Dear Dr. Califf, Dr. Marks and Advisory Committee members: I am Mira Klingenberg from Marcus, Iowa, and the Mother of Matt Klingenberg of Brandon, South Dakota. Matt has ALS. He was a participant in the NurOwn Phase 3 randomized, controlled trial, then he received 6 doses of NurOwn via an Expanded Access protocol. Matt’s neurologists are Dr. Anthony Windebank and Dr. Nathan Staff at Mayo Clinic. I am writing today to share the “substantial evidence” proving NurOwn works and to ask the FDA to approve NurOwn with a Phase 4 post-marketing study. I am a healthcare professional, with my BSN, RN. I spent 35 years in psychiatric nursing, working at the Cherokee Mental Health Institute, a state of Iowa hospital. I cared for the most mentally ill people in the state. This type of nursing required expertise in observational assessment and evaluation, using subjective scales and tools. The evidence that I am sharing with you today is no different than the clinical documentation I provided every day in my nursing career. I’m also a level-headed Midwestern mom. I have seen many people die, and buried many family and friends. There is no deluding myself about this disease and the ravages it causes. All this is to say, my observations are objective and not optimistic. I know ALS will kill my son. But I also know that NurOwn has improved how he feels and functions, improved his quality of life, and most importantly, given him more time with our family and especially his three young children. “I know ALS will kill my son.” These are the most painful words I’ve ever uttered or written. I can’t adequately express the difficulty of this journey, how hard it is for Matt, my sunshine boy; Kelly, his wife, and the kids: Mason, James and Aubrey. Matt faces this path with grace and a sense of humor that sustains all of us. Matt deserves the chance to live longer. Kelly works all day every day without fail or complaint. She deserves the chance to love Matt longer. I worry about Mason, the oldest, already so responsible. He’s 8 years-old. He helps his Dad and Mom with the work of life because he’s called upon to do so. Because of ALS, his childhood will be cut short. James at 5 years old doesn’t quite know this yet but it’s around the corner. Aubrey sits on Matt’s lap, climbing up without assistance, and kisses him like he is her everything. The reality of this disease hits like a tsunami. Grief, anger, fear are constant companions now. I find ways to stay afloat. One way is knowing my family needs me and another is the firm belief that NurOwn works and that it will be approved. Matt’s ALS Diagnosi s At 32 years old, Matt was diagnosed with ALS. His onset was in his upper limbs, on his non-dominant side. The initial symptom prompting medical care was left shoulder fasciculations. My no-nonsense son knew his body and knew something was wrong. He pushed for answers and was diagnosed on March 18, 2018 at the University of Iowa Hospitals. He was diagnosed based upon his fasciculations, his EMG and his abnormal neurological exam. In June of 2018, a second opinion by Dr. Crum at Mayo confirmed ALS. On August 26, 2018, Matt’s ALSFRS was 48/48. Last week, Matt celebrated his 38th birthday. When he was diagnosed at 32 years old, we didn’t know if we would see these birthdays. Matt is now 5+ years post-diagnosis. He has outlived the average 2-5 year prognosis. We’d like to keep that streak going. The NurOwn Trial On September 24, 2018. Matt was evaluated for BrainStorm Cell’s Phase 3 interventional clinical trial of NurOwn at Mayo Clinic. At screening, his ALSFRS was 46/48. He reported to Dr. Staff that, since June, his left arm, thumb and foot were worse. To qualify for the trial, you had to lose at least 1 point/month in the ensuing 12-week run-in phase. Matt met that threshold and was accepted into the trial. His first dose was January 2019. On July 30, 2019, Matt had his last appointment for the NurOwn trial. His progression halted. He functioned normally, with minor lifestyle changes (electric can opener). We did not tell family or friends of his diagnosis until January 2020. Everyone was shocked as no one could see any impairments. Eighteen months after his diagnosis, Matt had no observable symptoms of ALS. After the NurOwn Trial Once the NurOwn trial was over, these are my observations about Matt’s disease manifestation: Disease was evident by February 2020 – over a year after his last dose in the trial , but much of 2020 Matt was able to live normally with little progression. His bulbar function was normal. He ate, talked, and breathed without difficulty. His gross and fine motor skills showed limited impairment. His walking was slower and less steady. But, he walked at parks, worked in the garden, held the kids and gave horsey-back rides. At Christmas he sat on the floor and played games with the kids. He worked with tools around the house with his dad. In June 2020, he built a sandbox for the kids, only needing help with the heaviest lifting and screwing boards together after he got tired. By the end of 2020 and into 2021 , progression was steady. Decreased balance. Falling occurred and increased in frequency, typically several times a week. Increasingly unable to use arms, decreased mobility and strength in arms/shoulders. Walking was slower and gait demonstrated further foot drop. In April 2021 , due to declining mobility, he retired from work at just 35 years old and moved his family to South Dakota so his wife Kelly and his children, Mason, James and Aubrey, would be close to Kelly’s parents after he died. Matt supervised the moving, but was unable to lift or carry boxes or items. Dressing and showering were more difficult. Kelly took over more household chores. Notably, Matt experienced increased pain, cramping and spasticity, as is common with upper motor neuron involvement. It is a fallacy that ALS is painless. Without NurOwn, the pain increased and progression sped up. Assistive devices such as w/c, scooter, larger eating utensils were used. On the ALSFRS assessment, the areas most affected were the fine and gross motor domains. The bulbar and respiratory domains were mostly unaffected – though his voice was slower with a different cadence. NurOwn Expanded Access Program: Doses #1 - 3 in 2021 In June 2021 , Matt received NurOwn via an expanded access protocol. In this round of EAP, he received 3 doses. Matt immediately noticed his walking improved. He had better balance, with fewer falls. In his statement to the FDA in a Patient Listening Session in October 2021, Matt told them: After my first injection of NurOwn on June 10th my balance improved immensely. Before that injection I was falling down several times a week and after the injection I stopped falling down. His fine motor skills improved as well as he was able to open wrappers on chewy bars for he and the kids. He was also able to buckle their car seats again, which meant he could help with getting the kids or car rides. He could also buckle his own seat belt. Overall, he reported “feeling better.” With the second treatment in August 2021, Matt experienced stabilization and some improvement. He continued to have no difficulties with breathing. This second dose caused a change in his speech. Matt’s voice was stronger with improved cadence. This was noted by myself and others, who commented about his voice. Matt explained this to the FDA in the October Patient Listening session: After my second injection I noticed that my voice improved dramatically. Before the injections, my tongue would get very tired during long conversations and now that doesn’t happen. Matt has stated he hopes his voice goes last, as he wants to be able to talk to the kids until the end. NurOwn helps his voice. Each dose in EAP helped his gross motor function. The ability to climb stairs is one of the questions in the gross motor skills domain of the ALSFRS. Quite compelling are the two videos from June of 2021 comparing Matt walking up/down the stairs in his home before and after the first NurOwn dose in EAP. The third video shows him descending wooden stairs in July 2021. In this video , you can see that Matt is able to walk up the patio steps at my home on September 21, 2021 – this is 3.5 years after his ALS diagnosis. His improvement wasn’t just limited to climbing stairs, but walking as well. Because of how frequently he was falling, previously Matt had been confined to the farmhouse when they visited his wife's grandmother’s property. After receiving NurOwn, Matt was able to walk on the rutted, uneven dirt and gravel road on the family farm. Fearful of him falling, I was one step back and to his left as he walked on the road. But he never tripped or lost his balance. As Matt told the FDA in October of 2021: Before the injection, I was confined to the little area in the blue rectangle because it was flat. After the injections, I can travel down the sloped gravel road to the machine shed. This is a huge quality of life win for me because my three children love hanging out in the machine shed and climbing around on the equipment. After the Nurown injection, I get to walk down there and enjoy that with them. This regained function is about so much more than just the ability to walk better... it’s about what it enabled Matt to do with the kids. For Matt, this is everything. Matt started EAP at 37/48 on the ALSFRS. He finished EAP at 38/48. Recall that his ALSFRS score at trial screening was 46/48, and to qualify for the trial, he had to lose at least 1 point per month during the run-in phase. Thus, from the September 2018 screening to the September 2021 end of EAP – in 36 months – Matt had only lost 8 points of function. Even including the quicker earlier progression during the run-in phase, this is still an overall average of just 0.22 points per month – approximately 20% of an average ALS progression. Sadly, with no NurOwn doses for 6 months, the steady decline resumed, albeit more gradually than before the trial. Matt needed assistance with walking. He predominantly used the walker, switching intermittently to a wheelchair or scooter. He needed more help with ADL’s such as putting on shirts and shoes. But, there were still things to celebrate. This video in March 2022 demonstrates Matt’s core strength as he was able to sit up from a lying flat position – without using his hands. And this video shows, as of April 2022, he was still able to walk slowly up the patio stairs. NurOwn Expanded Access Program: Doses #4 - 6 in 2022 In May 2022, just before Memorial Day, Matt began the second round of EAP. Again NurOwn improved how Matt felt and functioned. After that first dose in May, Matt said to me: “Mom, I feel whole, I feel like my body is working again.” Those are words a mother never forgets. Matt’s body responds. Within the first day, the symptoms like fasciculations (muscle twitching) are less severe and intense as well as his stiffness and spasticity are less severe and intense with every NurOwn treatment . This is critical as the latter are what causes pain. Matt has a significant amount of pain and although he never complains, the look on his face and his activity level are revealing. Demonstrating the changes in fine motor skills and core strength, this video shows that he was able to bend at the knees to squat a little, lean over, and pick up a leaf with his right hand Matt’s ROM in his upper limbs improved. Compare this video at the hotel in Minnesota the night before the NurOwn dose at Mayo, and this video one week later in his front yard in South Dakota. There is marked improvement. The ability to raise his arms higher and move his arms more freely is important to Matt’s ADLs such as the ability to shower, shave and groom himself. It also made it easier for Matt to hug his kids. Matt’s upper limb improvements mirror those reported by Nicole Cimbura’s husband, Mike, after he received his one dose of NurOwn in the Phase 2 trial in 2015. It is my understanding this was repeatedly communicated to the FDA at that time. It was also shared by Nicole during the Patient Listening Session with EAP participants and Dr. Wilson Bryan (CBER's OTAT) on October 12, 2021: Mike was able to raise his arms above his head to wash his hair, shave his own face, put on a tee-shirt over his head, stand up without assistance, walk around a National Park – all abilities he had lost prior to his NurOwn treatment. And again, this was shared with the FDA in the December 2022 Press Release wherein people in the EAP advised that they had regained the ability to “put our arms over our head, and wash our bodies and hair unassisted.” With that single EAP dose in May 2022, Matt’s walking, drop foot and balance improved. He relied on assistive walking devices less. Although he had previously used a walker consistently, he was now able to walk without one around the house. Before the NurOwn dose, this May 19th video shows Matt in his Minnesota hotel. His gait is stilted and he is relying upon a walker to walk . On Memorial Day weekend – after receiving the dose the prior week – Matt walked on the sidewalk and grass independently. The grass is significant as it is tall, “sticky” and makes walking with drop foot even more difficult. You can also see improvements from the May 27th video to the May 29th video, where Kelly, a physical therapist, comments that he’s “walking with his heels down.” Matt’s improvement was so profound that his two young sons noticed the difference. That weekend, they started by Matt watching the boys and Aubrey race each other on the front lawn. This was followed by 4-year-old James noticing the speed of Matt’s gait in this video : “DaDa, you walking a lot better... yeah, you walking a lot faster... but I still beat you.” Both boys join in the pronouncement that they can both beat their Dad in a race. With a hopeful response , Matt tells the boys: “Well maybe if I can keep getting more medicine, then I’ll beat you guys.” In response, you can also hear Kelly, a physical therapist, affirming James’ observation and remarking how fast Matt can walk now and that he’s putting his heels down. A few days later in this video on May 29th, 6-year old Mason again proclaims, rather matter of factly: “DaDa’s walking better!” Matt’s stabilization was sustained through the next two treatments, with the last dose in September 2022. And the effects of NurOwn endured for a while. Just as he had climbed stairs in September 2021 during the first round of EAP, in January 2023, Matt maintained the ability to walk up basement steps independently, only requesting help for stabilization when he got to the top step where there was no handrail. This was approximately 5 years (58 months) from his date of diagnosis. NurOwn improves Matt’s Quality of Life One of the most significant things about Matt’s improvements in and maintenance of functionality are how it impacts his ability to interact with his wife and the kids. This means everything to his quality of life. What NurOwn has given Matt is immeasurable. These are just some of the memories he has made because of how NurOwn made him “feel and function.” There is nothing more “clinically meaningful” than this. In January 2022 and 2023, our entire Klingenberg family vacationed together in Florida. In 2022, the kids had their first trip to Disney World. You’ll notice that Matt was still able to stand, and was able to take them on rides. They’ve traveled to historic Mt. Rushmore, were at Clearwater beach in 2023, and to the Omaha zoo in summer 2023. He was there, participating, when his kid’s experienced these new life events. These photos show you some of the recent memories Matt and Kelly have made with the kids in 2023. “Clinical meaningfulness” isn’t only measured by how long you can stand on your toes, how adeptly you can touch your finger to your thumb or how long you can blow into a spirometer. Each of these pictures is a glimpse into the “clinically memorable” moments that Matt has been making because of NurOwn. One particularly touching time was during camping weekend. Matt and his three-year-old daughter, Aubrey, have a special bond. Matt is a “Girl Dad.” This video was taken when the family went camping in August of 2021 (after he had received 2 doses of NurOwn in EAP). Functionally, it shows that Matt is walking in a slow saunter with almost no detectable impairments – 3.5 years after diagnosis. Most people who aren’t familiar with this disease would not know that he has ALS. But more importantly, it shows a father-daughter stroll on a lazy summer vacation ... and Matt making memories with Aubrey. A year later, on July 28, 2022, we went camping again. In this video are both the good and the bad . The kids love to camp – sleeping in the camper, playing in the water, with bugs, frogs, campfires, s’mores, and so much more. They especially love the “creaky bridge.” Matt was still able to walk on and maneuver the old swaying suspension bridge to throw rocks with the boys – an accomplishment when ALS strips your body of its core muscles and balance. But, you can also see that Matt has lost function without consistent doses of NurOwn. He can no longer raise his arms to throw the rocks and can only toss them sidearm. And as he walks, you can see that his gait is markedly different than it was on his father-daughter walk with Aubrey one year prior. This summer in 2023, Matt was no longer able to walk on the bridge. Matt has also been making sports-memories with the kids. When Matt was younger, he was a gifted, four-sport athlete. He played both ways in football, placed 2nd at 145 lbs at the Iowa HS state wrestling tournament, placed 5th two times in the 800 meter run at the Iowa HS state state track meet. His favorite sport was golfing and he once got a hole in one on our home town golf course. This photo of Matt is from 2018 - just before his ALS diagnosis. Matt was an outstanding golfer but with upper limb onset, he knew his days of playing 18 holes were over so he sold his clubs in 2019. While Matt no longer has the upper limb strength or range of motion to hit a drive, in this video from July 30, 2022 , you can see Matt standing and putting. Even now Matt is able to give Mason verbal golfing instruction and enjoys being on the golf course with the family. The Present Now in July 2023, Matt’s progression has become more rapid. Matt’s voice is more affected: softer, slower, and a little slurry. Today, my Matt is still walking. But, his walking is very slow with right leg immobility at times. He can still get up off the couch, but asks for assistance more frequently. His electric wheelchair is used. The bathroom is remodeled. We know how this is going. To date, he is not using any assistive breathing devices. This is significant as the collection of the breathing data in the trial was halted due to COVID. It’s an incalculable loss as nearly everyone in the EAP has reported improvements in breathing – even the people who were at the lower end of the ALSFRS scale. Some people had 40% improvements in FVC; others like Matt Bellina stopped using a bipap. Loss of respiratory function kills people with ALS when their phrenic nerve stops innervating the diaphragm. This improvement, alone, should be enough to support approval as it’s not just “clinically meaningful,” but clinically critical. Substantial Evidence Proves that NurOwn Works Our family's request is simple. Please give our son more time. Please approve NurOwn. NurOwn works for my son. I’ve witnessed his beginning symptoms, when progression halted, when some improvements were seen and felt, when symptoms were alleviated, and also when the normal progression of a 100% fatal disease resumed without NurOwn. There is “substantial evidence” that NurOwn works, improving how people feel and function. The clinical trial data demonstrated – with just three doses – that NurOwn met its pre-specified secondary endpoint, slowing loss of function. We believe there is a dose-dependent response. With six non-consecutive doses in EAP, Matt’s experience is even stronger and more sustained than the Phase 3 clinical trial data. NurOwn doesn’t just slow loss of function. In Matt, it halts his progression and helps restore some function. It improves his quality of life. For those who question whether NurOwn can halt or significantly slow ALS progression, I’d direct your attention to the clinical data published in the Supplement in Muscle and Nerve. Even with a small heterogeneous trial population, the p-value was .022 for people with scores of 34+. Matt was in this population during the Phase 3 trial and again in EAP. The biomarker data adds to the “substantial evidence” proving NurOwn works. It demonstrates that NurOwn is having a biological impact on the inside, matching Matt’s improvement on the outside. And no one in the placebo arm experienced these positive changes. Plus the biomarker data proves NurOwn is hitting its target engagement across the disease spectrum, not just helping those early in progression. To the best of my knowledge, these multiple CSF biomarker changes are a first in any interventional trial for sporadic forms of ALS. Accelerated Approval Advances Science & Ensures Humanity The test for Accelerated Approval is whether surrogate endpoints, like the CSF biomarkers, are reasonably likely to predict a “clinically meaningful” benefit. I will defer to Matt’s neurologists at Mayo to talk about how they correlate with and corroborate the clinical trial data, but I can say that our family is absolutely certain that NurOwn provided Matt with many clinically meaningful benefits. I can also say with absolute certainty that Matt will die more quickly if NurOwn is not approved. For those who query if we need another trial, that can be accomplished with Accelerated Approval. You can show humanity to my son and the other 32,000 people battling ALS by approving NurOwn, while concurrently conducting a Phase 4 study. And there is an upside to the scientific community too. Unlike cancer and COVID, where interventional trials enroll thousands, in a rapidly fatal rare disease like ALS, the trial populations are small. No Phase 3 trial with a few hundred could ever provide the treasure trove of CSF biomarker data that could be obtained in a Phase 4 study of thousands. This is a unique opportunity with a post-marketing study of NurOwn because of its method of delivery. When Matt receives NurOwn via intrathecal injection, Dr. Windebank removes a small amount of CSF to make room for the NurOwn dose. In a Phase 4 study, those CSF samples could populate a biorepository that could empower researchers to transform the science of not only ALS, but other neurodegenerative diseases too. Humanity and science need not be mutually exclusive. For all these reasons, our family is asking CBER to exercise the same regulatory flexibility as CDER has shown for other ALS therapies. We know NurOwn works, please don’t let a Type II error kill my son. Matt’s Goal Because of NurOwn, Matt is still making memories with his family over 5 years post-diagnosis. He is outliving the natural history of this disease. Matt wants to live long enough for his children to remember him. Even changes of a small magnitude can help him achieve this life goal. There is no scale that can measure what it would mean for his kids to remember their Dad alive. Please approve NurOwn. Thank you. Mira Klingenberg