Fighting Duchenne Muscular Dystrophy

Transcription

1 Peripheral and Central Nervous System Drugs Advisory Committee c/o Moon Hee V. Choi, PharmD Center for Drug Evaluation and Research (CDER) Food and Drug Administration 93 New Hampshire Avenue 93 New Hampshire Avenue Food and Drug Administration Center for Drug Evaluation and Research (CDER) do Moon Flee V. Choi, PharmD Peripheral and Central Nervous System Drugs Advisory Committee January 6, 6 W3-47 Silver Spring, MD 993- Dear Peripheral and Central Nervous System Drugs Advisory Committee Members: We at the Jett Foundation, a Duchenne Muscular Dystrophy patient advocacy organization, are pleased to present you with our report on the systematic collection of experiences of patients enrolled in the eteplirsen clinical trials. Our efforts are consistent with the statute, Section 37 of FDASIA. L The report describes the methods and findings of our collection of these experiences, which catalogue interviews with patients and non-parent caregivers (e.g., physical therapists, personal caretaker). These detailed personal accounts have been provided to FDA independent of Sarepta. On behalf of the Duchenne patient community, and especially the young men with Duchenne and families and caregivers who provided their experiences, we thank you for taking the time to read this report. As background, in April 3, the Jett Foundation met with Dr. Janet Woodcock and other CDER officials to discuss the experiences of caregivers of the pediatric patients enrolled in Sarepta's eteplirsen trial. As a result of the discussion, Dr. Woodcock requested that we provide the Center with video and other evidence to support our anecdotal accounts of the boys' experiences in the trial. In June 3, we returned to present such a set of video clips. Pleased with this information, CDER asked us to continue our efforts, including gathering additional videos, as well as collect information on outcomes important to patients, such as activities of daily living, in a measurable and quantifiable way. Beginning in late in 4, we more systematically gathered experiences of those Duchenne patients and their caregivers through semi-structured interviews designed to understand and describe patients' experiences before the trial and over the three years on eteplirsen at the time of the interviews. We also collected video clips of the boys participating in activities of daily living that the boys indicated as important to them. Interviews were conducted with eight of the twelve boys enrolled in the eteplirsen efficacy trial and their parents. Additionally, we conducted interviews with three boys with more progressed disease who are enrolled in a different eteplirsen study, and conducted interviews with three non-parent caregivers (two physical therapists and a college roommate). FDASIA Section 37 requires FDA to solicit "solicit the views of of patients during the medical product development process and consider the perspectives of patients during regulatory discussions. discussions." The Jett Foundation Fighting Duchenne Muscular Dystrophy 68 Evergreen Evergreen Street, Street, Suite One * Kingston, Kingston, MA MA * Telephone: Telephone: (78) (78) * info@jettfoundation.org info@jettfoundation.org wwwjettfoundation.org The Jeff Foundation Fighting Duchenne Muscular Dystrophy in the eteplirsen clinical trials. Our efforts are consistent with the statute, Section 37 of In June 3, we returned to present such a set of video clips. Pleased with this information, CDER as important to them. Interviews were conducted with eight of the twelve boys enrolled in the rr Beginning in late in 4, we more systematically gathered experiences of those Duchetme patients experiences before the trial and over the three years on eteplirsen at the time of the interviews. We with more progressed disease who are enrolled in a different eteplirsen study, and conducted eteplirsen efficacy trial and their parents. Additionally, we conducted interviews with three boys interviews with three non-parent caregivers (two physical therapists and a college roommate). also collected video clips of the boys participating in activities of daily living that the boys indicated and their caregivers through semi-structured interviews designed to understand and describe patients officials to discuss the experiences of caregivers of the pediatric patients enrolled in Sarepta s eteplirsen trial. As a result of the discussion, Dr. Woodcock requested that we provide the Center with video and other evidence to support our anecdotal accounts of the boys experiences in the trial. asked us to continue our efforts, including gathering additional videos, as well as collect information As background, in April 3, the Jett Foundation met with Dr. Janet Woodcock and other CDER on outcomes important to patients, such as activities of daily living, in a measurable and quantifiable way. pleased to present you with our report on the systematic collection of experiences of patients enrolled which catalogue interviews with patients and non-parent caregivers (e.g., physical therapists, personal caretaker). These detailed personal accounts have been provided to FDA independent of Duchenne and families and caregivers who provided their experiences, we thank you for taking the time to read this report. We at the Jell Foundation, a Duchetme Muscular Dystrophy patient advocacy organization, are FDASIA. The report describes the methods and findings of our collection of these experiences, Sarepta. On behalf of the Duchenne patient community, and especially the young men with Dear Peripheral and Central Nervous System Drugs Advisory Committee Members: Silver Spring, MD 993- W3-47 January 6,6

2 organization and submitted to FDA to be considered by FDA as part of the Agency's review of any NDA for any condition. CDER indicated to us that it intended to review this information as part of its review of the eteplirsen NDA. then also transmitted the report to Sarepta. To our knowledge, this is the first time such patientcentered information about outcomes in clinical trials has been collected by a patient advocacy review of the eteplirsen NDA. organization and submitted to FDA to be considered by FDA as part of the Agency s review of any NDA for any condition. CDER indicated to us that it intended to review this information as part of its The Jett Foundation presented this information to CDER officials in July 5, including Dr. Janet Woodcock, Dr. Richard Moscicki, Dr. John Jenkins, Dr. Ellis Unger, Dr. Billy Dunn, and Dr. Ronald Farkas. The Jett Foundation then submitted a final report to FDA in August 5, at which time we then also transmitted the report to Sarepta. To our knowledge, this is the first time such patientcentered information about outcomes in clinical trials has been collected by a patient advocacy The results of the interviews, and their corresponding video clips, indicate unexpected stabilization of motor function, activity of daily living, and quality of life outcomes in six of the eight patients in the eteplirsen efficacy study, as well as stabilization in non-ambulation-related activities in the patients in the eteplirsen safety study. There are also incremental improvements in certain activities in a number of the patients. It is wholly without precedent for Duchenne boys over a period of three years, starting at the age and baseline 6MW and rise times of these Duchenne patients, to have any gain in neuromuscular milestones and function over this extended a period of time. The maintenance and improvement in function have allowed these Duchenne boys to remain independent in performing activities of daily living, which was reported as a major contributor to their and their family's quality of life. Thank you again for your interest in our findings. They are important to the Duchenne community and were collected as requested by FDA officials. The Jett Foundation offers this report to the Peripheral and Central Nervous System Drugs Advisory Committee in hopes that this information will help you assess the impact of eteplirsen on Duchenne patients and aid you in your benefit-risk determinations related to the application for eteplirsen for the treatment of Duchenne Muscular Dystrophy. We commend FDA for its emerging efforts to reach out and to include the voice and the views of the patients themselves as a fundamental and integral part of developing and assessing therapies that are, after all, intended for those with Duchenne. It is the patients who must absorb all the risks, even those which may not have surfaced, as well as the patients for whom the benefits are intended. Therefore, the entire process should start with, involve, and give prominence to the voice and views of "We, the Patients." Christine McSherry President The Jett Foundation The Jett Foundation rff e Fighting Duchenne Muscular Dystrophy 68 Evergreen Evergreen Street, Suite One * Kingston, Kingston, MA MA * Telephone: Telephone: (8) (78) * info@jettfoundation.org info@jettfoundation.org The Jeff Foundation JOll Fighting Duchenne Muscular Dystrophy Christine McSherry President The Jett Foundation Sincerely,.7 of We, the Patients. after all, intended for those with Duchenne. It is the patients who must absorb all the risks, even patients themselves as a fundamental and integral part of developing and assessing therapies that are, those which may not have surfaced, as well as the patients for whom the benefits are intended. Therefore, the entire process should start with, involve, and give prominence to the voice and views We commend FDA for its emerging efforts to reach out and to include the voice and the views of the will help you assess the impact of eteplirsen on Duchenne patients and aid you in your benefit-risk Peripheral and Central Nervous System Drugs Advisory Committee in hopes that this information Dystrophy. and were collected as requested by FDA officials. The Jett Foundation offers this report to the Thank you again for your interest in our findings. They are important to the Duchenne community determinations related to the application for eteplirsen for the treatment of Duchenne Iviuscular family s quality of life. gj in neuromuscular milestones and function over this extended a period of time. The maintenance years, starting at the age and baseline 6MW and rise times of these Duchenne patients, to have any and improvement in function have allowed these Duchenne boys to remain independent in in the eteplirsen safety study. There are also incremental improvements in certain activities in a The results of the interviews, and their corresponding video clips, indicate unexpected stabilization of motor function, activity of daily living, and quality of life outcomes in six of the eight patients in the eteplirsen efficacy study, as well as stabilization in non-ambulation-related activities in the patients number of the patients. It is wholly without precedent for Duchenne boys over a period of three performing activities of daily living, which was reported as a major contributor to their and their Woodcock, Dr. Richard Moscicki. Dr. John Jenkins. Dr. Ellis Unger. Dr. Billy Dunn. and Dr. Ronald The Jett Foundation presented this information to CDER officials in July 5, including Dr. Janet Farkas. The Jett Foundation then submitted a final report to FDA in August 5, at which time we

3 JETT FOUNDATION REPORT TO FDA August 5, 5 Patient and Caregiver Input on Benefits and Risks of Eteplirsen

4 Table of Contents Page No. I. INTRODUCTION... A. Purpose... B. Background on DMD... C. FDA Solicited Input of Patients by Way of the Jett Foundation... D. Role of Patient-Initiated Patient and Caregiver Input... 3 II. METHODS... 6 A. Primary Interviews: Patients and Parent Caregivers Patient Interviews Parent Caregiver Interviews... 7 B. Secondary Patient Interviews... 8 C. Non-Parent Caregiver Interviews... 9 III. RESULTS... A. Primary Patients.... Baseline Characteristics.... Patient Input Parent Caregiver Input... 3 a. Motor Functions... 3 b. Activities of Daily Living... 6 c. Global Functioning and Quality of Life Non-Parent Caregiver Input Supporting Documents and Activity Videos... 4 B. Secondary Patients Patient Input Non-Parent Caregiver Input Supporting Documents and Videos... 7 IV. DISCUSSION... 9 V. CONCLUSION Appendix A: Primary Interviews Script Appendix B: Motor Function Rating Scale i

5 Appendix C: Activities of Daily Living Rating Scale Appendix D: Global Functioning and Quality of Life Questionnaire Appendix E: Daily Log of Patient C Spontaneous Collapses... 5 ii

6 I. INTRODUCTION A. Purpose This report is intended to provide FDA with detailed and personal accounts of the experiences of patients in the eteplirsen clinical trials as well as related input from their caregivers. The interviews of patients and their caregivers were structured and designed to understand and describe patients experiences before and over three years later at the time of the interviews. This knowledge might help the Duchenne Muscular Dystrophy (DMD) community and FDA to incrementally better and more fully understand the risks and benefits of eteplirsen for the treatment of DMD, from the unique perspectives of the patients themselves. These patient and caregiver interviews were designed by patients and their caregivers specifically to measure concepts highlighted by patients as important to each of them. To the knowledge of the Jett Foundation, this is the first time that this kind of systematic collection and analysis of patient-centered information has been accomplished and submitted to FDA by a patient advocacy organization. We at the Jett Foundation hope our efforts may serve as a model for future patientcentric drug development and benefit-risk assessment efforts. We commend FDA for its emerging efforts to reach out and to include the voice and the views of the patients themselves as a fundamental and integral part of developing and assessing therapies that are, after all, intended for those with DMD. It is the patients who must absorb all the risks, even those which may not have surfaced, as well as it is the patients for whom the benefits are intended. Therefore, the entire process should start with, involve, and give prominence to the voice and views of We, the Patients. B. Background on DMD DMD is the most common lethal genetic disorder diagnosed during childhood. It is a progressive muscle disorder that causes loss of muscle function and independence. DMD affects approximately one in every 3,5 boys, or, babies born each year worldwide. Because the Duchenne gene is found on the X chromosome, the disorder occurs primarily in boys. DMD affects families of every race and culture. It can occur in any pregnancy, regardless of family history. Random spontaneous genetic mutation is the cause of DMD in nearly 35% of families affected. There are approximately 5, boys/young men diagnosed with DMD alive today in the United States.

7 No FDA-approved treatment or cure currently exists for DMD. However, there are a number of therapies in development, addressing a wide range of mechanisms of action. One such strategy currently being developed for DMD is exon skipping, in which sections of genetic code (exons) are skipped, allowing the reading frame to be restored and leading to creation of a shorter, partially functional dystrophin. Exon skipping can potentially lessen the severe muscle weakness and atrophy that is the hallmark of the disease, making it more like Becker s muscular dystrophy. Exon skipping drugs, including eteplirsen, are currently under development by multiple biopharmaceutical companies. These drugs have shown encouraging results in Phase and Phase trials, and are now starting Phase 3 testing for patients with certain other dystrophin mutations (those in the vicinity of exon 5 and exon 44), with therapies targeting other areas of the dystrophin gene planned for future development. C. FDA Solicited Input of Patients by Way of the Jett Foundation We at the Jett Foundation, a DMD patient advocacy group, met in April of 3 with officials from the FDA s Center for Drug Evaluation and Research (CDER or the Center), the part of FDA responsible for ensuring that safe and effective drugs are available to improve the health of people in the United States. The Jett Foundation discussed with Dr. Janet Woodcock, the CDER Director, and other CDER officials the experiences of patients and caregivers of the pediatric DMD patients enrolled in the eteplirsen efficacy trial. As a result of the discussion, CDER officials requested that the Jett Foundation provide the Center with video and other evidence to support its anecdotal accounts of the boys experiences in the trial. In June of 3, the Jett Foundation returned to present such a set of video clips. Since that time, the Jett Foundation has more systematically gathered the experiences of the DMD patients and their caregivers from before the trial and currently, as well as additional boys on eteplirsen. Based on the Jett Foundation s See DMD Pipeline, Muscular Dystrophy Ass n, Here, and throughout this report, references to the eteplirsen efficacy trial refers to the Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients (NCT39639) in combination with the Efficacy, Safety, and Tolerability Rollover Study of Eteplirsen in Subjects with Duchenne Muscular Dystrophy (NCT5449).

8 experience with the DMD community and as mothers of boys with the condition, the Jett Foundation selected a set of motor functions, activities of daily living, and aspects of quality of life that are important to DMD patients. The Jett Foundation then collected information on those outcomes by conducting semi-structured interviews, administering rating scales, and obtaining other supportive information (e.g., additional video clips, healthcare provider accounts). This information is presented in this report in order to provide a patient- and caregiver-reported account of the outcomes of patients enrolled in the eteplirsen clinical trials. D. Role of Patient-Initiated Patient and Caregiver Input The DMD patient advocacy community has been an active participant and collaborator in the research and development of therapies for the disease. Several DMD patient advocacy organizations fund preclinical and clinical research. 3 Patient advocacy organizations have a history of engaging regulators at FDA and other key stakeholders (e.g., researchers, healthcare professionals) to bring the patient voice to important discussions about issues regarding drug development generally and, in particular, specifically on DMD. Patient advocacy groups have provided a forum for the DMD community to raise and discuss the challenges involved in designing and implementing clinical trials for DMD. This led to the development of the first proposed draft guidance independently prepared by an advocacy group. FDA credited the DMD patient community for serving as an example of collaboration between engaged stakeholders and FDA and highlighting how input from patients and caregivers can contribute to drug development. 4 As FDA stated in its own draft guidance for DMD, [a]s development proceeds and the potential benefits and risks of a drug become more clearly understood, input from patients and caregivers should be further elicited. 5,6 This 3 See, e.g., Duchenne Alliance, Muscular Dystrophy Association, Parent Project Muscular Dystrophy, Cure Duchenne, 4 FDA, Press Release, FDA issues draft guidance on developing drugs for Duchenne Muscular Dystrophy (June 9, 5), available at 5 FDA, Draft Guidance for Industry, Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment, at 3 (June 5), available at M459.pdf [hereinafter DMD Draft Guidance ]. 3

9 is the reason that we at the Jett Foundation have been engaged with FDA in order to systematically gather input from patients and caregivers based on the experience of the DMD patients in the eteplirsen clinical trials as reported by the patients and their caregivers themselves and according to the issues that are of the most concern to these boys (and now young men) with DMD. As discussed in FDA s DMD Draft Guidance, patient and caregiver input, including those measuring activities of daily living, assess the abilities and experiences of patients, and such input can help FDA assess the clinical meaningfulness of study findings. 7 In addition, evidence generated from the collection of such patient input may be important to benefit-risk considerations when reviewing applications for drugs for DMD. 8 While this patient-generated information was not collected by the sponsor developing the drug and was not collected with the rigor that would normally be expected by FDA in an adequate and well-controlled study, the Agency has a long history of demonstrating flexibility in the review and approval of drugs for rare diseases. 9 Key principles about flexibility and risk are articulated in FDA regulation:... while the statutory standards of safety and effectiveness apply to all drugs, the many kinds of drugs that are subject to them, and the wide range of uses for those drugs, demand flexibility in applying the standards. The [FDA] has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that physicians and patients are generally willing to accept 6 For other examples of FDA s commitment to involving patients in the regulatory decision-making process, see Food and Drug Administration Safety and Innovation Act, Pub. L. No. -44, 37, 6 Stat. 993, 4 (); FDA, Draft Guidance for Industry, FDA Staff, and Other Stakeholders, Patient Preference Information Submission, Review in PMAs, HDE Applications, and De Novo Requests, and Inclusion in Device Labeling (May 8, 5), available at nts/ucm44668.pdf. 7 DMD Draft Guidance at 3. 8 Id. at. 9 Frank J. Sasinowski et al., Quantum of Effectiveness Evidence in FDA s Approval of Orphan Drugs: Update, July to June 4, Ther. Innov. Regul. Sci., Apr. 7, 5; Frank Sasinowski, Quantum of effectiveness evidence in FDA s approval of orphan drugs: cataloging FDA s flexibility in regulating therapies for persons with rare disorders, 46() Drug Inf. J. 38 (). 4

10 greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses. These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated. As FDA stated when it issued the Agency s DMD Draft Guidance: FDA recognizes the unmet medical need that exists with patients with DMD, the devastating nature of the disease for patients and their families and the urgency to make new treatments available. Given the severity of DMD and its great unmet medical need, we at the Jett Foundation hope that FDA will exercise flexibility and give this patient input appropriate consideration during the Agency s review of eteplirsen for DMD. C.F.R. 3.8 (sometimes referred to as Subpart E, as it is from Part 3, Subpart E of FDA s regulations). FDA, Press Release, FDA issues draft guidance on developing drugs for Duchenne Muscular Dystrophy (June 9, 5), available at 5

11 II. METHODS Interviews conducted by the Jett Foundation of patients enrolled in the eteplirsen efficacy trial and their parent caregivers were called the primary interviews. In addition to these primary interviews, secondary patient interviews were conducted with patients enrolled in Sarepta s recent eteplirsen safety trial in advanced-stage DMD patients. Additional non-parent caregiver interviews were conducted with non-parent caregivers identified by primary or secondary interview participants as having insight into the experiences of the patients (e.g., physical therapists, other non-parent caretakers). Interviews were conducted between November 4, 4 and May, 5. The topics covered in the interviews were selected by the Jett Foundation, based on their experience with the DMD community and as mothers of boys with the condition, as outcomes that are important to DMD patients. Since interviews were only conducted with patients receiving an investigational drug for treatment of DMD, particular motor function, activities of daily living, and quality of life outcomes were chosen that would be expected to decline or even be lost by DMD patients of a similar age over a similar period of time. Finally, these outcomes were also thought to provide relevant insight into the clinical meaningfulness of the outcome measures formally assessed in the eteplirsen clinical trials. A. Primary Interviews: Patients and Parent Caregivers The Jett Foundation attempted to contact the parent caregivers of all boys enrolled in the eteplirsen efficacy trial by using phone numbers, addresses, and social media that they had obtained independently through the interactions of its staff with the DMD patient community. The parent caregivers of all boys were successfully contacted and these parents and the patients were invited to participate in an entirely voluntary interview to be conducted by Jett Foundation staff. Eight sets of parent caregivers and patients accepted the invitation to participate in an interview, and these patients are identified in this report as Patients through Here, and throughout this report, references to the eteplirsen safety trial refers to the Safety Study of Eteplirsen to Treat Advanced Stage Duchenne Muscular Dystrophy (NCT86947). The three patients that are thought to be the worst off in the eteplirsen efficacy trial were included in the eight patients that participated in the Jett Foundation interviews (i.e., the two patients that lost ambulation early in the trial and the patient that broke his femur). Of the four patients that did not participate in the interviews, press and social media have provided accounts during the past year on three of these patients. One boy completed a 5 kilometer footrace. Another boy plays little league baseball and ice hockey. The third boy is now able to operate a push lawnmower. All three accounts suggest the patients are doing well. 6

12 If the parent caregivers and patients agreed, an interview was scheduled at a location and during a time that was convenient for them. Before beginning the interviews, the parent caregivers provided informed consent for their own participation, as well as for that of their child (the patient). The patients, all of whom were minors, were also asked to provide assent in order to participate. The informed consent and assent process included an understanding that these interviews were being conducted by the Jett Foundation, not by the clinical trial sponsor, and that the decision of whether to participate in the interview would have no bearing on the patient s continued participation in the eteplirsen efficacy trial. Interviews with the patients were video recorded, while the oral components of the interviews with parent caregivers were audio recorded only. Each combined patient-caregiver interview lasted approximately one hour. See Appendix A for the full interview script.. Patient Interviews The interviews of the patients were conducted using a set of pre-specified, semi-structured interview questions. The patient question topics included how the patient was feeling, what they enjoy doing most, whether and how their ability to do those things has changed over time, what bothers them most about having DMD (the most bothersome aspect of having this condition), whether and how these things have changed over time, and anything else they would like to say about their disease. The recordings from each of the interviews were reviewed and responses were considered complete when the patient articulated his selfevaluation on that outcome for both before the trial and at the time of the interview. This allowed an informed assessment of whether that particular aspect of the patient s condition had improved, was maintained, or declined. In addition to video recording the patient interviews, patients were offered an opportunity to be video recorded doing the activities they discussed in their responses. Alternatively, patients could provide the Jett Foundation with their own historical and current video recordings that capture their abilities before the trial as well as after substantial participation in the trial.. Parent Caregiver Interviews The interviews of the parent caregivers were conducted using a set of prespecified, semi-structured interview questions, as well as quantitative rating scales and a questionnaire. The caregiver question topics covered their child s motor functions, activities of daily living, and quality of life (see Table for a full list of topics and Appendices B, C, and D for each question on each topic). For outcomes measured using the quantitative rating scales and questionnaire, scores from before the trial were compared to those at the time of the interview to assess relative improvement, maintenance, or decline in outcomes. In addition, average 7

13 scores were calculated for both the motor function and activities of daily living categories of outcomes for each patient. Finally, an analysis of trends was conducted comparing responses for two categories of patients: () those who have maintained ambulation and () those who are no longer ambulatory. Table Caregiver Interview Topics 4 Motor Functions (Ability & Frequency) (see Appendix B) Jump, hop, and run Rise from floor Sit from lying supine Use of Gower s Stair climb Rise to stand from chair Walk independently Stand in place Reach overhead Reach their scalp Place hands on top of table Gait Spontaneous collapses Activities of Daily Living (Ability & Frequency) (see Appendix C) Dress independently Bath independently Walk independently Self propel a wheelchair Wash/comb hair independently Handwrite Lift a cell phone to ear Participate in recreational activities Open a door Retrieve a fallen object from the floor and return to standing Use of wheelchair or other mobility assistance device Global Functioning and Quality of Life (see Appendix D) Weakness Fatigue Global assessment of independence Global impression of change Side effects B. Secondary Patient Interviews The Jett Foundation contacted the parents of three of the known patients in the eteplirsen safety trial using the same methods as for the primary interviews. If the parent caregivers and minor patients agreed, or adult patients agreed, an interview was scheduled at a location and during a time that was convenient for them. Before beginning the interviews, for the patients who were minors, the parent caregivers provided informed consent for their child (the patient) and the patients were also asked to provide assent in order to participate. For patients who were adults, the patients provided informed consent for their participation. The informed consent and assent process included an understanding that these interviews were being conducted by the Jett Foundation, not by the clinical trial sponsor, and that the decision of whether to participate in the interview would have no bearing on the patient s continued participation in the eteplirsen safety trial. Interviews with the patients were video recorded. All three patients accepted the invitation to participate in an interview, and these patients are identified in this report as Patients A, B, and C. The interviews of patients enrolled in the eteplirsen safety trial were unstructured. A list of outcomes was provided in advance and patients were 4 Topics used as the basis for interviews with both parent caregivers and non-parent caregivers, as well as for interviews of secondary patients. 8

14 provided an opportunity discuss their experiences related to those outcomes (see Table ). The recordings from each of the interviews were reviewed and responses were considered complete when the subject articulated his selfevaluation on that outcome for both before the trial and at the time of the interview. This allowed an informed assessment of whether the outcome improved, was maintained, or declined. In addition to video recording the patient interviews, patients were offered an opportunity to be video recorded doing the activities they discussed in their responses. Alternatively, patients could provide us with their own historical and current video recordings that capture their abilities before the trial and at any time during the trial. C. Non-Parent Caregiver Interviews Non-parent caregivers who were identified by the primary or secondary interview participants as having insight into the experiences of the patient (e.g., physical therapist, roommate) were contacted by the Jett Foundation. If the nonparent caregiver agreed, an interview was scheduled at a location and during a time that was convenient for them. Before beginning the interviews, the nonparent caregivers provided informed consent for their participation. The informed consent process included an understanding that these interviews were being conducted by the Jett Foundation, not by the clinical trial sponsor, and that the decision of whether to participate in the interview would have no bearing on the patient s continued participation in the eteplirsen clinical trial. Interviews with the non-parent caregivers were video recorded. The interviews of non-parent caregivers were not structured. A list of outcomes was provided in advance and interview participants were provided an opportunity discuss their observations related to those outcomes (see Table ). Three such non-parent caregiver interviews were conducted with the following: () one of the study physical therapists for the eteplirsen efficacy study, 5 () Patient A s college roommate and personal caretaker, and (3) Patient C s personal physical therapist. The recording from each of the interviews was reviewed and responses were used to support and supplement the interview results from the corresponding primary or secondary interview(s). 5 The physical therapist was identified by a parent caregiver because she was the most experienced of all the study therapists and had worked with and assessed each of the boys in the eteplirsen efficacy study from the start of the trial. 9

15 III. RESULTS A. Primary Patients. Baseline Characteristics Based on the recollections of the parent caregivers of the eight boys enrolled in the eteplirsen efficacy trial, on average, the boys were aged 9 years,.5 months when they started the trial (range: 7 years to years, 9 months). 6 All eight boys were on steroids prior to trial enrollment. See Table for the baseline characteristics for each patient. 7 Table Patient Characteristics at Time of Enrollment Patient On Age Steroid Use Identifier Placebo Dose 8 years, months Yes, since age 6 No 3 mg/kg years 8 years, months Yes, since age 6 No 3 mg/kg years 3 9 years, 7 months Yes, for 7 years No 5 mg/kg 4 years, 9 months Yes, for 6 years No 3 mg/kg 5 9 years, month Yes, since age 6 No 3 mg/kg years 7 months 6 years, month Yes, since Sept. Yes 3 mg/kg years Yes, for 7 years Yes Did not provide 8 8 years months Yes No 5 mg/kg For initial, placebo-controlled 4 week study. For rollover, open-label study. 6 Caregivers had difficultly recalling the height and weight of the boys at the time of enrollment, so these results are not reported. In addition, most of the caregivers were not aware of the boys baseline 6-Minute Walk Test, so this result is also not reported. 7 Due to the open-ended format of the secondary patient interviews, baseline characteristics were not collected for Patients A, B, and C.

16 . Patient Input The eight patients enrolled in the eteplirsen efficacy trial responded to the semi-structured interview questions in a free-form manner. These patient responses of their ability to do things they enjoy and things that bother them about their disease were classified as either improved, maintained, or declined from before the trial to the time of the interview. See Table 3 for a summary of the responses provided in the primary patient interviews.

17 Patient Identifier Table 3 Summary of Input from Primary Patient Interviews Input from Primary Patient Interviews Maintained Did not address Improved Easier to wake up in the morning Declined Swimming (can no longer tread water and gets tired more easily) Maintained Still cannot play sports with friends; generally, things he can do have stayed the same Improved Did not address Declined Did not address 3 Improved Able to take a step up onto a deck; easier to walk up a hill; preparing lunch at school (someone used to help him get lunch; can now open milk cartons on his own); swimming ability (ability to get in and out of the swimming pool); easier to lift objects; can now walk to get around school, airports, and the hospital (no longer needs to use a wheelchair); can now open a soda can on his own; walking long distances Maintained Getting dressed Declined Did not address 4 Improved Ability to walk longer distances (e.g., in the neighborhood, at amusement parks); can jump higher on the trampoline; can run faster; can now open screw-top bottles; can more easily open up plastic bags and plastic food containers; can now climb up onto tall chairs/stools himself (no longer needs assistance from another person) Maintained Creative gameplay with friends; playing with toys (e.g., Legos) Declined Not as good at climbing stairs 5 Improved Generally, feels better than he did before; can now walk up and down the steps in front of his house; can do more pool/swimming activities; can now get out of the pool on his own (no longer needs his parents to lift him out of the pool); more energy/less tired (can do more activities after school, when he used to have to rest); can keep up with his friends and can walk further Maintained Did not address Declined Did not address Improved Did not address 6 Maintained Overall, things have been about the same; ability to participate in physical education activities have been about the same or maybe a little better Declined Did not address Improved Did not address 7 Maintained Cooking/preparing food for himself and his family; hiking ability (requires a push buggy for the same amount of time); difficulty getting up from the floor Declined Did not address Improved Ability and frequency of playing sports (he plays volleyball, basketball, football, catch, and street hockey) 8 Maintained Throwing a football; difficulty running; ability to prepare food and open food containers Declined Did not address Although neither Patient or mentioned loss of ambulation, this decline was self-evident.

18 3. Parent Caregiver Input The parent caregiver interview topics consisted of three categories: motor functions, activities of daily living, and quality of life. For each interview topic, parents were asked to assess aspects of their son s condition both before the trial and after the trial or currently. All eight parent caregivers rated their son s motor function after the trial or currently based on their son s function or ability at the time of the interview. 8 a. Motor Functions The parent caregivers of boys enrolled in the eteplirsen efficacy study were asked to assess the following motor functions:. Jump, hop, and run. Rise from floor 3. Sit from lying supine 4. Use of Gower s 5. Stair climb 6. Rise to stand from chair 7. Walk independently 8. Stand in place 9. Reach overhead. Reach their scalp. Place hands on top of table The parent caregivers were prompted to identify the number ( to 4) that best described their son s motor function. See Table 4 for the description for each value. The parent caregivers were asked to do this for both the patient s ability to perform the function and the frequency with which they performed the function. The ability and frequency of each function was scored separately for before the trial and after the trial or currently. See Appendix B for the Motor Function Rating Scale. 8 While the interview questions, rating scales, or questionnaire prompted the parent caregivers to rate their son s function or ability after the trial/currently in order to accommodate the possibility that a patient may have discontinued the clinical trial, no patient interviewed by the Jett Foundation discontinued from the eteplirsen efficacy study. 3

19 Table 4 Description of Rating Scales for Both Motor Function and Activities of Daily Living Outcomes Rating Score Ability Rating Description Frequency Rating Description Absent Never Slightly Seldom Mildly Sometimes 3 Moderately Frequently 4 Completely Almost always The average ability and frequency scores across all motor function outcomes for each patient, as well as for both ambulation-related subgroups, are provided in Table 5. Table 5 Average Caregiver-Reported Motor Function Outcomes by Patient and Ambulation Subgroup Patient Identifier Average Ability (-4) Average Frequency (-4) Before After Before After Non-Ambulatory Subgroup Ambulatory Subgroup In addition to the rating scale, interview questions addressed the DMD patients gait and daily spontaneous collapses. The majority of parent caregivers reported either an improvement or maintenance in their child s gait. Examples include the following: Patient 3 s gait was described as a waddle before the trial and is now reported as without a waddle. 4

20 Patient 4 was described as an extreme toe walker ( like a ballerina ), however it was reported that about three months into the trial he began coming down off his toes. Patient 4 s parent caregiver also reported that the boy s physical therapist described his base, or stance, as much closer than it used to be, and his balance as improved. These improvements ultimately resulted in a reduction in physical therapy services from twice a week to twice a month. Patients 6 and 8: their gates were described as the typical Duchenne waddle and it was reported that their gates have remained the same. Patient 7 s gait was described as slightly wide-stanced at baseline and a little slower than other kids, and is now reported to have become a little more slow than it was before, although some days, at a glance, you cannot tell much of a difference between him and anyone else. The daily spontaneous collapses outcome, as reported by the parent caregivers, is provided for each patient, as well as for both ambulation-related subgroups, in Table 6. Where spontaneous collapses were reported on a less frequent basis than daily, the daily rate was extrapolated (e.g., a fall one out of every four days equates to.5 daily spontaneous collapses). The two patients who lost ambulation reported the second highest number of daily spontaneous collapses before the trial. The remaining six boys who are still ambulatory are not currently having any daily spontaneous collapses. This reflects an average decrease of.5 daily spontaneous collapses within this subgroup. 5

21 Table 6 Caregiver-Reported Daily Spontaneous Collapses by Patient and by Ambulation Subgroup Patient Identifier Daily Spontaneous Falls Before After 4.5 N/A 4.5 N/A Non-Ambulatory Subgroup 4.5 N/A Ambulatory Subgroup.5 Not applicable because patient has lost ambulation. b. Activities of Daily Living The parent caregivers of boys enrolled in the eteplirsen efficacy study were asked to assess the following activities of daily living:. Use a computer. Self feed/prepare food 3. Lift a drinking glass 4. Brush teeth 5. Dress independently 6. Bath independently 7. Walk independently 8. Self propel a wheelchair 9. Wash/comb hair independently. Handwrite. Lift a cell phone to the ear. Participate in recreational activities 3. Open a door 4. Retrieve a fallen object from the floor and return to standing The parent caregivers were prompted to identify the number ( to 4) that best described their son s activities of daily living. See Table 5 for the description for each value. The parent caregivers were asked to do this for both the patient s 6

22 ability to perform the activity and the frequency with which they performed the activity. A number was selected for the ability and frequency of each activity for before the trial and after the trial or currently. See Appendix C for the Activities of Daily Living Rating Scale. The average ability and frequency scores across all 4 activities of daily living outcomes for each patient, as well as for both ambulation-related subgroups, are provided in Table 7. Table 7 Average Caregiver-Reported Activities of Daily Living by Patient and Ambulation Subgroup Patient Identifier Average Ability Average Frequency Before After Before After Non-Ambulatory Subgroup Ambulatory Subgroup In addition to the rating scale, an interview question addressed the percentage of time the patients used a wheel chair or other mobility assistance device before the trial and after the trial or currently. This outcome, as reported by the parent caregivers, is provided for each patient, as well as for both ambulationrelated subgroups, in Table 8. 7

23 Table 8 Caregiver-Reported Percentage of Time Using Wheelchair or Other Mobility Assistance Device by Patient and Ambulation Subgroup Patient Identifier Time Using Wheelchair (% of Time Used) Before After Non-Ambulatory Subgroup 3 Ambulatory Subgroup % use because patient has lost ambulation. c. Global Functioning and Quality of Life The parent caregivers of boys enrolled in the eteplirsen efficacy study were asked to assess the following aspects of quality of life:. Weakness. Fatigue 3. Ability to accomplish everyday activities 4. Total improvement Weakness and fatigue were differentiated by definition. Weakness was defined as a lack of physical or muscle strength and the feeling that extra effort is required to move their arms, legs, or other muscles. Fatigue was defined as a feeling of tiredness or exhaustion, or a need to rest because of lack of energy. For these two outcomes, parent caregivers were prompted to identify the number ( to 4) that best described what their son usually felt. See Table 9 for the description for each value. See Appendix D for the Global Functioning and Quality of Life Questionnaire. 8

24 Table 9 Description of Rating Scales for Both Weakness and Fatigue Outcomes Rating Score Weakness Description Fatigue Description Normal: No weakness. Normal: No fatigue. Slight:Weakness occurs. Slight:Fatigue occurs. However it However it does not cause my does not cause my child trouble child trouble doing things or doing things or being with people. being with people. 3 4 Mild: Weakness causes my child some troubles doing things or being with people. Moderate: Weakness causes my child a lot of troubles doing things or being with people. However, it does not stop my child from doing anything. Severe: Weakness stops my child from doing things or being with people. Mild: Fatigue causes my child some troubles doing things or being with people. Moderate: Fatigue causes my child a lot of troubles doing things or being with people. However, it does not stop my child from doing anything. Severe: Fatigue stops my child from doing things or being with people. The weakness and fatigue scores for each patient, as well as averages for both ambulation-related subgroups, are provided in Table. 9

25 Table Caregiver-Reported Weakness and Fatigue by Patient and Ambulation Subgroup Patient Identifier Weakness (-4) Fatigue (-4) Before After Before After Non-Ambulatory Subgroup 3 3 Ambulatory Subgroup For the patient s ability to accomplish his everyday activities or, in other words, ability to accomplish what he needs to get done, parent caregivers were prompted to identify the number ( to 7) that best described their son s level of dependence or independence. This measure served as a global assessment of the patients independence. See Table for the description for each value. Table Description of Rating Scale for Global Assessment of Independence Outcome Rating Score Global Assessment of Independence Not sure/not assessed Completely dependent Moderately dependent 3 Mildly dependent 4 Slightly independent/slightly dependent 5 Mildly independent 6 Moderately independent 7 Completely independent The scores for the global assessment of independence for each patient, as well as averages for both ambulation-related subgroups, are provided in Table.

26 Table Caregiver-Reported Global Assessment of Independence by Patient and Ambulation Subgroup Global Assessment of Patient Identifier Independence (-7) Before After Non-Ambulatory Subgroup 6 Ambulatory Subgroup As an assessment of global impression of change, parent caregivers were prompted to identify the number ( to 7) that best described their son s total improvement whether or not, in their judgment, it was due to drug treatment. See Table 3 for the description of each value. Table 3 Description of Rating Scale for Global Impression of Change Outcome Rating Score Total Improvement Not sure/not assessed Very much improved Much improved 3 Minimally improved 4 No change 5 Minimally worse 6 Much worse 7 Very much worse The scores for the global impression of change for each patient, as well as averages for both ambulation-related subgroups, are provided in Table 4.

27 Table 4 Caregiver-Reported Global Impression of Change by Patient and Ambulation Subgroup Patient Identifier Total Improvement (-7) Non-Ambulatory 6 Subgroup Ambulatory.67 Subgroup Side Effects and Adverse Events. In addition to the questionnaire, an interview question addressed whether the parent caregiver was aware of any side effects or adverse events related to their son s participation the trial. The responses as to what, if any, side effects or adverse events occurred are provided for each patient in Table 5. Table 5 Caregiver-Reported Side Effects/Adverse Events by Patient Patient Identifier Side Effects/ Adverse Events None None 3 None 4 None 5 None 6 None 7 None 8 None

28 4. Non-Parent Caregiver Input The study physical therapist for the eteplirsen efficacy trial provided testimonial about the experiences of all twelve patients enrolled in the study. These responses were classified as improved, maintained, or declined. See Table 6 for a summary of the responses provided in the study physical therapist interview. Table 6 Summary of Input from Primary Non-Parent Caregivers Patient Identifier Patients and Caregiver Relationship Study Physical Therapist Patient Study 6 Physical Therapist Patient Study Physical Therapist Entire eteplirsen efficacy trial patient cohort Study Physical Therapist Input from Non-Parent Caregivers Improved Maintained Declined Improved Maintained Declined Improved Maintained Declined Improved Maintained Declined Did not address Breathing; reasonable arm strength (e.g., to feed themselves, to play) Ambulation Strength in leg and ability to walk in leg after being incapacitated from broken leg Did not address Did not address Did not address Ambulation despite being a tall, stocky boy (and would have predicted him to be off his feet two years ago because of his level of progression the time of enrollment and his body type; she was most shocked about him of all the boys) Did not address See Patient 6 above; other ambulatory patients with sprained ankles and hurt feet have been able to return to their previous walking ability Ambulation (all but two patients); breathing/respiratory; not collapsing Slowed progression of the disease in outcomes measured ( its been dramatic in some, its been nice in others ), including strength, walk times, and stairclimbing Patient who broke his femur during the trial. One of the patients enrolled in the eteplirsen efficacy trial, but not one of the 8 patients interviewed by the Jett Foundation. All patients enrolled in the eteplirsen efficacy trial, including the 8 patients interviewed by the Jett Foundation. 3

29 5. Supporting Documents and Activity Videos In addition to the interview videos recorded by the Jett Foundation, the patients and parent caregivers were prompted to provide videos of the patients participating in activities that they highlighted in their interviews. These videos could be supplied by the patient/parent caregiver or could be recorded by the Jett Foundation at the time of the interview. Patients and parent caregivers provided activity videos for Patients 4 and 6. The Jett Foundation recorded activity videos for Patients 3, 4, 5, and 8. These video recordings were themselves illuminating as further evidence of the changes reported in the abilities of patients to accomplish activities of daily living, which are inherently clinically meaningful. The content of these video recordings include the following: A current video of Patient 3 walking up and down a steep hill which demonstrates both strength and coordination (Jett Foundation video). This activity would not have been permitted by the parent caregiver if there was any fear that her son with DMD lacked sufficient strength or ability and would be at any risk of falling and breaking a bone. A current video of Patient 3 vigorously and easily taking off and putting back on his shirt (Jett Foundation video). A video from before the trial of Patient 4 dancing, depicting his extreme toe walking (patient-supplied video), juxtaposed with a current video of Patient 4 walking up and down a steep driveway, depicting how much he has come down off his toes (Jett Foundation video). A current video of Patient 5 playing billiards, depicting his upper body coordination and strength (Jett Foundation video). A video of Patient 6 during the trial, regaining fully the same ability to walk as he had before breaking his femur (patient-supplied video). A current video of Patient 8 shooting a basketball and another current video of him playing volleyball with his team, demonstrating his ability to play sports, especially upper body strength (shoulder and upper arm) and coordination, and to participate in normal social activities. 4

30 B. Secondary Patients. Patient Input The three patients enrolled in the eteplirsen safety trial provided testimonials about their experiences related to any of the outcomes they chose. These three patients were given the list of outcomes in Table as a list of activities that may have been or may be impaired in DMD. These responses were classified as improved, maintained, or declined. See Table 7 for a summary of the responses provided in the secondary patient interviews. Table 7 Summary of Input from Secondary Patient Interviews Patient Identifier A B C Improved Maintained Declined Improved Maintained Declined Improved Maintained Declined Input from Secondary Patient Interviews More strength; more independent; can eat more easily; sleep quality improved (i.e., not snoring as much, less tired and generally better); preparing food and opening food packaging and cans Did not address Did not address Able to roll himself around in bed (no long needs to use bars to do so); pull down and up pants independently (used to need assistance); can now adjust leg guards, which enables him to use a restroom on his own (a tremendous social barrier removed while his self esteem and autonomy are enabled). Did not address Did not address Number/frequency of spontaneous collapses; endurance, including for walking and playing sports; more active and able to play outside; ability to play sports (e.g., passing and kicking a soccer ball); stairclimbing; can now get into the family van independently, sometimes stepping on something (no longer requiring assistance to get into the family van); ease of picking things up from the ground (e.g., picking up a football); ability to run without falling; greater speed and less use of Gower s when getting up from the floor; energy at the end of the day Did not address Did not address 5

31 . Non-Parent Caregiver Input Patient A s college roommate and personal caretaker, as well as Patient C s personal physical therapist provided testimonial about the experiences of the patient enrolled in the eteplirsen safety study. These responses were classified as improved, maintained, or declined. See Table 8 for a summary of the responses provided in these non-parent caregiver interviews. Table 8 Summary of Input from Secondary Non-Parent Caregivers Patient Identifier Patient A Patient C Caregiver Relationship College Roommate and Personal Caretaker Personal Physical Therapist Input from Non-Parent Caregivers Improved Maintained Declined Improved Maintained Declined Significant reduction in amount of snoring; can put his leg up himself when lying in bed (used to require his caregiver to assist him); retrieving food and opening food packaging (requires less help); can raise hand up higher; improved ability to eat independently (i.e., bring food up to his mouth rather than bend down to his food); ease of reaching and picking up items (e.g., laptop, water bottle, or controller off desk or in drawers) Did not address Did not address Increase in normalization of movement patterns; stands with feet closer together (indication of strength in pelvis and balance is improved); gate is more normal; walking, including feet not as far apart, not rotating hips side-to-side to get leg forward, able to step through using hip flexor muscles better, and better balance; improved ability to sit up from a lying position; stairclimbing; easier to walk up steep ramp (improved stability); generally these improvements were capable of being noticed over a period of a couple weeks, and the physical therapist had very good baseline period of observation since she had been his physical therapist for years (since he was diagnosed with DMD) Did not address Did not address 6

32 3. Supporting Documents and Videos Patient C s parent caregiver provided supplemental information on Patient C s most troublesome outcomes which she, as the caregiver, identified as the activities that the patient struggled with the most or had most recently lost the ability to perform. 9 The parent caregiver independently decided to video-record or keep a daily log of these activities from about the time Patient C started in the eteplirsen safety trial through the time of Patient C s interview. Patient C s parent caregiver identified the patient s four most troublesome outcomes as: climbing stairs, getting up from the floor, getting into the family van, and spontaneous collapses. a. Stair climbing In a video-recording of Patient C climbing stairs very early in the eteplirsen safety trial, he must walk at an angle and lean heavily on the railing. Then, in the video of Patient C currently, he no longer needs to lean on the railings or other support. b. Getting up from the floor In a video-recording of Patient C getting up from the floor from supine early in the trial, the patient must use his arm to pull his legs into position to begin to stand. The patient also uses a full two-handed Gower s to complete the standing motion. Then, in the video of Patient C currently, while he does not rise at a greater overall speed, he does so more normally, able to pull in his legs without using his arm and stand upright using a minimal one-handed Gower s. c. Getting into the family van In a video-recording of Patient C attempting to get into the family van from early in the trial, he was unable to step up or pull himself in, failing to get into the van and expressing frustration. In a second video, from after being in the eteplirsen safety trial for 7 weeks, Patient C was now able to get into the van, however needed to use his momentum and upper body strength to pull himself in. In a third, and final, video, from after being in the trial for 4 weeks, Patient C was much more easily able to get himself into the van. 9 Patient C had participated in a previous clinical trial for another investigational product during which Patient C s parent caregiver could not tell, based off her own observation, if there was evidence of any drug effect. Because of this experience, the parent caregiver decided to capture information that could give a more objective sense of the patient s outcomes during the eteplirsen safety trial. 7

33 d. Spontaneous collapses In a daily log of Patient C s spontaneous collapses from November 4 through May 5 (see Appendix E for the daily log), the number of daily spontaneous collapses reduced from an average of.86 collapses per day at its peak in December 5 to either zero or one fall per month in March through May 5. After having no collapses in April 5, the one fall in May came after a day of Patient C playing one-on-one soccer shooting exercises for about 8-9 hours, an activity that the patient was not able to at all do prior to his participation in the eteplirsen safety study. For all four of Patient C s most troublesome aspects of having DMD, as identified prospectively by his parent caregiver, there is documentation of clear improvement. 8

34 IV. DISCUSSION The results of the interviews of DMD patients enrolled in the eteplirsen clinical trials and their caregivers provide detailed information on a wide range of outcomes, including motor functions, activities of daily living, and quality of life. These outcomes, as reported by patients and caregivers, offer insights into the clinical meaningfulness of the results of the eteplirsen clinical trials and serve as an important basis of benefit-risk considerations for the review of eteplirsen by FDA. The global impression of change outcome measured the total improvement of the patient from before the trial to currently. Two of the patients were very, very much improved from baseline, three were minimally improved, while one who remained ambulatory was minimally worse in the three years since baseline. It is not surprising, however, that the two patients that lost ambulation very early in the course of the trial were reported to be much worse. See Figure. Figure Global Impression of Change by Patient Meanwhile, Figure shows the DMD patients ability to perform and frequency of performing activities of daily living were very stable across the eight patients as a combined metric. In general, the patients had high scores before the trial, indicating greater ability to perform activities of daily living with greater 9

35 frequency. With the inclusion of a number of ambulation-related activities, the decline in the overall activities of daily living in the two non-ambulatory patients was expected. Of the six ambulatory patients, three improved in their ability to perform and frequency of performing activities of daily living, two declined, and one remained stable. Figure - Change in Ability and Frequency of Activities of Daily Living from Baseline to Present The greatest difference between the ambulatory patients and nonambulatory patients was with respect to change in ability to perform and frequency of performing motor functions. A number of ambulation-related motor functions were included, such as the ability to walk independently. Figure 3 shows these outcomes as a combined metric. The two non-ambulatory patients experienced a significant decline (decrease of.55 points), which is attributable to their loss of ambulation. However, the results of the six ambulatory patients reflect immense stability in their ability to perform and frequency of performing motor functions, with two patients improving, one patient declining, and three patients remaining relatively stable. 3

36 Figure 3 Change in Ability and Frequency of Motor Functions from Baseline to Present Spontaneous collapses are the result of major functional weakness in the DMD patient s quadriceps, where a collapse of this muscle causes the patient to fall. In his interview, Patient C described this as he would be standing there one moment and the next thing he knew he would be laying on the ground or floor for no reason (e.g., not because he tripped or stumbled). This was very startling or surprising because the collapse came on without any warning or signal. Figure 4 shows the average number of daily spontaneous collapses by patient for Patients - 8. Two of the six ambulatory patients experienced a sizeable decrease in the number of spontaneous collapses, two experienced a minor decrease, and two remained stable. Of note, none of the six ambulatory patients are currently experiencing any spontaneous collapses. This is potentially critical since a large number of spontaneous collapses is thought to be a harbinger of imminent loss of ambulation. Such was indeed the case for Patients and. The absence of spontaneous collapses in the six patients still ambulant suggests none are at high risk of loss of ambulation any time soon. Joe M. Watt and Michael H. Brooke, Applications of principles of training to neuromuscular disorders, in Principles and Practice of Restorative Neurology 6, 9 (Robert R. Young and Paul J. Delwaide eds., 99). 3

37 This trend was also seen in Patient C, who saw a reduction in collapses from an average of.68 collapses per day at its peak to zero to one collapses per month currently. In one of the non-parent caregiver interviews, the study physical therapist testified to the fact that a protective effect against spontaneous collapses is a very remarkable outcome given other DMD patients of similar age would expect to see an increase. This is of particular importance because trends in reports received by the Jett Foundation from DMD caregivers and medical experts alike have associated an increase in spontaneous collapses as proximate to loss of ambulation. This anecdotal finding is supported by clinical experience in the field of neurology, where the extension lag test of the quadriceps is used in prognosticating loss of ambulation. In addition, preventing spontaneous collapses reduces the risk of injury as a result of such a fall. If a fall were to result in a broken leg, the study physical therapist estimated that 9 out of times the result would be a loss of ambulation. Figure 4 - Change in Daily Spontaneous Collapses from Baseline to Present Another outcome that is a predictor of a decline in or complete loss of ambulatory ability is the use of a wheel chair or other mobility assistance device. As is expected, the two patients that lost ambulation now require use of a wheel chair all of the time. However, as shown in Figure 5, of the six ambulatory Jeffrey S. Chamberlain and Thomas A. Rando, Duchenne Muscular Dystrophy: Advances in Therapeutics (6) 84. 3

38 patients, one decreased their use of a wheel chair, three use a wheel chair the same amount, and only two have increased wheel chair use. Patient 3 went from a large number of spontaneous collapses at baseline and a 5% reliance on his wheelchair to an absence of collapses and has not needed to use his wheelchair in years. The concordance between the two is reassuring. Similarly, Patients 5 and 7 slightly improved on spontaneous collapses and those two patients have not increased their wheelchair use even after more than three additional years with DMD. Figure 5 Change in Percentage of Time Using a Wheel Chair or Other Mobility Assistance Device from Baseline to Present Quality of life measures of weakness and fatigue, two of the primary complaints of patients with DMD, are displayed in Figures 6 and 7. In the two non-ambulatory patients, both weakness and fatigue increased from mild to moderate. However, in the six ambulatory patients, three patients had a robust decrease in weakness, one patient had an increase in weakness, and two patients were stable. With regard to fatigue in the six ambulatory patients, two patients had a decrease in fatigue, one patient had an increase in fatigue, and three patients were stable. 33

39 Figure 6 Change in Weakness from Baseline to Present Figure 7 - Change in Fatigue from Baseline to Present The ability to accomplish everyday activities, which served as a global assessment of independence in the DMD patients day-to-day life, is displayed in Figure 8. As with some of the other outcomes, the two non-ambulatory boys 34

40 experienced a decline. Of the six non-ambulatory patients, two patients had robust increases, two declined, and two maintained their independence. Of note, four of those six patients are currently either moderately or completely independent. During parent caregiver interviews, the patients independence on a daily basis is a major factor for the quality of life of the parent caregiver and the rest of the family. Figure 8 Global Assessment of Independence These results of the quantitative input from caregivers provide evidence that the boys in the eteplirsen efficacy trial are stable on many outcomes. Moreover, three of the patients in the eteplirsen efficacy study appear to be better than at baseline across the eight caregiver interview topics: Patient 3 has improved on all eight outcomes. Patient 4 has improved on seven outcomes and remained stable on one outcome. Patient 5 has improved on three outcomes and remained stable on five outcomes. While the entire cohort of patients disease progression is slower than we would expect and is beating natural history, these three patients are clearly doing so. See Study Physical Therapist Full Interview. 35

41 This is because, in the natural history of DMD, nobody gets better. 3 Where a response is observed in a number of subjects in a clinical trial for that disease where patient would not otherwise be expected to spontaneously improve, as is the case in DMD, FDA has approved the therapy when a sufficient number of such responses are seen, regardless of whether there is statistical significance. For example, in the 983 approval of etoposide for testicular cancer, just five of the clinical trial participants survived for one year when none were expected to (an unexpected response rate of 5%). FDA approved this product based on when it deemed informally the rule of five. Here, even assuming that none of the four patients if the eteplirsen efficacy study who were not interviewed had outcomes similar to Patients 3, 4, and 5, then three out of, or 5%, of the patients in the study experienced outcomes that would never be seen in the natural history of the disease. If we add in Patients A and C, both advanced DMD patients with little hope of improvement, each who experienced meaningful improvements, then the response rate for those patients who are beating natural history increases to five out of 5, or 33%. These improvements reported by parent caregivers are supported by responses given directly by the patients. See Table 3. For example, Patient 3 described how he used to require a wheel chair to get around school and that he now no longer needs to use one. He also can now prepare food for himself without assistance, such as not needing someone to open milk cartons for him anymore. Patient 4 reported that he can now walk longer, jump higher on the trampoline, and run faster. Patient 5, who previously required his dad to lift him out of the pool, is now able to climb out of the pool on his own. He also noted that he feels less fatigued, so he is able to do more activities when he gets home from school when he used to need to rest. Patient 8 spoke of how he was able to get better at sports, like basketball and volleyball, and even scored the game-winning point for his grammar school volleyball team in a championship game. These improvements are further corroborated by the interviews with the patients in the eteplirsen safety trial and their non-parent caregivers. See Tables 7 and 8. For example, Patient A reported regaining the ability to raise his arms higher, making self-feeding easier and less messy. He is also now able to lift his own leg when lying in bed, when his caretaker used to have to do that for him. Patient B is able to pull up his own pants, no longer needs to use his railings to roll over in bed, and can more easily adjust his wheel chair s leg guards. These were all things he said he had lost the ability to do and has regained since being in the 3 Id. 36

42 trial. Patient C shared how frightening his spontaneous collapses had been and reported how they are happening a lot less now. He is also able to get into the family van on his own, sometimes using something to step on, but no longer requiring assistance from his mother. While the baseline outcomes were measured retrospectively, asking patients and caregivers to recall to more than three years prior, which introduces the potential for recall bias, these results should not be dismissed. Although the patients or caregivers may have erred in their recall of these outcomes, their responses still provide valuable information. For example, Patient 3 s parent caregiver, hypothetically, could have erred in reporting the number of daily spontaneous collapses, reporting five collapses per day because that is what it felt like when recalling the number. However, the number of collapses could have really been two or three per day. The important fact is that there were still daily collapses, and that fact that they have reduced to does not change. In other words, with appropriate discounting, the recalled values still tell the same story. Finally, while ambulation itself was not an interview topic, it is important to highlight that out of patients in the eteplirsen efficacy study have remained ambulatory after more than three years. This outcome is noteworthy because, due to the initial efficacy evaluation lasting just 4 weeks, the trial participants were selected because they were clinically assessed as being close to losing ambulation. For example, Patient C s parent caregiver reported that Patient C was screened out of the trial for being too functional. Despite the progressed nature of this cohort, of those are still ambulatory, which is different than any natural history data or other datasets (e.g., the ataluren placebo group that even included Becker s patients, and the drispersen study subjects which was not enriched to select boys who were specifically close to loss of ambulation). 37

43 V. CONCLUSION In summary, there appears to be stabilization of motor function, activity of daily, and quality of life outcomes in six of the eight patients in the eteplirsen efficacy study (i.e., the ambulatory patients), as well as stabilization in nonambulation-related activities in the other two patients. There are incremental improvements in certain activities as well. Based on additional interviews with the study physical therapist and Patient C s physical therapist, such stability and improvement would not have expected if the boys had not been in the eteplirsen clinical trials. 4 The results of the Jett Foundation s systematic collection of input from patients and caregivers, based on the experiences of the DMD patients enrolled in the eteplirsen clinical trials, provide detailed information about outcomes from both before the trials and at the time of the interviews. The findings associated with these outcomes are important to the DMD community and were collected as requested by FDA officials. We at the Jett Foundation offer this information to FDA in hopes that this information will help the Agency assess the clinical meaningfulness of the eteplirsen study findings and serve as an important basis of benefit-risk considerations by FDA when reviewing the application for eteplirsen for the treatment of DMD. In addition, we at the Jett Foundation provide this report as a model for the collection of patient and caregiver input designed to measure concepts highlighted by patients as important, which to our knowledge are for the first time being collected, analyzed, and submitted to FDA by a patient advocacy organization. 4 Id. 38

44 Appendix A: Primary Interviews Script [Begin after receiving informed consent from the parent caregiver for both the caregiver and patient interviews and assent from the patient for the patient interview]. Introductory Statement to Patient Caregiver Thank you for your participation in this interview. We provided you with an informed consent document and received your informed consent for both you and your son to participate in this interview. We also provided your son with an assent document and received his asset to participate in this interview. To begin, we will ask your boy to join us for a set of oral questions. We anticipate this will take 5 minutes for your son. We will then move to some oral questions for you, as well as provide you with rating scales to aid answering our questions. We will begin with some baseline questions. After those, we will ask you, as the caregiver of a patient enrolled in the trial, to answer questions that are divided into three categories: first will be motor function questions, second will be questions related to activities of daily living, and last will be global functioning and quality of life questions. We anticipate your interview will take 45 minutes. Please stop us at any time if you have a question, and remember that you may choose to not answer any question, and we will not ask you to give any reason or explanation for your choosing not to answer. [Have patient join the interview]. Patient Interview and Questions Hello. We are going to spend some time talking together so that I can get to know you and learn about how you feel about your disease, Duchenne Muscular Dystrophy. We are going to record our talk on this video recorder to help remember our time together and share your story, if you say it is okay. Are you okay with talking with me? [Wait for answer] Are you okay with me recording our time together? [Wait for answer] Okay, let s start with an easy question: How are you feeling? [Note: not for research purposes, just to get the child comfortable with the interview.] 39

45 Can you tell me some of the things that you enjoy doing the most? o Follow-up: Can you give me an example or tell me a story about when you [insert activity(ies)] recently? o Follow-up: Have you always been able to do [insert activity(ies)]? o Follow-up: How has your ability to do [insert activity(ies)] changed, if at all, over the last few years? What would you say bothers you the most about having your disease, Duchenne Muscular Dystrophy? o Follow-up: How much has this bothered you? o Follow-up: Can give me an example or tell me a story of how this has bothered you? o Follow-up: How much does this problem bother you? [Wait for answer] So would you say this is all the time? Most of the time? Or only some of the time? What would you say bothers you the next most? [Note: try to get the top four answers] o Follow-up: How much has this bothered you? o Follow-up: Can give me an example or tell me a story of how this has bothered you? o Follow-up: How much does this problem bother you? [Wait for answer] So would you say this is all the time? Most of the time? Or only some of the time? I have a few more questions and then we ll be done: Have any of the activities you do or things that have bothered you gotten better? Have any of them gotten worse? o Follow-up: Which ones? How so? Has anything else gotten better? Has anything else gotten worse? o Follow-up: Which ones? How so? Last question: Is there anything else you would like to tell us about your disease, Duchenne Muscular Dystrophy? Thank you for talking with us. [Transition to the caregiver interview] 4

46 3. Parent Caregiver Interview and Questions a. Baseline Questions To begin, we have a few questions about your son s baseline prognostics at the time he enrolled in the trial. What was the age of your son at the time of enrollment? Years and months if possible. What was the height of your son at the time of enrollment? What was the weight of your son at the time of enrollment? Was your son on steroids at the time of enrollment? o If yes: how long was your son on steroids prior to enrollment? What was the result of your son s baseline six-minute walk test? Would you please tell me whether your son was enrolled in the 5mg/kg or the 3mg/kg study group, and whether he started in the placebo or control group? If you need to get back to me with any of these answers in order to assure the accuracy of your recollection, please do. You can call or us at the information provided on this contacts sheet. [Hand Contact Sheet to caregiver] b. Motor Function Questions Our first set of questions relate to your son s motor functions before and after the trial. [Hand caregiver the Motor Function Rating Scale] We have provided a rating scale that lists a series of motor functions. For each item, you will be prompted to rate your son s ability to perform the function, as well as the frequency he performs that same function. You will be asked to do this for both before the trial and after the trial, or currently. Do you have any questions about the rating scale or how you are to complete it? Okay, please fill out the Motor Function Rating Scale and let me know when you are finished. [Caregiver completes Motor Function Rating Scale] We have some follow-up questions related to your son s motor function: Please describe your son s gait prior to the trial. Please describe your son s gait after the trial, or currently. How many spontaneous falls daily was your son experiencing prior to the trial? How many spontaneous falls daily is your son experiencing after the trial, or currently? 4

47 c. Activities of Daily Living Questions We are now moving on to our second set of questions, which relate to your son s activities of daily living, which are routine activities that people tend to do everyday. [Hand caregiver the Activities of Daily Living Rating Scale] Similarly to the previous set of questions, we have provided a rating scale that lists a series of activities of daily living. For each item, you will be prompted to rate your son s ability to perform the activity, as well as the frequency they perform that activity. You will be asked to do this for both before the trial and after the trial, or currently. Do you have any questions about the rating scale or how you are to complete it? Okay, please fill out the Activities of Daily Living Rating Scale and let me know when you are finished. [Caregiver completes the Activities of Daily Living Rating Scale] We have a follow-up question related to your son s activities of daily living: What percentage of time did your son spend using a wheelchair or other mobility assistance device prior to the trial? What percentage of time is your son using a wheelchair or other mobility assistance device after the trial, or currently? d. Global Functioning and Quality of Life Questions We are now moving into our third and final set of questions, which relate to your son s overall functioning and quality of life. [Hand caregiver the Global Functioning and Quality of Life Questionnaire] We have provided a short questionnaire with a series of questions and responses for you to select from. Each question has a part A and a part B, which relate to before the trial and after the trial, or currently, respectively. Do you have any questions about the questionnaire or how you are to complete it? Okay, please fill out the Global Functioning and Quality of Life Questionnaire and let me know when you are finished. [Caregiver completes Global Functioning and Quality of Life Questionnaire] Our final question for you is, over the course of the trial, were you aware of any side effects or adverse events related to the trial? 4

48 Before we ask your son some questions, we wanted to stop and see if there any other changes in your son that are relevant. 4. Conclusion Thank you and your son for your responses. We have made note that for certain outcomes your son experienced either improvement, stabilization or slowed progression. For these outcomes it would be helpful if we could support your observations with documents, photos or videos that you may have kept over time. Would you be willing to provide us with those documents? For example; a school PT/OT report may have captured a change in your son s balance, your son s pediatrician may have noted your son s difficulties prior to the trial, your son s teacher may have documented an increase in your son s ability to keep up with peers or noted no decline from the previous school year. You may also have videos that capture any of the activities that we have discussed, such as demonstrating walking, standing. In addition, you and your son may choose to have us record a video now that captures any of those activities presently. Please send us this information to the s provided on the Contact Sheet we gave you earlier. 43

49 Appendix B: Motor Function Rating Scale 44

50 Appendix C: Activities of Daily Living Rating Scale 45