FDCs for CO PD: From Famine to a Feast of Therapeutic Choices

FDCs for CO PD: From Famine to a Feast of Therapeutic Choices LAURA RUNKEL, PhD Associate Director, CNS, AutoImmune/Inflammation, Ophthalmology

Historically, there have been few therapies developed for the treatment of chronic obstructive pulmonary disease (COPD), a life threatening, progressive obstructive respiratory disease that interferes with normal breathing and has detrimental effects on quality of life 1. In the 5 years between 19 and only a handful of drugs were approved for COPD. Those drugs included Boehringer Ingelheim s Spiriva (tiotropium), a long-acting muscarinic antagonist (LAMA), and twice-daily inhaled fixed dose combinations (FDCs) of long acting beta adrenoceptor agonist (LABA) plus inhaled corticosteroid (ICS). GlaxoSmithKline s (GSK) Advair (fluticasone propionate + salmeterol) and AstraZeneca (AZ) Symbicort, (budesonide + formoterol) were initially approved for asthma and their label expansions for COPD in ushered in the use of FDC therapies for symptom relief and maintenance therapy in that indication. In the past decade, as COPD clinical development intensified, the focus shifted towards developing FDCs of two novel bronchodilators. Four recently approved FDCs were developed, as dry powder formulations, specifically for moderate to severe COPD patients, and aimed to deliver once-daily symptom relief and maintenance treatment. In this report we provide insights from Citeline s and Trialtrove data into how these FDCs are carving out distinctive niches and what pipeline status FDCs are poised to enter this now competitive market in the near future. 1. World Health Organization: Chronic Obstructive Pulmonary Disease (COPD) Fact Sheet. http://www.who.int/mediacentre/factsheets/fs315/en/. [October 13].. (launched and approved COPD drugs, data accessed January 15)

Table 1 provides a snapshot of approved COPD therapeutics, highlighting the characteristics of the drugs, the program sponsors, and their approval timelines. Three LABA+LAMA FDCs (Ultibro, Anoro, and Brimica) and a once-daily ICS+LABA (Relvar) have been approved recently. Each of these programs was a partnership between sponsors that collaborated to develop novel components and provide clinical funding and the logistical support necessary to run global programs. Ultibro, Relvar, and Anoro gained their first approvals in 13, while the Brimica program achieved its first recommendation for approval approximately one year later. Anoro is the only program that has gained approval in all the major markets (US, EU and Japan) to date, while the other programs are still striving to gain wider approvals. table 1. approved therapies for chronic obstructive Pulmonary Disease Drug active agent moa sponsor first approvals Japan approval Unicontin (slow release) theophylline adenosine antagonist Purdue 19 199 Pulmicort budesonide ICS AstraZeneca 199 NA Oxis formoterol LABA AstraZeneca 199 1 Combivent salbutamol/ ipratropim Spriva tiotropium LAMA Brovana aformoterol LABA Advair Symbicort fluticasone +salmeterol budesonide +formoterol SABA+SAMA Boehringer Ingelheim Boehringer Ingelheim Dainippon Sumitomo 1997 NA 7 ICS+LABA GSK 9 NA ICS+LABA AstraZeneca 1 Onbrez indacaterol LABA Novartis, Sosei 9 11 Daxas roflumilast phosphodiesterase inhibitor Almirall, Forest, Takeda 1 Phase III Seebri glycopyrrolate LAMA Novartis, Sosei 1 1 Ultibro/ Xoterna Relvar/ Breo Anoro indacaterol +glycopyrrolate fluticasone +vilanterol umeclidinium +vilanterol LABA+ LAMA Novartis, Sosei 13 13 ICS+LABA GSK, Theravance 13 Withdrawn LABA+ LAMA Bretaris aclidinium LAMA Striverdi olodaterol LABA GSK, Theravance 13 1 Almirall, Forest, Kyorin Boehringer Ingelheim 1 Filed 1 13 Phase II Incruse umeclidinium LAMA GSK, Theravance 1 Filed 1 Brimica/ Duaklir aclidinium+ formoterol LABA+ LAMA Almirall/Forest, Kyorin 1 Phase III Abbreviations: LABA (long acting beta adrenoceptor agonist), LAMA (long-acting muscarinic antagonist), ICS (inhaled corticosteroid), Mechanism of Action (MOA) Source: Citeline s. Data Accessed January 15 3

scope and scale of clinical programs of recently approved fdcs for copd The timelines and scale of the four FDC clinical programs are shown by profiling the number of phase I III trials initiated in each year between and 13 (Figure 1). All programs ran in parallel from through 1, with notable differences in the number of phase I studies reported for each program. The Brimica program reported primarily phase II and III studies, while Ultibro development ran not only the largest program, but also the widest range of phases, including phase I/II and II/III trials not reported for other programs. The Ultibro clinical program included some studies for its novel monotherapy components, indacaterol (Arcapta/Onbrez) and glycopyrrolate (Seebri), which contributed some dose finding data. Pivotal trials of the three programs that achieved once-daily dosing, and gained approvals in 13, initiated over a span of three years: 9 (Relvar), 1 (Ultibro) and 11 (Anoro). The Brimica program aimed to achieve once-daily dosing originally, but did not achieve sufficient efficacy at that dosing regimen in a phase II study run in. Brimica s pivotal studies for twice-daily dosing initiated in 11, which created a delay for Brimica s first approval. The Ultibro program encountered hurdles to US approval in 11 for the once-daily dosing regimen. Hence, Novartis evaluated additional doses and settled on twice-daily indacaterol+glycopyrrolate (7.5/1.5 mcg) for later trials for US regulatory submission. 1 1 1 1 1 1 1 1 Relvar 3 Anoro Figure 1. COPD Trial Starts/Year for Recently Approved FDCs 3 5 7 9 5 7 9 1 11 1 13 1 11 I 1 13 I/II II 1 1 1 1 1 1 1 1 Ultibro Brimica 3 II/III 5 III 3 5 7 9 1 11 1 13 7 9 1 11 1 13 Trial starts (per year) and trial phases (I, I/II, II, II/III, III) for recently approved FDCs for COPD. Asterisk (*) denotes year when first pivotal trials initiated. Source: Citeline s Trialtrove. Data accessed November 1

Gaining approvals in the major markets requires coordination of study designs and safety/efficacy endpoints for a diverse subject population, and must satisfy different regulatory agencies. In particular for Japan, which often has distinctive requirements based on safety concerns for drugs tested in other populations, it is important to run adequate trials in the Japanese population to gain approval. The heat map (Figure ) illustrates the global scale of these programs, which is most pronounced for the phase III studies (Total Country Counts). It is interesting to note which programs ran studies in Asian countries in the context of their approvals. The Ultibro program achieved simultaneous EU and Japanese approvals supported by global, pivotal studies that included Japanese sites. On the other hand, Brimica was evaluated in some phase II and III studies run separately for Japanese subjects. These studies were sponsored by Almirall s Japanese partner, Kyorin, and some are still ongoing currently. Both of GSK s programs included Japanese sites in their global pivotal trials. Although Anoro gained approval in Japan in 1, the week safety data for Relvar was not sufficient to support filing for COPD approval in Japan in 13. A longer term Relvar study for Japanese COPD subjects may be used to support an eventual future filing in Japan 3. In addition, the Relvar program currently is running a 1, patient phase III study (the SUMMIT or Outcomes trial) for moderate COPD patients with a history, or risk, of cardiovascular disease to evaluate mortality out to months of treatment. The SUMMIT trial was designed to test the hypothesis that treatment with ICS+LABA can provide a mortality benefit to COPD subjects with less severe disease, and risk of cardiovascular disease, as was suggested by the post hoc analysis of the data from the TORCH trial 5. The SUMMIT trial s accrual accounts for ~5% of the number of patients in their phase III program, leaving the Ultibro program as the largest program by far in terms of number of total trials, pivotal trials, country counts, and number of patients. Figure. Global Scope and Scale for Phase II III Trials in the Recently Approved FDC Programs for COPD Program Phase total country count china hong kong india Japan malaysia Philippines singapore s. korea taiwan thailand Vietnam total trials Pivotal trials number of Patients Relvar Anoro Brimica Ultibro II 5 3 113 III 59 5 5 5 3 17 355 II 1 1 15 III 1 1 1 7 3 7 1 5 7 1391 II 1 5 1 1 13 195 III 31 3 1 19 3 113 II 9 1 1 31 III 51 5 1 9 7 1 9 11 391 Total country counts (per phase), count of trials per Asian country (per phase) and number of patients (by phase) for COPD trials of recently approved FDCs. Source: Citeline s Trialtrove. Data accessed November 1 3. NCT119191. A Long-term Safety Study of Fluticasone Furoate (FF)/GW in Japanese Subjects With COPD https://clinicaltrials.gov/ct/show/nct119191. NCT13137. Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease https://clinicaltrials.gov/ct/show/nct13137 5. Calverley PMA, Anderson JA, et al (1) Cardiovascular events in patients with COPD: TORCH study results. Thorax 1; 5:719-75 5 5

accrual numbers and enrollment rates for phase iii copd trials of recently approved fdcs The four FDC programs each enrolled primarily moderate to severe COPD patients, and were running in parallel to each other, thus, competing for trial subjects in many locations. Trial size and enrollment rates for global phase III studies were compared to determine what competitive advantages could be observed for these programs (Figure 3). The Brimica and Relvar phase III trials enrolled at a consistent rate across all of their trials that was slightly slower than the average rate (indicated by the red line, Figure 3). The Ultibro trials showed greater variation in enrollment rates and enrolled its larger studies much more slowly than its smaller studies. Interestingly, the Anoro phase III trials all enrolled at above average rates, perhaps contributing to the shorter timelines between the start of pivotal trials (11) and the first regulatory filing (December 13). Figure 3. Accrual Numbers and Enrollment Rates for Phase III COPD Trials for Recently Approved FDCs 5.5 Actual Accural 15 1 5 1.5 1.5 Patients per Site per Month Brimica Relvar Anoro Ultibro Accrual numbers (bars) and enrollment rates (orange line) for global phase III COPD trials for recently approved FDCs. Red dotted line and arrow denote average enrollment rate of phase III trials. Source: Citeline s Trialtrove/Trialpredict. December 1

Primary endpoints and study design details for phase ii iii trials for recently approved fdcs Since all of these FDC programs aimed to provide once-daily inhaled therapy to the same COPD population, it is interesting to evaluate their strategies to gain approvals globally and to distinguish themselves from their competitors. Comparisons of the primary endpoints for these programs are shown in Figure. Primary endpoints for efficacy (lung function measured by FEV1) and safety were evaluated in phase II and III trials for all FDC programs. These programs evaluated efficacy (FEV1) measurements out to weeks, and safety evaluations of both short ( weeks weeks) and long (5 weeks) term. Several programs also included studies with primary endpoints that allowed correlation of lung function improvements with other important measures of therapeutic benefits, such as exacerbations, dyspnea, exercise endurance, peak inspiratory capacity and quality of life (QoL). Exercise endurance was evaluated in 3 or more phase III trials for all programs, except Relvar, a program that only evaluated FEV1, safety and exacerbation rates. The Ultibro phase III program stands out for its large number of phase III trials and the widest range of primary endpoints that support claims of functional benefits associated with improved lung function (FEV1). Figure. Primary Endpoints of Completed Phase II and III COPD Trials for Recently Approved FDCs Ultibro Brimica Anoro Relvar III II III II III II III II Efficacy (FEV1) Dyspnea Exacerbations Exercise endurance Peak Inspiratory Capacity PK QoL Safety 1 3 5 Source: Citeline s Trialtrove. Data accessed December 1 Study design features for these programs also shared common elements (Table ). For example, the comparison of each FDC to its individual components was a requirement for pivotal trials. However, the Anoro and Ultibro programs also included pivotal trials evaluating the novel FDC compared to the standard of care, tiotropium (Spiriva). In addition, the Ultibro program included a pivotal trial comparing it to Advair, the other market leader for COPD maintenance therapy. Dose response studies were previously run for the monotherapies comprising Ultibro. Hence, dose response studies played a smaller role in the Ultibro program and were not required for the regulatory filings in the EU or Japan. Taken together with the wide range of primary endpoints evaluated, the benefits of Ultibro are better demonstrated in clinical studies than they were by the other programs. 7

table. study Design features of completed Phase ii and iii copd trials for recently approved fdcs Drugs monotherapy comparator active comparator (approved Drug) Dose response Relvar Anoro Brimica Ultibro Exacerbations, Safety, FEV1 Exercise endurance, Safety, FEV1 PK, Safety, FEV1, Exercise endurance Exacerbations, Safety, FEV1 Tiotropium (Safety, FEV1) Advair (FEV1) Tiotropium (FEV1, Safety) Salmeterol (Safety) Advair (FEV1) Tiotropium (FEV1) Advair (FEV1) Tiotropium (Peak IC, Dyspnea, Exacerbations, Safety, QoL, Exercise endurance, FEV1) Salmeterol (Safety, FEV1) Advair (FEV1) Exacerbations, Safety, FEV1 Exercise endurance, Safety, FEV1 FEV1 FEV1, Safety Monotherapy comparators are the individual components of each FDC. Blue text highlights the primary endpoints of trials presented in regulatory filings. Source: Citeline s Trialtrove. Data accessed December 1 Pipeline status fdc copd therapeutics The recently approved FDCs have just been launched but already will be facing additional competition in the near future, as illustrated by the late stage FDCs summarized in Table 3. Boehringer Ingelheim s (BI) olodaterol+tiotropium and AstraZeneca s (AZ) PT-3 are delivered as aerosolized inhaled drugs, rather than dry powders, which distinguishes them from the approved FDCs by delivery system. In addition to the LABA+LAMA FDCs, GSK and Chiesi advanced their ICS+LABA+LAMA triple combination FDCS into phase III trials in 1. table 3. Late stage fdcs in clinical Development for copd Drug moa sponsor formulation global status olodaterol+tiotropium LABA +LAMA Boehringer Ingelheim Aerosolized solution (once daily) Pre-registration formoterol+glycopyrrolate (PT-3) LABA +LAMA AstraZeneca/ Pearl Pharma Aerosolized HFA MDI ( puffs, twice daily) Phase III beclometasone +formoterol+glycopyrrolate ICS+ LABA +LAMA Chiesi Aerosolized solution HFA-pMDI (twice daily) Phase III fluticasone furoate +vilanterol+umeclidinium ICS+ LABA +LAMA GSK, Theravance Dry powder (once daily) Phase III Abbreviations: LABA (long acting beta adrenoceptor agonist), LAMA (long-acting muscarinic antagonist), ICS (inhaled corticosteroid), Mechanism of Action (MOA) Source: Citeline s. Data accessed December 1

Insights into distinctive features of the pipeline FDCs can be observed from the patient populations enrolled in phase II -III trials and their primary endpoints (Figure 5). BI and AZ trials target both the moderate to severe COPD population and include very severe COPD patients in some trials. In addition, a greater focus on reducing exacerbation rates is observed, particularly for the triple (ICS+LABA+LAMA) FDCs, as more trials are enrolling patients with exacerbations and exacerbation rates are being evaluated as the primary endpoint. Figure 5. Patient Segments (Left) and Primary Endpoints (Right) of Phase II and III COPD Trials for Pipeline FDCs 1 1 1 1 Moderate, Severe, Very Severe Moderate, Severe Moderate 1 1 1 1 Safety PK Exercise endurance 1 Mild, Moderate 1 Exacerbations Exacerbation, Severe, Very severe Exacerbation, Severe Efficacy (FEV1), QoL Efficacy (FEV1) Exacerbation Device reliability Boehringer Ingelheim LABA + LAMA AstraZeneca LABA + LAMA Chiesi ICS + LABA + LAMA GSK ICS + LABA + LAMA Boehringer Ingelheim LABA + LAMA AstraZeneca LABA + LAMA Chiesi ICS + LABA + LAMA GSK ICS + LABA + LAMA Source: Citeline s Trialtrove. Data accessed December 1 9

conclusions The therapeutic options available to COPD patients have recently grown dramatically as global clinical programs reached fruition in 13-1. Two novel once-daily FDCs of LABA+LAMAs (Ultibro, Anoro), and a once-daily ICS+LABA (Relvar), have been widely launched, while twice-daily Brimica was just approved in the EU in November 1. Study design, scope and scale of the clinical trials, and primary outcome comparisons illuminated aspects of the program strategies that led to their successes and, in some case, to delays. Novartis Ultibro program was the largest clinical program and achieved approvals for once-daily FDC in the EU and Japan simultaneously in 13. This program evaluated the widest range of primary endpoints and included more active comparator studies. These broader clinical objectives are reflected in the German Federal Joint Committee s granting Ultibro an additional benefit rating vs. tiotropium and formoterol, and Health Canada s consideration that Ultibro significantly reduced shortness of breath as part of their approval 7. Although the Ultibro approval was delayed in the US, Novartis submitted their NDA in Q 1 with results from two phase III trials that evaluated twice-daily dosing. If Ultibro is approved after its lag coming onto the US market, its prospects may benefit from the disappointing launches of GSK s Anoro and Relvar in the US. This is a good example of how the clinical development race is important in initially positioning new drugs in major markets, but the later steps play a big role in securing the return on investment. The competition for this active market is already looming large. BI s pre-registration status FDC (olodaterol + tiotropium) is formulated as an aerosolized solution, delivered by the Respimat inhaler. Although BI s program was late to reach this status, it may have advantages from being familiar to COPD patients already using Spiriva Respimat. AZ s PT-3 (formoterol + glycopyrrolate) is a twice-daily, hydrofluoroalkane metered dose (HFA-MDI) formulation that could offer an alternative to COPD patients who prefer this delivery system. AZ did not join the first round of competition for once-daily FDCs, but now is developing several respiratory portfolios. In addition to the PT-3 program, AZ acquired Almirall s respiratory program in July 1, and is in phase II for a triple combination of budesonide + formoterol + glycopyrrolate. AZ s rich portfolio of monotherapy agents, available in different formulations and delivery systems, positions them to step into a bigger role in the future COPD market. GSK and Chiesi already have triple FDCs (ICS+LABA+LAMA) in phase III trials. The focus of these programs is on reducing exacerbations in a more severe COPD population, which carves out a different niche from that of the recently approved FDCs. Chiesi s phase III trials are projected to complete in early 1 and are running primarily in the EU. GSK s 1, patient IMPACT trial 9 is its only pivotal study for their triple FDC program. Although the IMPACT trial is projected to complete later, in mid-17, the study enrolls patients in the three major markets and may show the same efficiencies shown by GSK s Anoro program. By enrolling the IMPACT trial quickly and casting the broadest net for first approvals, GSK could gain the edge among triple FDC products. No results have been reported yet for the triple combination FDCs, but a balance between risk and benefit will likely to be the critical factor in gaining approvals for COPD. After 3 years with few therapeutic breakthroughs, COPD patients can now breathe easier with a feast of options to manage their symptoms and improve quality of their life.. BioMedTracker: Drug Impact Events (Ultibro), May, 1 7. BioMedTracker: Drug Impact Events (Ultibro), December 3, 13. Scripintelligence, October 3, 1, GSK climbs as structural overhaul revealed 9. NCT1513. A Study Comparing the Efficacy, Safety and Tolerability of Fixed Dose Combination (FDC) of FF/ UMEC/VI With the FDC of FF/VI and UMEC/VI; Administered Once-daily Via a Dry Powder Inhaler (DPI) in Subjects With Chronic Obstructive Pulmonary Disease (COPD) https://clinicaltrials.gov/show/nct1513 1