Exploring New Advances and Best Practices to Personalize Therapy and Improve Lung Function in Cystic Fibrosis

CME/CNE/CPE Exploring New Advances and Best Practices to Personalize Therapy and Improve Lung Function in Cystic Fibrosis Course Director Jerry Nick, MD National Jewish Health University of Colorado Denver, Colorado What s Inside 3 Advances in Cystic Fibrosis Therapy: Class III, IV, and V CFTR Mutations 8 11 14 Advances in Cystic Fibrosis Therapy: Class II CFTR Mutations Advances in Cystic Fibrosis Therapy: What Is on the Horizon? Optimizing Cystic Fibrosis Management: A Case-Based Discussion Participate in interactive questions, download activity slides, and obtain your instant CME/CNE/CPE credit online. www.peerviewpress.com/bgd9

Activity Information Activity Description and Educational Objectives In this activity, an expert in pulmonology outlines methods of personalizing therapy and improving lung function for patients with cystic fibrosis. Upon completion of this activity, participants will be able to: Assess approved and emerging therapeutic options in terms of efficacy, safety, and clinical potential to improve pulmonary and nonpulmonary outcomes of patients with cystic fibrosis Employ or support the employment of evidence-based, individualized treatment plans for patients with cystic fibrosis throughout the continuum of disease Discuss current challenges with medication and treatment adherence in the cystic fibrosis population Target Audience This activity has been designed to meet the educational needs of pulmonologists, pediatricians, registered nurses, advanced-practice nurses, physician assistants, pharmacists, and other clinicians involved in the management of cystic fibrosis (CF). Requirements for Successful Completion In order to receive credit, participants must view the activity and complete the post-test and evaluation form. There are no pre-requisites and there is no fee to participate in this activity or to receive CME/CNE/CPE credit. Statements of Credit are awarded upon successful completion of the post-test and evaluation form. Participants should review all presentations in this activity before proceeding to the post-test to claim CME/CNE/CPE credit for the activity. Media: Enduring Material Release and Expiration Dates: March 3, 217 - March 29, 218 Time to Complete: 6 minutes Faculty & Disclosure / Conflict of Interest Policy In accordance with ACCME requirements, National Jewish Health has a conflict of interest policy that requires faculty to disclose relevant financial relationships related to the content of their presentations/materials. Any potential conflicts are resolved so that presentations are evidence-based and scientifically balanced. Course Director Jerry Nick, MD Director, Adult CF Program Professor of Medicine National Jewish Health Professor of Medicine Division of Pulmonary and Critical Care Medicine University of Colorado Denver, Colorado Jerry Nick, MD, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from Vertex Pharmaceuticals Incorporated. Advisory Board for Cystic Fibrosis Foundation; Gilead; and Vertex Pharmaceuticals Incorporated. CME Reviewer Steven E. Lommatzsch, MD National Jewish Health Denver, Colorado Steven E. Lommatzsch, MD, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from Corbus and Gilead. Nurse Reviewer Allidah Poole Hicks, RN, AE-C, MS National Jewish Health Denver, Colorado Allidah Poole Hicks, RN, AE-C, MS, has no financial interests/relationships or affiliations in relation to this activity. CPE Reviewers Renee Sprik, RPh, PharmD National Jewish Health Denver, Colorado Renee Sprik, RPh, PharmD, has a financial interest/relationship or affiliation in the form of: Consultant for Gerson-Lehrem Group. Andrea Harshman, MHA, CHCP, has no financial interests/relationships or affiliations in relation to this activity. Medical Director Chris Washburn, PhD PVI, PeerView Institute for Medical Education Chris Washburn, PhD, has no financial interests/relationships or affiliations in relation to this activity. CME/CNE/CPE Disclaimer National Jewish Health ("NJH") and its officers, Board of Directors, faculty, employees, representatives, and other agents (collectively, "NJH Parties") shall not be responsible in any capacity for, and do not warrant any content whatsoever, in any NJH publication or other product (in any medium), or the use or reliance on any such content, and expressly disclaim any and all liability for such content. 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Nurses National Jewish Health is a provider approved by the California Board of Registered Nursing, Provider Number CEP 12724. This activity is approved for a total of 1.2 Nursing Contact Hour(s). Pharmacists National Jewish Health is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. National Jewish Health designates this enduring material for 1. contact hour(s) (.1 CEUs) of the Accreditation Council for Pharmacy Education. Universal Activity Number: 831-9999-17-1-H1-P Type of Activity: Application-Based Support This activity is supported by an educational grant from Vertex Pharmaceuticals Incorporated. Disclosure of Unlabeled Use The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our reports. No responsibility is taken for errors or omissions in reports. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView Press or any of its partners, providers, and/or supporters. Andrea Harshman, MHA, CHCP National Jewish Health Denver, Colorado 2 Go online to complete the post-test and evaluation for CME/CNE/CPE credit www.peerviewpress.com/bgd9

Exploring New Advances and Best Practices to Personalize Therapy and Improve Lung Function in Cystic Fibrosis Advances in Cystic Fibrosis Therapy: Class III, IV, and V CFTR Mutations Dr. Nick: Hello, this is Jerry Nick from National Jewish Health. Welcome to this educational activity on cystic fibrosis. After completing the activity, access the post-test and evaluation form by clicking the red Get Certificate button. I encourage you to download the slides, Practice Aids, and any other activity features that may interest you. Cystic Fibrosis 1 Rare, life-shortening, autosomal recessive disease caused by mutations in the CFTR gene 75, people in North America, Europe, and Australia Results in thick sticky mucus that obstructs the airways and ducts of the pancreas Median age at death in 215 was 3 years Number of Deaths 4 3 2 1 Number of deaths Cumulative percentage Age at Death in 215 <1 5 1 15 2 25 3 35 4 45 5 55 6 65 7 Years 1. https://www.cff.org/our-research/cf-patient-registry/215- Patient-Registry-Annual-Data-Report.pdf. Accessed February 21, 217. Cystic fibrosis is a rare, life-shortening, autosomal recessive disease caused by mutations in the CFTR gene. Approximately 75, people in North America, Europe, and Australia are affected with the disease. The mutation in the CFTR gene results in thick, sticky mucus that obstructs the airways and ducts of the pancreas. Although median predicted survival has increased over the last 2 years, the median age of death in 215 was only 3 years old. 1 75 5 25 Cumulative Percentage CFTR Dysfunction: Cystic Fibrosis Lung Pathology Vicious Cycle 1 CFTR gene defect Abnormal CFTR protein Defective ion transport Airway surface liquid depletion Defective mucociliary clearance Mucus obstruction Infection Cycle of destruction End-stage lung disease Scarring Inflammation 1. Schmidt BZ et al. Clin Pharmacol. 216;8:127-14. Gene therapy DNA or RNA editing CFTR modulators Osmotic agents Dornase alfa Inhaled antibiotics Airway clearance techniques Azithromycin Lung transplant Defects in the CFTR gene result in abnormal CFTR proteins and a defective ion transport. This results in airway surface liquid that is dehydrated and depleted, which results in [defective] mucocilliary clearance and contributes to a cycle of mucus obstruction, infection, inflammation, and scarring. The result of this cycle over decades of life is end-stage lung disease. Traditionally, CF [treatment] has been focused on the end-stage manifestations of the disease. In particular, patients are treated with dornase alfa, inhaled antibiotics, and a variety of airway clearance techniques. In addition, chronic azithromycin has been demonstrated as an effective immunosuppression and an antiinflammatory medication. In patients with end-stage lung disease, lung transplant can be offered. More recently, osmotic agents, including hypertonic saline and inhaled mannitol, have been used to rehydrate the airway surface liquid. Now, CFTR modulators are available for approximately 6% of CFTR genotypes. These are focused on correcting both abnormal CFTR protein synthesis, as well as restoring partially the defective ion transport. In the future, gene therapy or DNA or RNA editing may be available to directly address the CFTR gene defect. 3

Challenge in Targeted CFTR Therapy 1 Patients (1 or 2 copies), % 1 8 6 4 2 F58/F58 (46%) a G551D, R117H, and other gating mutations (7.3%) a a Represents mutations for which there is an approved therapy. CFTR modulator therapy is currently limited to specific genotypes Nearly all CFTR mutations are rare and are not completely characterized F58del G542X G551D a R117H a N133K W1282X R553X 621+1G T 1717-1G A 3849+1kbC T 2789+5G A 312+1G A I57del R1162X 1898+1G A 3659delC G85E D1152H R56T R347P 2184insA A455E R334W Q493X 2184delA +1,8 mutations 1. http://www.cysticfibrosisdata.org/reportsus.html. Accessed February 23, 217. The challenge in targeted CFTR therapy is the extensive array of CFTR mutations. Currently, CFTR modulator therapy is limited to specific genotypes, and among the top 2 CFTR mutations, only delta-f58, G551D, and R117H currently have approved CFTR modulators. The additional approximately 1,8 mutations are rare, and for the most part not completely characterized, which imposes a tremendous challenge to the development of new modulators based on the current method of clinical trials. The class III mutations include the G551D mutation, of which approximately 4.4% of CF patients in the United States have a single copy. Other gating mutations account for an additional 1.1%, and the R117H mutation, which shares some of the gating mutation features, accounts for 2.9% of CF patients. Mechanism of Ivacaftor 1 CFTR Chloride ion Golgi complex Proteosome Endoplasmic reticulum mrna DNA Increase the opening time of CFTR protein, resulting in greater ion flow Potentiators Prolong presence of CFTR protein GSNOR inhibitors Facilitate processing and trafficking of CFTR protein Correctors Next-generation correctors Increase the amount of immature CFTR protein Gene therapy DNA editing mrna editing Read-through premature stop codons Amplifiers (increased translation) 1. Adapted from: Lukacs GL et al. N Engl J Med. 23;349:141-144. Ivacaftor was the first CFTR modulator, and it was developed specifically for the class III mutations. The mechanism of action is to increase the opening time of the CFTR protein, resulting in greater ion flow. These types of CFTR modulators have been labeled as potentiators. Class III CFTR Mutations 1 Ivacaftor: Change in Lung Function in G551D Patients 1,2 Cl - Cl - Cl - Cl Cl - - Cl - 16 Normal CFTR is created, reaches cell surface, and functions properly, allowing transfer of chloride and water Class III CFTR protein is created and reaches cell surface, but the gate does not function properly G551D S549N V52F R117H Mutation Class III Mutation Prevalence All People With CF, % Heterozygous G551D 4.4 Other gating mutations 1.1 Heterozygous R117H 2.9 Absolute Change in ppfev 1 From Baseline, With 95% CI 12 8 4-4 8 16 24 32 4 48 Weeks PBO IVA Study 12 Study 13B 1. https://www.cff.org/our-research/cf-patient-registry/215- Patient-Registry-Annual-Data-Report.pdf. Accessed February 21, 217. The first available CFTR modulator was focused on class III CFTR mutations. The class III mutations feature a CFTR protein that is created and reaches the cell surface but does not gate properly. Therefore, it has reduced ion transport, resulting in dehydrated airway ciliary liquid phase. 1. Ramsey BW. N Engl J Med. 211;365:1663-1672. 2. Davis J. Am J Respir Crit Care Med. 213;187:1219-1225. The strongest evidence from phase 3 clinical trials for the efficacy of ivacaftor comes from studies in the G551D patients. This slide demonstrates the absolute change in FEV 1 percent predicted from baseline over a period of 48 weeks in the two phase 3 trials which led to FDA [US Food and Drug Administration] approval of the agent. 4 Go online to complete the post-test and evaluation for CME/CNE/CPE credit www.peerviewpress.com/bgd9

There was an approximately 1% improvement in FEV 1 associated with ivacaftor therapy, which occurred within the first 2 weeks and was sustained throughout the 48 weeks of the trial. This improvement in FEV 1 corresponded to a significant reduction in sweat chloride in the same subjects. PERSIST: Prolonged Benefit of Ivacaftor 1 Estimated ppfev 1 a P <.1. Initial Improvement Reduced rate of decline, P =.3 8 75 7 65 6 Baseline a 8.29 points Start of analysis a 9.9 points a G551D IVA group F58del control group 9.89 points Year 1 Year 2 Year 3 47% decrease in the rate of decline a 1.7 points 1. Sawicki GS et al. Am J Respir Crit Care Med. 215;192:836 842. The prolonged benefits of ivacaftor are demonstrated in this figure from the PERSIST study, in which patients treated with ivacaftor who had a G551D mutation were compared to a delta-f58 control group. Over a 3-year period, there was a sustained benefit with ivacaftor relative to delta-f58 as measured by the slope of FEV 1 decline, with a 4% decrease in the rate of decline associated with the ivacaftor treatment group. The response to ivacaftor was also demonstrated in regards to other gating mutations. In the KONNECTION trial, an additional ten gating mutations were tested in an aggregate and demonstrated a very similar improvement in FEV 1 compared to placebo, as depicted in the plot on the left. This improvement in FEV 1 was sustained, as well, through an open-label extension, which is depicted on the right. Ivacaftor in Children Aged 2-5: VX77-18 KIWI 1 A two-part, open-label study to evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor Patients with CF aged 2 through 5 years with a CFTR gating mutation G551D, G178R, S549N, S549R, G551S, G97R, G1244E, S1251N, G1349D, S1255P Absolute Change From Baseline Sweat Chloride, mmol/l 1-1 2-3 -4-5 -6 Baseline 2 8 16 24 Visit, wk 1. Davie JC et al. Lancet Respir Med. 216;4:17-115. IVA 5 mg every 12 h IVA 75 mg every 12 h The benefit of ivacaftor in children age 2 through 5 was also demonstrated in the KIWI study. In this trial, patients as young as age 2 with the G551D as well as the other gating mutations were administered ivacaftor either at 5 mg or 75 mg. And in that study, both doses resulted in a significant reduction in sweat chloride levels as early as two weeks, and which was sustained for up to 24 weeks. Response to Ivacaftor by Other Gating Mutations Ivacaftor Coverage of R117H Mutations: KONDUCT 1 KONNECTION Blinded, placebo-controlled, 8-week, crossover study of ivacaftor in other CFTR gating mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, and G97R) with open-label extension 1 Absolute Change From Baseline in ppfev 1, % Points, Mean ± SE 15 1 5-5 -1 n = 38 n = 37 n = 38 n = 37 IVA PBO n = 37 n = 37 2 4 8 Week Absolute Change From Baseline in ppfev 1, % Points, Mean ± SE 18 16 14 12 1 8 16-week open-label 6 period begins 4 2 N = 18 for all time points Baseline a 2 4 8 16 24 Week Absolute Change in ppfev 1, Percentage Points 1 8 6 4 2-2 -4 IVA IVA PBO IVA KONDUCT Washout period KONTINUE All patients on ivacaftor 2 4 8 16 24 a 2 12 Week a Defined as day 1 of treatment period 2 in part 1. Only patients from treatment sequence 2 (placebo ivacaftor) in part 1 are represented. 1. De Boeck K et al. J Cyst Fibros. 214;13:674-68. a At week of KONTINUE, data presented are mean change (±SE) from KONDUCT baseline at KONDUCT follow-up visit. 1. Moss R et al. Lancet Respir Med. 215;3:524-533. 5

Benefits of ivacaftor were also demonstrated in the context of the R117H mutation, which included both an adult and pediatric cohort. This plot demonstrates the absolute change in predicted FEV 1 for patients receiving ivacaftor compared to the placebocontrolled group. Ivacaftor May Act in Residual Function Mutations 1,2 Cl - Cl - Cl - Cl Cl - - Cl - Cl - Cl - Cl - Cl- - The KONDUCT trial went for 24 weeks with a washout period. During the washout period, both the treatment group and the placebo-controlled group returned to baseline. And then, on the KONTINUE trial, both cohorts were treated with open-label ivacaftor, and both of them regained their improvement in FEV 1 seen during the double-blinded phase. Of note, however, the relative and absolute improvement in FEV 1 achieved in the R117H cohort did not equal that which was seen with G551D or the other gating mutations. Normal CFTR is created, reaches cell surface, and functions properly, allowing transfer of chloride and water Class IV The opening in the CFTR protein ion channel is faulty R117H D1152H R347P Class V CFTR is created in insufficient quantities 3849+1kbC T 2789+5G A A455E Mutation Prevalence Mutation All People With CF, % Class IV-V 1.9 Long-Term Real-World Data for Ivacaftor 1 Outcome Death Organ transplant Interim Data From Long-Term Observational Safety Study Using US and UK CF Registries Presented at NACFC Hospitalization Pulmonary exacerbations IVA (n = 1,256) n (%) 8 (.6) 2 (.2) 346 (27.6) 349 (27.8) US CF Registry COMP (n = 6,2) n (%) 97 (1.6) 68 (1.1) 2,671 (43.1) 2,684 (43.4) RR (95% CI).41 (.2-.84).15 (.4-.59).64 (.58-.7).64 (.58-.7) IVA (n = 411) n (%) 3 (.7) 2 (.5) 17 (26.) 14 (34.1) UK CF Registry COMP (n = 2,69) n (%) 29 (1.4) 18 (.9) 937 (45.3) 1,157 (55.9) RR (95% CI).52 (.16-1.7).56 (P =.56) a.57 (.48-.68).61 (.53-.7) 1. https://www.cff.org/our-research/cf-patient-registry/215- Patient-Registry-Annual-Data-Report.pdf. Accessed February 21, 217. 2. De Boeck K and Amaral MD. Lancet Respir Med. 216;4:662-674. Going forward, ivacaftor is being evaluated for its effect in residual function mutations. These are mutations in class IV and class V, in which a protein is present on the surface of the cell, but in the case of class IV, it's not a properly functional protein. In the case of class V, the protein is functional, but present in insufficient quantities. Ivacaftor Improves Chloride Transport in Residual Function CFTR Mutations In Vitro 1 a Fisher's exact test P values are shown when the expected value was >5 in at least one cell of the contingency table. 1. Bessonova L et al. 3th Annual North American Cystic Fibrosis Conference. Abstract 494. Of tremendous interest to the CF community is the long-term realworld data for ivacaftor. As it's relatively new, during its worldwide rollout, we don't have an extensive body of literature. However, depicted here is a table, that was presented in the 216 North American CF conference which provides some preliminary evaluation of how patients are doing with ivacaftor in terms of endpoints, including death, organ transplant, hospitalizations, and pulmonary exacerbations. Chloride Transport, % Normal CFTR 25 2 15 1 5 With IVA Without IVA L26W R347H S977F S945L A455E F174L E56K P67L R17W D11H D579G D11E R17Q L997F A167T E193K R117H R74W K16T R668C D127N D1152H S1235R F152V Ussing chamber studies using FRT cells expressing the mutant CFTR forms indicated that ivacaftor is a broad-acting CFTR potentiator 1. Van Goor F et al. J Cyst Fibrosis. 214;13:29-36. In a comparison from the U.S. CF registry of ivacaftor with a comparator group of patients, a significant reduction in relative risk was achieved for death and organ transplant as well as hospitalization and pulmonary exacerbation. Similar effects were seen in the UK CF registry, although numbers were too small to reach significance in terms of a reduction in organ transplant. But together, these data, combined with the open-label long-term extension data, provides a good deal of confidence that the effects of ivacaftor are sustainable, both in terms of time and in terms of a more real-world experience. There are strong preclinical data from in vitro studies of FRT cells expressing mutant CFTR forms in class IV and class V, which indicate that there can be an improvement in chloride transport in these classes of mutations. In this plot, chloride transport is depicted on the left axis, and various mutations of interest are depicted on the y-axis. We see that in the absence of ivacaftor, the bars in red are enhanced with the presence of ivacaftor to varying degrees, as depicted by the bars, the stacked bars in blue. 6 Go online to complete the post-test and evaluation for CME/CNE/CPE credit www.peerviewpress.com/bgd9

Ivacaftor: Drug Drug Interactions 1 Increase Ivacaftor Exposure CYP3A inducers Rifampin St. John s wort Metabolized by CYP3A Ketoconazole Itraconazole Posaconazole Voriconazole Clarithromycin CYP3A inhibitors Reduce Ivacaftor Exposure 1. Kalydeco (ivacaftor) Package Insert. http://pi.vrtx.com/files/ uspi_ivacaftor.pdf. Accessed February 17, 217. For physicians prescribing ivacaftor, there are a number of concerns with regard to potential drug-drug interactions with medications that are often used in the treatment of CF. Ivacaftor is metabolized by CYP3A enzymes, and thus CYP3A inducers, such as rifampin or St. John wort will reduce ivacaftor exposure. In contrast, CYP3A inhibitors, including the azole groups of antifungal medications and clarithromycin, will increase ivacaftor exposure. However, azithromycin does not have this effect. 7

Advances in Cystic Fibrosis Therapy: Class II CFTR Mutations Class II CFTR Mutations 1,2 Cl - Cl - Cl - Cl Cl - - Cl - F58del Mutation Prevalence F58del Mutation All People With CF, % Homozygous F58del 46.1 The approved agent for the treatment of CFTR modulation in F58del is ivacaftor/lumacaftor, which uses a combinational approach to increasing CFTR activity. Lumacaftor serves to facilitate trafficking of the CFTR protein and is termed a corrector. It results in a protein reaching the cell surface. This protein is not typically functional. However, the combination of ivacaftor allows the increase in opening of the CFTR protein similar to the effect in the class III gating mutations. Long Term Lumacaftor/Ivacaftor Benefit in F58del Homozygotes 1 Normal CFTR is created, reaches cell surface, and functions properly, allowing transfer of chloride and water Class II CFTR protein is created but misfolded, keeping it from reaching the cell surface F58del N133K 157del Heterozygous F58del 4.3 LS Mean ppfev 1 Change With 95% CI 6 4 2 TRAFFIC/ TRANSPORT PROGRESS 4 mg lumacaftor/25 mg ivacaftor every 12 h PBO 1. https://www.cff.org/our-research/cf-patient-registry/215- Patient-Registry-Annual-Data-Report.pdf. Accessed February 21, 217. 2. De Boeck K and Amaral MD. Lancet Respir Med. 216;4:662-674. Dr. Nick: Going forward, the greatest target for benefit in the CF community is the class II mutations, which include delta-f58. Class II mutations are characterized by a CFTR protein that is created but is misfolded and never reaches the cell surface. Approximately 46% of patients with CF in the United States are homozygote or F58del, and approximately 4% are heterozygote or F58del. Mechanism of Ivacaftor/Lumacaftor Combination Approach to Increasing CFTR Activity 1 CFTR Chloride ion Golgi complex Proteosome Endoplasmic reticulum mrna DNA Increase the opening time of CFTR protein, resulting in greater ion flow Potentiators (ivacaftor) Prolong presence of CFTR protein GSNOR inhibitors Facilitate processing and trafficking of CFTR protein Correctors (lumacaftor) Next-generation correctors Increase the amount of immature CFTR protein Gene therapy DNA editing mrna editing Read-through premature stop codons Amplifiers (increased translation) -2 4 8 16 24 8 16 24 36 48 6 72 84 96 Week Also saw significant reduction in pulmonary exacerbations on lumacaftor/ivacaftor, which may be related to improvement in FEV 1 1. Konstan MW et al. Lancet Respir Med. 217;5:17-118. The best evidence to date of the long-term benefit of lumacaftor/ ivacaftor comes from the TRAFFIC and TRANSPORT trials, which are phase 3 double-blinded placebo-controlled trials, which led to FDA approval of the drug. With patients receiving ivacaftor/lumacaftor, we see a rapid and sustained improvement in FEV 1 over 24 weeks. At that time, both groups shifted to an open-label phase, and we see that the placebo group quickly achieved the same improvement that was seen with the drug-treated group. There was, over the 96-week trial, a gradual decrease in FEV 1 noted. It's also important to observe that the overall improvement in FEV 1 was far short of what was achieved in the context of ivacaftor treatment of the G551D mutation, and that the error bars, which represent the amount of patient-to-patient variability, were also quite large in the setting of ivacaftor and lumacaftor. Not shown on this graph was a significant improvement in reduction of frequency of pulmonary exacerbations for patients on the study drug, and this was likely a major component of the improvement in FEV 1. 1. Adapted from: Lukacs GL et al. N Engl J Med. 23;349:141-144. 8 Go online to complete the post-test and evaluation for CME/CNE/CPE credit www.peerviewpress.com/bgd9

Long Term Lumacaftor/Ivacaftor Benefit in F58del Homozygotes (Cont d) 1 ppfev 1 (GLI) Estimate 65 6 55 2.38 Lumacaftor 4 mg every 12 h/ ivacaftor 25 mg every 12 h (n = 455) PBO (n = 1,588) Lumacaftor/ivacaftor treated patients ppfev 1 loss -1.33/y (95% CI, -1.8 to -.85) 3.35 F58del-CFTR controls ppfev 1 loss -2.29/y (95% CI, -2.56 to -2.3) Start Year 1 Year 2 4.31 42% decrease in the rate of decline In some patients, there was a severe decrease in lung function, and in particular this occurred in patients with more advanced disease and an FEV 1 less than 4%. Both in clinical practice and in the clinical trials, the majority of patients had a resolution of these effects within the first ten to 14 days. Therefore, if patients are counseled ahead of time, the majority of them are able to work through these symptoms and continue with the treatment. There is a small incidence in liver enzyme elevation also associated with the use of lumacaftor/ivacaftor. In general, the best strategy for initiating treatment is to optimize ongoing CF care, in particular, increase the use of dornase alfa, hypertonic saline, and bronchodilators, and certainly the agents should not be started when patients are sick or below baseline with regard to their lung function. 1. Konstan MW et al. Lancet Respir Med. 217;5:17-118. Long-term benefit of lumacaftor/ivacaftor has also been demonstrated in a preliminary fashion, and similar to what we saw with G551D group, ivacaftor/lumacaftor-treated patients demonstrated a significant decrease in the rate of FEV 1 decline, although FEV 1 decline did continue. Considerations Before Initiating Lumacaftor/Ivacaftor 1 AEs That Should Be Monitored and May Necessitate Stopping/ Discontinuing Lumacaftor/Ivacaftor Liver enzyme elevation >3x normal limit Severe respiratory symptoms (more commonly seen in patients with severe CF [ie, FEV 1 <4% predicted]) Bronchospasm, chest tightness Severe decrease in lung function Managing Potential AEs Explain to patients that the first week or 2 on lumacaftor/ivacaftor can be difficult, and what to expect Optimize airway clearance prior to initiating therapy Increase use of dornase alfa or hypertonic saline to open up the airways, augmenting bronchodilators Ivacaftor/Lumacaftor: Drug Drug Interactions 1 CYP3A inducers Lumacaftor Rifampin St. John s wort Reduce Ivacaftor Exposure Metabolized by CYP3A Increase Ivacaftor Exposure Ketoconazole Itraconazole Posaconazole Voriconazole Clarithromycin CYP3A inhibitors 1. Kalydeco (ivacaftor) Package Insert. http://pi.vrtx.com/files/ uspi_ivacaftor.pdf. Accessed February 17, 217. As with ivacaftor, ivacaftor/lumacaftor has a number of drug-drug interactions. The ivacaftor component is, of course, metabolized by CYP3A, and the same inducers and inhibitors are in play, but in addition, lumacaftor itself is a CYP3A inducer. 1. Orkambi (lumacaftor/ivacaftor) Package Insert. http://pi.vrtx. com/files/uspi_lumacaftor_ivacaftor.pdf. Accessed February 17, 217. There's a number of considerations physicians face before initiating lumacaftor/ivacaftor. There was a considerable frequency of bronchospasm and chest tightness reported both on the clinical trial and in clinical use, which is associated with the initiation of treatment. So lumacaftor serves to reduce ivacaftor exposure, and for that reason, the dose of ivacaftor in the lumacaftor/ivacaftor combination is much higher than the dose of ivacaftor given as a single agent to the class III of gating mutations. 9

Lumacaftor: Drug Drug Interactions 1 Complicated Induction and Inhibition of Several CYP Enzymes Montelukast Prednisone Ibuprofen Antifungals Clarithromycin Antidepressents Proton pump inhibitors H2 blockers Warfarin Hormonal contraceptives (all routes) Decreased Exposure and Efficacy 1. Kalydeco (ivacaftor) Package Insert. http://pi.vrtx.com/files/ uspi_ivacaftor.pdf. Accessed February 17, 217. Other drug drug interactions can be quite complicated due to induction and inhibition of several CYP enzymes. Some of the drugs commonly used in the treatment of CF that can be affected include montelukast, prednisone, ibuprofen, the various azole antifungal group, clarithromycin, a variety of antidepressants, proton pump inhibitors, H2 blockers, and warfarin. In this case, these have decreased exposure and efficacy. Lumacaftor is also associated with a decreased efficacy of hormonal contraceptives administered by all routes, so patients need to be counseled that they could experience a higher rate of birth control failure when on treatment with lumacaftor. 1 Go online to complete the post-test and evaluation for CME/CNE/CPE credit www.peerviewpress.com/bgd9

Advances in Cystic Fibrosis Therapy: What Is on the Horizon? Tezacaftor (VX-661) + Ivacaftor 1 Tezacaftor (CFTR corrector), which has similar effects as lumacaftor with a few different characteristics, was evaluated in a randomized, double-blind phase 2 trial In this phase 2 trial, through day 28, a significant decrease in sweat chloride was seen in the delta-f58 homozygote group, as well as an additional decrease in sweat chloride seen in the G551D group in addition to what they had already achieved through ivacaftor. Likewise, a small but significant improvement in FEV 1 was achieved in both patient cohorts. Tezacaftor (VX-661) + Ivacaftor Eligibility Criteria Aged 12 y (n = 18) Had received ivacaftor for an average of ~1 y Homozygous or heterozygous for the F58del-CFTR mutation R Tezacaftor (1 mg) + Ivacaftor (15 mg) Ivacaftor (15 mg) + PBO Phase 3 program generates safety and efficacy data in 1,+ patients Key role in development of triple combination with next-generation corrector F58del Residual function Genotype Trial Name (n), Duration Status F58del F58del EVOLVE (n = 5) 24 weeks 1 Met primary and secondary endpoints EXPAND (n = 2) Two 8-week crossover treatment periods 2 Met primary and secondary endpoints 4 weeks Gating F58del (n = 2) Enrollment completion 8 weeks 3 in early 217 1. http://clinicaltrials.gov/show/nct1531673. Accessed March 23, 217. Minimal function F58del a Study stopped based on futility analysis. (n = 15) Contributes to safety 12 weeks 4,a database for VX-661 Dr. Nick: In part, due to the number of side effects, drug drug interactions, and the relatively small benefit achieved to date with lumacaftor, additional agents are undergoing clinical trials. The agent that is now in phase 3 trials is tezacaftor, which is administered in combination with ivacaftor. A phase 2 trial is now completed in which two cohorts of patients were studied. First, patients with F58del, G551D, in which tezacaftor was added to ivacaftor, which the patients were already being administered, and then a second cohort of F58del homozygote patients in which the combination tezacaftor/ ivacaftor were added. Tezacaftor (VX-661) + Ivacaftor: Relative Change in FEV 1 at Day 28 1 Phase 2: Addition of tezacaftor to ivacaftor in F58del/G551D or tezacaftor with ivacaftor in F58del/F58del Sweat chloride Mean absolute change in lung function (ppfev 1 ) Tezacaftor + Ivacaftor, Day Through Day 28 F58del/F58del (n = 128) -5.7 mmol/l (P <.5; n = 14) +4.8 absolute points (P =.1; n = 15) F58del/G551D (n = 18) -7. mmol/l percentage points (P =.53; n = 13) +4.6 absolute points (P =.12; n = 14) 1. https://clinicaltrials.gov/ct2/show/nct2565914. Accessed January 3, 217. 2. https://clinicaltrials.gov/ct2/show/nct251641. Accessed January 3, 217. 3. https://clinicaltrials.gov/ct2/show/nct2565914. Accessed January 3, 217. 4. https://clinicaltrials.gov/ct2/show/nct2347657. Accessed January 3, 217. Based on these encouraging phase 2 results, four phase 3 trials were initiated. The study groups included delta-f58 homozygote, delta-f58 combined with a residual function or a class IV or V CFTR mutation, delta-f58 in combination with a gating mutation, and then delta-f58 in combination with a minimal function mutation. In this setting, it was essentially studying the role of a single delta-f58 in response to tezacaftor/ivacaftor. The minimal function delta-f58 mutation cohort study has been stopped at this time based on a futility analysis at 12 weeks. The other three trials are continuing, with expected completion of enrollment and data in the year 217. 1. Pilewski JM et al. J Cystic Fibrosis. 215;14:S1. 11

VX-44 Phase 2 Study Design 1 Regimen: 4 weeks of triple combination or PBO (Parts A and B) VX-44/tezacaftor/ivacaftor Part B includes 4-week lead-in and washout periods of only tezacaftor/ivacaftor Part A F58del/minimal function (n = ~4) Cohort 1a Part B F58del/F58del (n = ~25) A second next-generation corrector that is undergoing a similar study design is VX-152, which also will be dosed in combination with tezacaftor and ivacaftor as a three-drug combination. And again, F58del with minimal function is being studied in a small cohort as well as F58del homozygote patients with similar endpoints of safety and efficacy. Primary endpoints: safety, tolerability, and absolute change in ppfev 1 Secondary endpoints: relative change in ppfev 1, sweat chloride, CFQ-R respiratory score, others Data expectation: second half 217 Phase 2 study of VX-152/tezacaftor/ ivacaftor also planned to begin in 216 Cohort 1b Part C F58del/minimal function (n = ~13) Part B Phase 3 1. https://clinicaltrials.gov/ct2/show/nct2951182. Accessed January 3, 217. The next phase for corrector therapy includes the use of a triple combination in which the potentiator ivacaftor would be included with two correctors, tezacaftor and VX-44. A phase 2 trial is now underway, which includes a cohort of F58del combined with a minimal-function mutation as well as F58del homozygote patients. The primary endpoint will be safety and tolerability, as well as secondary endpoints including change in FEV 1 and sweat chloride levels, along with quality of life and respiratory scores. Data from this trial are expected in the second half of 217. VX-152 Phase 2 Study Design 1 Class I CFTR Mutations 1,2 Cl - Cl - Cl - Cl Cl - - Cl - Normal CFTR is created, reaches cell surface, and functions properly, allowing transfer of chloride and water X Class I No functional CFTR created G542X W1282X R553X F58del Mutation Prevalence F58del Mutation All People With CF, % Heterozygous G542X 4.6 Heterozygous W1282X 2.3 Heterozygous R553X 1.8 1. https://www.cff.org/our-research/cf-patient-registry/215- Patient-Registry-Annual-Data-Report.pdf. Accessed February 21, 217. 2. De Boeck K and Amaral MD. Lancet Respir Med. 216;4:662-674. The class I CFTR mutations are also an important clinical target. Approximately 9% of the CF population has one of the three most common class I mutations. Class I mutations are severe mutations that feature no functional CFTR protein based on transcription failure. Regimen: 2 weeks of triple combination or placebo VX-152/tezacaftor/ivacaftor Part B includes 4-week lead-in and 2-week washout period of only tezacaftor/ivacaftor Primary endpoints: safety and tolerability Secondary endpoints: absolute and relative change in ppfev 1, sweat chloride, CFQ-R respiratory score, others Data expectation: second half 217 (Parts A and B) Part A F58del/minimal function (n = ~35) Cohort 1a Cohort 1b Cohort 1c Part B F58del/F58del (n = ~25) Cohort 1a Cohort 1b 1. http://investors.vrtx.com/releasedetail.cfm?releaseid=844677. Accessed January 3, 217. Mechanism of Ataluren: Increase CFTR Activity Through Increased Immature CFTR Protein Availability 1 CFTR Chloride ion Golgi complex Proteosome Endoplasmic reticulum mrna DNA Increase the opening time of CFTR protein, resulting in greater ion flow Potentiators (ivacaftor) Prolong presence of CFTR protein GSNOR inhibitors Facilitate processing and trafficking of CFTR protein Correctors (lumacaftor) Next-generation correctors Increase the amount of immature CFTR protein Gene therapy DNA editing mrna editing Read-through premature stop codons Amplifiers (increased translation) 1. Adapted from: Lukacs GL et al. N Engl J Med. 23;349:141-144. 12 Go online to complete the post-test and evaluation for CME/CNE/CPE credit www.peerviewpress.com/bgd9

The drug under furthest development was ataluren, which works to increase CFTR activity through increased immature CFTR protein availability. Two phase 3 trials have been conducted now, in which ataluren was given to CF patients with a CFTR nonsense mutation greater than age 6 with critical endpoints of FEV 1 as the primary study endpoint. The results of both of these trials were essentially negative and development of the drug has now been discontinued. However, the CF Foundation therapeutics is spearheading a nonsense and rare mutation program, which includes screening and development of compounds that will allow for creation of a full-length protein, specifically for patients with these type 1 nonsense mutations. CFTR Modulator Pipeline Is Diversified 1 Name Class PTI-428 Amplifier GLPG2451 Potentiator GLPG2222 Corrector GLPG2665 Corrector QBW267 Corrector CTP-656 Potentiator BAY 63-2521 Corrector FDL169 Corrector N91115 GSNOR inhibitor VX-152 Corrector GLPG1837 Corrector VX-44 Corrector VX-661 Corrector Phase 1 Phase 2 Phase 3 1. https://www.cff.org/trials/pipeline. Accessed February 21, 217. Although time does not permit us going through each of the different CFTR modulators in development, there is a diversified pipeline in which a variety of potentiators, correctors, amplifiers, and a GSNOR inhibitor are being tested in phase 1, phase 2, and phase 3 trials. So there certainly is a great deal of optimism that additional patient mutations will soon receive therapy, and that existing cohorts that are currently being treated may have improved therapies available in the foreseeable future. 13

Optimizing Cystic Fibrosis Management: A Case-Based Discussion Participation in a Clinical Trial Enhances Adherence Reported Adherence in CF Trials Tobramycin inhalation solution (88% to 93%) 1 Used at least 75% of ampules Ivacaftor (89% to 91%) 2 Total dose counted Adherence to Non Trial-Related Treatments Also Tends to Increase 3 Medication refills increased during trial but then decreased back to baseline afterward 1. Ramsey BW et al. N Engl J Med. 1999;34:23-3. 2. Ramsey BW et al. N Engl J Med. 211;365:1663-1672. 3. van Onzenoot HA et al. Hypertension. 211;58:573-578. It is now understood that participation in clinical trials enhances adherence to both study of medications as well as adherence to non trial-related treatment. In trials of inhaled tobramycin solution, as many as 93% of patients used three-quarters of their ampules. And in the ivacaftor trials, approximately 9% of patients completed the total dose count. In addition, these study patients, while on trial, tended to have increased med refills of their non trial-related treatment, correlating with improved adherence. However, this improvement in adherence decreased to baseline when the clinical trial ended. For this reason, in real-world settings, the benefits seen in a clinical trial may not be achieved in a particular patient. Patient Profile: Matt Age: 19 y Weight: 175 lbs Height: 6 1 CFTR mutations: F58del and F58del Previous Medical History Diagnosed with CF at age 1 y P aeruginosa positive sputum cultures since childhood Presentation More cough than normal A little more sputum production Fatigue, but also not getting adequate sleep Medications Ivacaftor/lumacaftor Dornase alfa Hypertonic saline 7% Azithromycin 5 mg MWF Pancreatic enzymes with meals Inhaled tobramycin every other month Visit Notes Feels anxious/overwhelmed with workload during first semester at college FEV 1 down 1% from baseline (7%) after starting ivacaftor/lumacaftor Reports discontinuing dornase alfa and inhaled tobramycin Matt is a 19-year-old with cystic fibrosis and is homozygote for the F58del mutation. He presents to his clinic with increased cough and sputum production, as well as fatigue, although he admits to not getting adequate sleep. Matt was diagnosed with CF at age 1 year old, and has been positive for Pseudomonas throughout childhood and his adolescence. At this time, he is being treated with ivacaftor/lumacaftor; dornase alfa; hypertonic saline; azithromycin on Monday, Wednesday, and Fridays; pancreatic enzymes with meals; and inhaled tobramycin, one month on, one month off. He notes that he feels anxious and overwhelmed from his workload during his first semester at college. His FEV 1 is approximately 1% below baseline, which is 7% after starting ivacaftor/lumacaftor. And he reports that since starting the CFTR modulator, he elected to discontinue dornase alfa and inhaled tobramycin due to a decrease in the amount of sputum that he's producing. Treatment Considerations for Matt Acute Considerations How do we get him feeling better in the quickest period of time? Chronic Considerations Do we have the optimal regimen? How can we help him take this optimal regimen? The treatment considerations for Matt are, first, how do we get him to feel better in the quickest possible period of time? And second, is he on an optimal regime, and can we make this a better regime to fit his life? 14 Go online to complete the post-test and evaluation for CME/CNE/CPE credit www.peerviewpress.com/bgd9

Challenges and Goals for Adolescents and Adults With CF 1 Goal: Improve adherence Challenges to adherence And finally, there's a wide variety of problem-solving techniques that can be modified for specific situations. For patients with intelligent and unwitting nonadherence, it's up to the physician to reeducate our patients about the importance of treatments and adherence, and explore the patient's opinions on treatment regimes. Intend to take medications but high treatment burden Intelligent nonadherence (personal beliefs about medications) Unwitting nonadherence (patient misunderstands therapy) 1. Sawicki GS et al. Pediatr Pulmonol. 212;47:523-533. Erratic nonadherence (integrating CF treatment into life as a college student) The challenges and goals for adherence in adolescents and adults with CF are now being studied. The challenges to adherence are broadly classified in four categories. First, patients that intend to take meds but, due to the high treatment burden, fail; patients who have intelligent nonadherence based on personal beliefs and experience about various medications; patients with unwitting nonadherence due to misunderstandings about dose and frequency of therapies; and finally, patients with erratic nonadherence, in particular, this example of integrating CF treatment into the life of a busy college student. Solutions for the Challenges in Adolescents and Adults With CF 1 In some cases, we need to remember that there is a significant nonresponder rate in all our medications, and a specific medication may not be effective in a particular patient. We need to encourage active participation with a patient in their care. For example, evaluating together a patient's lung function over time or reviewing chest CTs together so the patient can understand areas of mucus plugging that need to be addressed. And then finally, follow-up by checking how the patient has assimilated new information to get feedback of what is understood and what's not understood. For patients with erratic nonadherence, the approach is similar to those with a high treatment burden. Again, we need to assess the regime and ask, can it be simplified? And in particular, explore the role of family, friends, and other support resources to overcome these challenges. Matt Follow-Up 1 Reviewed recommendations that standard treatments not be stopped after adding ivacaftor/lumacaftor High treatment burden Intelligent/unwitting nonadherence (poor understanding of need for medications) Assess regimen can it be simplified? Electronic reminders or apps can aid in prompting use of medications Problem-solving techniques Re-educate about importance of treatment and adherence Explore patient s current opinions on treatment regimen Active participation in his care (eg, evaluate change in lung function over time, chest CTs) Follow up by checking how he has assimilated the new information Simplify regimen: switched to dry powder tobramycin from solution Simplify life: decreased from 18 to 15 credits Matt agreed to recommit to making his medications and airway clearance a priority Returned to clinic in 2 weeks; FEV 1 improved to 78% of predicted Agreed to follow up again in 6 weeks in effort to keep momentum Erratic nonadherence (integrating CF treatment into life as a college student) Assess regimen can it be simplified? Explore role of family, friends, other support resources 1. Sawicki GS et al. Pediatr Pulmonol. 212;47:523-533. A number of solutions have been proposed to improve adherence in adolescents and adults with CF. First of all, in patients with a high treatment burden, we need to assess the regime and ask, can it be simplified? In addition, a number of electronic reminders or apps are available, which can in some cases help with reminding and prompting the use of medications. 1. Courtesy of Jerry Nick, MD. In the case of Matt, the approach taken was to review recommendations that standard treatments not be stopped after adding ivacaftor and lumacaftor. Although in many cases, patients report that they don't produce as much sputum, in the clinical trials, the benefit was achieved only in the setting of continuing all current medications. Thus, patients should be encouraged to consider airway clearance and anti-pseudomonas antibiotics. The treatment regime was simplified by switching from a tobramycin solution to the dry powder tobramycin, which greatly shortened time of administration. 15

In addition, Matt reduced his college credits from a high load of 18 to a normal load of 15 per semester. He agreed to recommit to making his medications and airway clearance a priority, and returned to clinic in two weeks with an FEV 1 that was improved to 78% of predicted. In order to keep up this effort and momentum, he agreed to follow up again in six weeks and further evaluate his response at that time. Request a Live Meeting To take advantage of the next step of this educational curriculum, click the Request a Free Meeting link in the activity menu, and we will schedule a live, interactive session at your institute moderated by an expert in cystic fibrosis Conclusions Ivacaftor for treatment of G551D demonstrates the potential of CFTR modulation as a therapy for CF More severe mutations, including F58del, require combinations of CFTR modulating agents, and to date clinical response has been smaller and more variable Personalizing care based on CFTR mutations is the central goal of future CF research A broad drug-development pipeline is in place with a variety of CFTR modulator candidates focusing on various mechanisms of CFTR dysfunction So in conclusion, ivacaftor for the treatment of G551D served to demonstrate the potential of CFTR modulators as a therapy for CF lung disease. Certainly, more severe mutations, including F58del, will require combinations of CFTR-modulating agents, and this is a more challenging clinical proposition. To date, the treatment of F58del has resulted in a clinical response that is smaller and more variable than what was seen with the G551D treatment with ivacaftor. To take advantage of the next step of this educational curriculum, click the Request a Free Meeting link in the activity menu, and we will schedule a live interactive session at your institute moderated by an expert in cystic fibrosis. CME/CNE/CPE Disclaimer National Jewish Health ("NJH") and its officers, Board of Directors, faculty, employees, representatives, and other agents (collectively, "NJH Parties") shall not be responsible in any capacity for, and do not warrant any content whatsoever, in any NJH publication or other product (in any medium), or the use or reliance on any such content, and expressly disclaim any and all liability for such content. All such responsibility for content and use of product solely rests with the authors or the advertisers, as the case may be. By way of example, without limiting the foregoing, this disclaimer of liability applies to the accuracy, completeness, effectiveness, quality, appearance, ideas, or products, as the case may be, of or resulting from, any statements, references, articles, positions, claimed diagnosis, claimed possible treatments, services, or advertising, express or implied, contained in any NJH live meeting, publication, online course or other product. Furthermore, the content should not be considered medical advice and is not intended to replace consultation with a qualified medical professional. Under no circumstances, including negligence, shall any of the NJH Parties be liable for any DIRECT, INDIRECT, INCIDENTAL, SPECIAL or CONSEQUENTIAL DAMAGES, or LOST PROFITS that result from any of the foregoing, regardless of legal theory and whether or not claimant was advised of the possibility of such damages. However, personalized care based on CFTR mutations is a central goal for future CF research, and a broad drug development pipeline is in place with a variety of CFTR modulator candidates focused on various mechanisms of CFTR dysfunction. 16 Go online to complete the post-test and evaluation for CME/CNE/CPE credit www.peerviewpress.com/bgd9

CME/CNE/CPE Exploring New Advances and Best Practices to Personalize Therapy and Improve Lung Function in Cystic Fibrosis Expert commentary is based on data from recent medical literature. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView Press or any of its partners, providers, and/or supporters. This activity is supported by an educational grant from Vertex Pharmaceuticals Incorporated. PVI, PeerView Institute for Medical Education, and National Jewish Health are responsible for the selection of this activity's topics, the preparation of editorial content, and the distribution of this activity. The preparation of PeerView activities is supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and National Jewish Health. Our activities may contain references to unapproved products or uses of these products in certain jurisdictions. For approved prescribing information, please consult the manufacturer's product labeling. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our activities. No responsibility is taken for errors or omissions in activities. Copyright 2-217, PeerView Press Sign up for e-mail alerts on new clinical advances and educational activities in your specialty: www.peerviewpress.com/signup www.peerviewpress.com/bgd9 New and improved source for free CME/CE