC SCIENCE THAT HAS OCCURRED OVER THE PAST 20 YEARS.” RICHARD PAZDUR, FDA GETTING BETTER ALL THE TIME seeing is -- with targeted drugs and the new molecules that are targeting Pazdur told BioCentury there is a simple explanation for his shift from the immunological pathways -- response rates of sometimes 50%.” skepticism to enthusiasm about new cancer drugs: “Drugs got better.” MEDIAN NOT THE MESSAGE Unambiguous efficacy signals make it easier, and quicker, for FDA to A strong efficacy signal led FDA to push for a very rapid review of BMS’s approve new cancer drugs, he said. FDA is consistently beating PDUFA Opdivo nivolumab to treat patients with metastatic squamous non-small goals by 50 days or more (see “Beating the Clock,” page 6). cell lung cancer (NSCLC) who have progressed on or after platinum- “We’re not seeing drugs and arguing with sponsors about whether the based chemotherapy, Pazdur told BioCentury TV in a program on the drug should be approved or not,” Pazdur said. “What we’re asking our future of lung cancer therapies. reviewers and the sponsor is how rapidly we can approve these drugs. “I remember very well sitting down at my desk at home and opening up We’re not dealing with drugs that have a response rate of 7%. We’re my computer and putting in the password, because the survival curves dealing with drugs that have response rates of 50, 60, 70%, so it’s a much were protected in an encrypted email, and seeing those survival curves, easier regulatory decision whether the drug should be approved or not and I was very impressed by them,” Pazdur said. approved.” The data showed a 3.2-month survival advantage for patients who Improvements in efficacy, which Pazdur noted are often accompanied by received Opdivo compared with those who received docetaxel. improved safety, are likely to continue because they are based on broad scientific advances, he said. Pazdur immediately began calling reviewers and the division director, Patricia Keegan, to talk about how to approach the review, because he “I really see this as a major foundation change, and it really has to do with thought it was important to get the drug to patients. “It really represented a better understanding of both the drug and the disease,” Pazdur said. a paradigm shift in how we treat squamous cell lung cancer, especially in a “Really what it represents is the fruition of a lot of investigation and basic second-line setting,” he said. science that has occurred over the past 20 years.” But Gideon Blumenthal added, “When we’re looking at these Efficacy and safety readouts from early studies are leading FDA to approve immunotherapy agents, the median is not the message.” Blumenthal is a cancer drugs based on Phase II, and even in some cases Phase I trials, clinical team leader in the Office of Hematology and Oncology Products, Pazdur said. told BioCentury TV “When drugs have very profound activity in a particular disease, what “We learned this also in melanoma with ipilimumab and other PD-1 we’re doing is basically expanding Phase I studies into cohorts of patients inhibitors,” Blumenthal said. “There are certain patients, and we don’t that could be entered into a registration schema,” Pazdur noted. know exactly who those patients are as of yet, who derive a great deal of Merck & Co. Inc.’s Keytruda pembrolizumab is an example. FDA benefit, and even may have five-year survival. If you look at the melanoma approved the drug in September 2014 based on a 24% response rate literature, maybe 20% of patients can live five years out.” among 173 patients with advanced melanoma in a Phase Ib trial that was FDA approved Opdivo on March 4, more than three months ahead of the ongoing. The agency approved the drug for patients previously treated PDUFA goal (see “Opdivo Urgency,” page 3). with Bristol-Myers Squibb Co.’s Yervoy ipilimumab. Pazdur decided Opdivo needed to be approved quickly both because “The traditional response rate for a Phase I study in oncology, for patients who had run out of options were waiting, and because the conventional cytotoxic drugs in the ’80s, ’90s, and the early part of this approval could affect ongoing lung cancer trials, such as the Lung-MAP century was basically about 5%, or less than 5%,” Pazdur said. “What we’re trial, a master protocol trial designed to evaluate several compounds simultaneously to treat squamous cell lung cancer. 2 WEEK OF APRIL 20, 2015 BIOCENTURY TOC EMERGING STRATEGY REGULATION FINANCE COMPANIES OPDIVO URGENCY MOVING UP IN BLOOD CANCERS FDA pulled out all the stops to approve Bristol-Myers Squibb Co.’s Opdivo nivolumab to treat patients with metastatic squamous non- small cell lung cancer who have progressed on or after platinum- Hematologic cancer drug development has been so successful that based chemotherapy. The agency began reviewing trial data before FDA views it as a paradigm for the development of therapies for it was available to the company, and completed the review in March, other kinds of cancer, Richard Pazdur, director of FDA’s Office of more than three months ahead of the PDUFA goal. Hematology and Oncology Products, told BioCentury TV. Opdivo is the first PD-1 modulator to be approved for NSCLC. He cited early successes in developing drugs for Hodgkin’s disease, Three other PD-1 or PD-L1 modulators are in Phase III NSCLC trials: acute lymphoblastic leukemia (ALL) and childhood leukemia, as well MEDI4736 from AstraZeneca plc, Keytruda pembrolizumab from as large cell and B cell lymphomas. Merck & Co. Inc. and RG7446 from Genentech Inc. For some hematologic cancers, numerous drugs with different Full approval of Opdivo based on a survival advantage over docetaxel mechanisms of action have been approved, so there is a pressing does not raise the bar for approval of other PD-1 modulators for need to study how they should be combined and sequenced, NSCLC, FDA’s Gideon Blumenthal told BioCentury TV. Blumenthal Pazdur said. Chronic lymphocytic leukemia (CLL) — for which nine is a clinical team leader in the Office of Hematology and Oncology treatments are approved — is an example. Products at the Center for Drug Evaluation and Research. Nicole Gormley, a medical officer in the Division of Hematology “It doesn’t change our sense of urgency,” Blumenthal said. He noted Products, noted two anti-CD20 mAbs have been approved for the other modulators may have different toxicity profiles, and he added indication: Arzerra ofatumumab from Genmab A/S and Novartis that they are being tested using different clinical design strategies. AG, and Gazyva obinutuzumab from Biogen Inc. and Genentech Inc. Genentech and Biogen also market Rituxan rituximab, an anti- “They’re looking at various stages, different histologies, CD20 mAb that is used in combination with several of the newer CLL adenocarcinoma versus squamous. Some are looking at earlier therapies. stages, even adjuvant curative setting. So there’s still a strong all- hands-on-deck mentality for some of these other agents,” he said.
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