Clinical Therapeutic Intelligence Report: 2015 Year in Review

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1 Clinical Therapeutic Intelligence Report: 2015 Year in Review This issue highlights the many ground-breaking therapies approved by the U.S. Food and Drug Administration over the course of Highlights include immunotherapies, new treatment options for breast cancer patients, and financial assistance options for cancer patients. Breakthrough therapies for blood, lung and skin cancers dominated 2015 oncology approvals. There were 17 new oral and infusion approvals, with 10 expanded indications for drugs approved prior to 2015*. Only eight new drugs and one expanded indication were approved in 2014, representing a 200 percent increase in just one year. Immunotherapies swept the approvals, with s nivolumab and Merck Oncology s pembrolizumab, previously approved for melanoma, adding indications for non-small cell lung cancer and renal cell carcinoma over the course of the year really established a new line of therapy for, essentially, the vast majority of non-small cell lung cancer patients, and that was immunotherapy, said Dr. Mark Socinski, Director of the Lung Cancer Section of the Divison of Hematology/Oncology at the University of Pittsburgh School of Medicine. These approvals created choices, and from that perspective, 2015 was a monumental year. Of 50 oncologists surveyed by MedPage Today, 37 cited immunotherapy drugs as game-changers in 2015 i. Checkpoint s spread into new tumor types heralded new thinking about ways in which certain cancers can be treated, while also showing promise for more difficult types of cancers. AstraZeneca s osimertinib, approved for the treatment of patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer, has also garnered attention in the oncology space. Oncologists are optimistic about its benefit for patients, despite the relatively small patient population ii. Osimertinib is the first of it s kind, the issue is that it s a much smaller patient population, said Socinski. Palbociclib, developed by Pfizer,, was granted accelerated approval in February for postmenopausal women with ER+/ HER2- advanced breast cancer, the largest subgroup of breast cancer cases iii. Palbociclib targets a family of proteins responsible for cell growth, and is the first new first-line therapy for this patient population in 10 years. Other key approvals include s panobinostat and Takeda Oncology s ixazomib, both approved for the treatment of multiple myeloma. Approved for advanced colorectal cancer, trifluiridine/tipiracil is a new treatment option for patients who no longer responded to other therapies developed by Taiho Oncology. * Biosimilars have not been included See full list of oncology drug approvals on pages 3-4.

2 A look ahead: the 2016 pipeline According to the Pharmaceutical Research and Manufacturers of America (PhRMA), of the 771 new drugs and vaccines in the development pipeline, 98 are being developed for lung cancer, 87 for leukemia, 78 for lymphoma, 73 for breast cancer, 56 for skin cancer, and 48 for ovarian cancer iv. A noteworthy drug in the pipeline is AbbVie s venetoclax, an of the b-cell lymphoma-2 (bcl-2) protein, that has received two Breakthrough Therapy designations v. The FDA has recently granted Breakthrough Therapy designation to venetoclax in combination with rituximab for patients with relapsed/refractory Chronic Lymphocytic Leukemia. In a Phase 1b study, it has been reported that 41 percent (20 of 49 patients) have acheived either a complete response or complete response with incomplete marrow recovery. Eighty-four percent of patients acheived an objective response to the treatment vi. In April 2015, the FDA granted Breakthrough Therapy designation to single agent venetoclax for the treatment of patients with relapsed/refractory Chronic Lymphocytic Leukemia with the 17p deletion genetic mutation. This single agent application was also granted Priority Review. Roche s PD-L1 checkpoint, atezolizumab, is already causing excitement among oncologists vii. At the 2015 European Cancer Congress, Roche investigators reported atezolizumab showed a 7.7-month survival advantage over chemotherapy for lung cancer patients with a significant expression of PD-L1. Twenty-seven percent of the same type of patients saw tumors shrink, while in another trial, 27 perecent of bladder cancer patients with significant PD-L1 expression responded to atezolizumab. According to Roche s chief of global product development, these results represent the first major treatment advancement for advanced bladder cancer patients in nearly 30 years. Financial assistance for oncology therapies Many cancer patients experience financial hardships during treatment. Even with insurance, the copay and out-ofpocket costs for medications is often hard to manage. Due to this financial strain, an estimated 10 to 20 percent of patients do not take or otherwise compromise their treatment viii. Often, the greater the out-of-pocket cost for the oral cancer therapy, the lower the compliance. The main forms of assistance available for medication costs are foundations and manufacturer assistance programs. Foundation Assistance Most foundations only offer copay assistance programs; the full price of the drug will not be covered ix. For insured patients with high out-of-pocket copays, foundation Biologics, assistance programs will be able to help with that cost. Foundations have different assistance programs 120 for Weston various Oaks disease Court states, so patients must apply to the specific program within the foundation. Depending on Cary, the time NC of year, funding is not always available. Requirements for receiving financial assistance vary across foundations, but most programs have an income limitation of percent of the Federal Poverty Guidelines, and some consider the cost of living index. Manufacturer Assistance Programs Assistance programs for patients without insurance are run by the manufacturer of the drug. The majority of these programs provide free drug to eligible patients for a specified amount of time, with the option to reapply. Similar to foundations, these programs have income limitations of percent of the Federal Poverty Guidelines. Eligibility for Manufacturer Assistance Programs is often restricted to patients without insurance, or with Medicare Part D benefits or insurance plans that do not cover any of their medication. Applying for Assistance Some organizations will let healthcare providers complete all or most of the application process on behalf of the patient. While the application process varies across programs, patient and prescriber contact information, proof of income, prescription information, medical history and insurance coverage is often required.

3 2015 Drug Approval Breakdown Drug Name Manufacturer Indication Genetics Route of Administration Mechanism Clinical Trial Results Biologics Availability IMBRUVICA (ibrutinib) Janssen Waldenström s macroglobulinemia (WM) N/A PO BTK 62% of patients had cancer shrink for (WM) IBRANCE (palbociclib) Pfizer, ER-positive, HER2-negative advanced breast cancer ER, HER2 PO CDK4/ of progression free survival, compared to 10.2 LENVIMA (lenvatinib) Eisai, Radioactive iodine-refractory differentiated thyroid cancer N/A PO Multi-kinase Median of 18.3 of progression free survival, compared to median of 3.6 FARYDAK (panobinostat) vartis Multiple myeloma N/A PO HDAC 10.6 of progression-free survival, compared to 5.8 Metastatic squamous non-small cell lung cancer BRAF IV PD-1 blocking 15% experienced objective response rate, 59% had response durations of 6 or longer UNITUXIN (dinutuximab) United Therapeutics Pediatric high-risk neuroblastoma N/A IV GD2-binding monoclonal Three year estimate of overall survival was 80%, compared to 67% CYRAMZA (ramucirumab) Eli Lilly and Company Metastatic colorectal cancer (mcrc) VEGFR2 IV VEGFR2 antagonist Median overall surival was 13.3, compared to 11.7 with placebo IRESSA (gefitinib) AstraZeneca Metastatic non-small cell lung cancer EGFR mutationpositive PO EGFR 70% overall response rate, with a median duration of response of 8.3 ODOMZO (sonidegib) vartis Locally advanced basal cell carcinoma N/A PO Hedgehog signaling pathway 58% overall response rate, with a duration of 1.9 to 18.6 Kyprolis (carfilzomib) Onyx, Multiple myeloma N/A IV Proteasome 22.9% overall response rate, with a median duration of 7.8 ADCETRIS (brentuximab vedotin) Seattle Genetics Classical Hodgkin lymphoma, Systemic anaplastic large cell lymphoma N/A IV CD30-directed -drug conjugate 73% of patients achieved either a complete or partial response to treatment, responses lasted on average 6.7 LONSURF (trifluridine/ tipiracil) Taiho Oncology, Metastatic colorectal cancer N/A PO Nucleoside metabolic, thymidine phosphorylase Median overall survival lasted an average of 7.1 compared to 5.3 In combination with ipilimumab for BRAF V600 wild-type, unresectable or metastatic melanoma BRAF IV PD-1 blocking Overall response rate of 60% in nivolumab plus ipilimumab group, compared to 11% in ipilimumab group, an improvement in ORR of 49%

4 2015 Drug Approval Breakdown Drug Name Manufacturer Indication Genetics Route of Administration Mechanism Clinical Trial Results Biologics Availability KEYTRUDA (pembrolizumab) Merck Sharp and Dohme Metastatic non-small cell lung cancer Tumors shrank in 41% of patients, and effect lasted between 2.1 and 9.1 Metastatic non-squamous nonsmall cell lung cancer Overall survival of 12.2, compared to 9.4 in patients treated with docetaxel ONIVYDE (irinotecan liposome injection) Merrimack, Metastatic adenocarcinoma of the pancreas N/A IV Topoisomerase Median overall survival of 6.1 for patients who received irinotecan liposome in combination with 5FU and LV YONDELIS (trabectedin) Janssen Biotech liposarcoma or leiomyosarcoma N/A IV Alkylating drug Median overall survival lasted 13.7, with median progression free survival of 4.2 YERVOY (ipilimumab) COTELLIC (cobimetinib) TAGRISSO (osimertinib) DARZALEX (daratumumab injection) NINLARO (ixazomib) MEKINIST (trametinib) TAFINLAR (dabrafenib) Cutaneous melanoma N/A IV CTLA-4-blocking Genentech, AstraZeneca melanoma Metastatic EGFR T790M-positive non-small cell lung cancer Median recurrence-free survival of 26 BRAF PO MEK Median progression free survival of 12.3 EGFR PO EGFR-TKI Two studies showed overall response rates of 57% and 61%, respectively Jannsen Biotech Multiple myeloma N/A IV Human CD38- directed monoclonal Takeda vartis Multiple myeloma N/A PO Proteasome BRAF-mutated melanoma BRAF PO MEK1/2, BRAF Objective response rate of 29% with a median response duration of 7.4 Median progression free survival of 20.6, compared to 14.7 Overall survival of 25.1 in combination, compared to 18.7 compared to dabrafenib monotherapy PORTRAZZA (necitumumab) EMPLICITI (elotuzumab) ALECENSA (alectinib) KEYTRUDA (pembrolizumab) Advanced renal cell carcinoma N/A IV PD-1 blocking Eli Lilly and Company Metastatic squamous non-small cell lung cancer Median overall survival of 25, with a median response duration of 23 N/A IV EGFR antagonist Median overall survival of 11.5, with median progression free survival of 5.7 Multiple myeloma SLAMF7 IV SLAMF7-directed immunostimulatory Hoffmann-La Roche, Merck Sharp and Dohme ALK+ metastatic non-small cell lung cancer melanoma (First-Line therapy) Median progression free survival of 19.4, with an overall response rate of 78.5% ALK PO ALK 44% of patients experienced tumor shrinkage, effect lasted for an average of 7.5 Median progression free survival of 5.5 and 4.2 for pembrolizumab, compared to 2.8 for ipilimumab

5 Sources: i Immunotherapy Is Game-Changer for Oncology, Roger Sergel. December 27, ii FDA Updates: Oncology, Surabhi Dani-Garimella, PhD, December 16, iii FDA approves groundbreaking new drug, Ibrance, for patients with estrogen-receptor positive advance breast cancer, Science Daily, February 3, iv The 2015 Oncology Drug Pipeline: Innovation Drives the Race to Cure Cancer, American Health & Drug Benefits, June v AbbVie s venetoclax receives Breakthrough Therapy designation from FDA in combination with rituximab for the treatment of patients with relapsed/refractory Chronic Lymphocytic Leukemia, AbbVie, January 20, vi For Refractory CLL, Venetoclax s Complete Response Rate Is Tops, Medscape, June 15, vii Roche wins kudos for game-changing atezolizumab cancer data, FierceBiotech, September 28, viii In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs, Mayo Clinic Proceedings, July 23, ix Financial Assistance for Oncology Therapies, Biologics, vember 5, More Information To sign up to receive additional information about the Oncology Pipeline, please info@biologicsinc.com. Contact Us Phone: info@biologicsinc.com biologicsinc.com Biologics, 120 Weston Oaks Court Cary, NC Connect with us on LinkedIn, just search for Biologics, Like us on Facebook, just search for Biologics, Follow us on Twitter, we Copyright Biologics, All rights reserved.