Coney Islands infamous Cyclone roller-coaster doesn’t hold a candle to my life. My life is so scary... How scary is it you ask? It's so scary that I recently threw-up in my Dutch Bros cup.
Jonah attends school year-round. He has a small break at the end of summer before school starts up again. I was torn between going to Oregon so he could have some family time or staying home so I could work. Jonah’s break coincides with one of the NIH/NINDS grant funding rounds. I had PTSD just thinking about being in Oregon last summer when our current grant was funded.
These grants are our community’s lifeline, I need to be able to drop everything to respond to an NIH/NINDS grant inquiry. The federal government takes them just as seriously. When you’re notified that your grant has been ‘recommended’ for funding you’re requested to submit numerous supporting documents. The process is called Just in Time (JIT), half of the supporting docs are regarding company financials. It’s basically like taking out a mortgage and closing on a house. The other half of the JIT articles relate to your grant’s specific aims. You’re given a deadline to get everything in, if you miss it, you miss the funding round, hence the acronym JIT. Last year’s grant included human participants, which involved getting certifications completed for JIT. It was intense and being 3 hours behind the east coast makes everything just a little bit harder. I knew if I went home this September that I could be in double trouble, but I went anyways.
Double trouble, we have potential funding coming in and we’re resubmitting the same grant just in case we don’t get awarded this time. Back story last spring, we won a grant, but funding was ‘deferred’. We received a great score, what they call an awardable score, but due to budget cuts only the perfect and near perfect scores got funded. Deferment meant that if another awardee did not make a milestone, then PN could get their funds. By September 5th we’d find out if somebody missed their milestones so that our ‘deferred’ grant could be awarded. September 5th was also the deadline for re-submission. Our program director told us to be prepared for both case scenarios.
PN’s Scientific Director, Sri does the grant writing, my job is to create the budget and gather the letters of support (LOS). It’s me that presses the submit button, so I need to be next to my computer and ready to trouble shoot error messages. I’ll tell you about error messages another day. I booked our tickets to Oregon and spent the next three days pulling together all the JIT articles that I knew they’d ask for and at the same time asked our collaborators for updated LOS. An outdated LOS or quote can give you bad marks on a submission and ultimately cost you the grant. Meanwhile Sri worked on updating quotes and adding in the new data. The second day into our trip to OR we received the letter acknowledging that our deferred grant had now been recommended for funding! JIT requests started coming in. At this point you’re still being warned not to get too excited, it’s not a done deal until the notice of award (NOA) is sent out.
One of the JIT requests questioned our use of a foreign research organization to manufacture our vector. The NINDS gave us 3 options the first was to find a US based manufacturer. This is not something that can be done in a few days. The thought of even trying to make this happen was staggering. The wait times for vector manufacturing can be over a year, the work involved is extraordinarily detailed, it costs millions of dollars. Manufacturers need to have the blueprints to our construct; they must have internal meetings to discuss if their facilities can even do the work. The second option was to pay for the vector out of our own pocket, moot point. The third option was to submit a justification as to why we had to use the foreign component. I thought we had sufficiently justified the need for the foreign manufacturer in the body of our grant. If the reviewers didn’t think that justification was good enough, then what else could we say to them now?!
I talked to Sri first thing in the morning, he assured me that we had good justification, he reiterated our stance in a letter to NINDS and we submitted to JIT. The next question from NINDS was for the credentials of the foreign manufacturer, which is Viralgen by the way, they’re located in Spain. Our grant program director said that funds going to Spain had to be approved by the State Department. Who says that? Well, who says that to little ole’ me anyways? I must get it approved by the State Department. Ha! She also informed us that approval could take a while. I thought to myself, no way we’re getting approval in time; good thing we re-submitted.
This was now the fourth time we submitted our gene therapy grant (JLK-247) for San C. The second time we submitted the grant it was kicked back due to ‘overstuffing’. Overstuffing... we had included FDA comments that the grant submission portal ‘gatekeeper’ (for the lack of a better title) said to be against grant rules. Our justification for doing this was because the first time we submitted the grant and didn't win, the reviewers commented that they’d like to see if the study design had FDA buy-in (I’m paraphrasing). We went to the FDA, received the nod, and included their comments regarding our study design to the grant as a letter of support and resubmitted. The gatekeeper did not like that approach and accused us of trying to get around the grant page limit by adding in FDA comments as a LOS. For the record we also added the comments in the body of the grant. We included the official comments as a LOS because we thought it was a nice touch and our program director agreed.
Sri and I fought for the grant to be permitted through and asked to let us go with a warning. She could have redacted the portion of the FDA comments that she felt were unfair (I'm pretty sure she actually used the word egregious) to the other applicants. It was a heated conversation. The gatekeeper demanded that I put in writing my justification as to why I was so special that I got to cheat (I’m not paraphrasing). At this point I was foaming at the mouth. I have a consultant that advises us on grant submissions, he highly recommended that I drop it, that I was not going to win this argument. I let it go and we resubmitted four months later at the following submission date; this is the grant that got deferred.
Not that we have come full circle, did we win the grant or not? I don’t know, I do know that the State Department approved our justification to working with Viralgen! I’m thrilled but trying to temper my expectations. I think we’re just waiting on the OLAW (Animal Welfare Assurance) confirmation now; we sent it in on Thursday but no response if it was enough. Radio silence.
There have been a handful of diagnosed San C patients this
year. It’s always how long how long how long. I respond I don’t know, it’s not
up to me. That doesn’t stop them from asking. I don’t blame them; I know
exactly how they feel. What brings me to tears is the overwhelming
feeling of helplessness, drug development does not come with a GPS! I'm trying to go as fast as I can families.
The grant funds will cover the study that analyzes the tissue from the mouse dosage study using our new vector (JLK-247) this study was supported in part by the Cure Sanfilippo Foundation. Among other things we will be looking at the biodistribution of JLK-247. If it and everything else is good, then we can go to the FDA and ask if we can go to trial. If they’re not convinced, we’ll have to do another animal study.
It has been an extraordinarily busy year. The grant that was awarded this time last year is funding for the Natural History Study (NHS) protocol design and implementation of Sanfilippo syndrome type D, the program name is ALL-127. I’ll spare you the gory details of securing that funding and skip to the exciting part. Writing a clinical protocol 101: Patient input matters more than most sponsors imagine. The FDA talks about how important patient engagement is for selecting endpoints and trial design every chance they get. I’m not getting the sense that sponsors have really understood or taken to heart that message. They can’t just send out a survey asking families what the biggest burdens are. That isn’t good enough.
Patients need a seat at the table, not just metaphorically
but literally. We need to have a say in how the symptoms are measured. Some
symptoms (endpoints) are easy to measure- straight forward. In the case of
Sanfilippo there is not one endpoint that is straight forward or easy to
measure. Which is mind-blowing because the syndrome affects every system of the
body. It hits the central nervous system (CNS) the hardest, a hit to the CNS radiates
out to the all the other bodily systems.
Affecting the way our kids: walk, talk, eat, think, sleep pee/poop, process
sensory input and behave. The children’s other organs are affected as well but
the impacts are subtle and don’t cause immanent death. Unless their lungs fill
with fluid from pneumonia, which doesn't make for a good endpoint either.
For the Sanfilippo community communication and mobility are two of the top-ranking symptoms. Improvement in communication gets lost in translation to sponsors. We can’t just say improvement in communication to a sponsor. The sponsors think speech. A parent of a Sanfilippo child sets the communication bar much lower. We want our kids to be able to communicate non-verbally, it can be as simple as a smile. A smile from our kids means everything to us. Think about it, what if your loved one stopped smiling? Will the FDA approve a million-dollar drug for smiles? A million-dollar smile, totally worth it 😊.
In the case of Sanfilippo, sponsors have leaned on cognitive tests for measurement of treatment improvement, think of the SAT. These types of assessments are guarded by the authors and license holders. To see them you must have your clinical team lined up and prove your intent of conducting a clinical trial. When we first wrote the grant, we had to include a synopsis of our intended clinical protocol for ALL-127. We chose assessments that were used in the other clinical trials for San A and B. At this point I had still not gained access to the cognitive assessments. It wasn’t until after the grant was awarded and our site and clinicians had been secured that I was permitted to see the assessments. By then we had finalized our protocol and sent it in for IRB approval, this was no small feat.
After reviewing the assessments well if you can’t guess by now… I was nauseous and plagued with doubts. The assessments in my opinion were not appropriate for the Sanfilippo patient population. At the same time, our FDA comments came back, they had reviewed our protocol and had numerous suggestions regarding out choice of cognitive assessments. The final straw was the results from the failed and divested San A and B drug trials that were finally being published. The data suggested further that the chosen cognitive assessments were not appropriate to measure their endpoints. Our ALL-127 protocol had literally just received IRB approval; we could start recruiting patients soon. We were faced with a major decision- continue with the status quo or start over. We started over. Now we were faced with missing a milestone and not having funds released in time to continue study startup. It’s a non-stop roller-coaster ride. I can’t say I never catch a break; the break was getting the chance albeit a last-minute chance to right a wrong. We were left with now trying to find the assessments that would work.
As mentioned, you can’t go to a library or store and browse through all the assessments available to license and use in trials. We must work with the companies that own them. They have specialists that help you zero in on topics of interest, I combed through endless assessments. Nothing was right. I called on Jonah’s therapists. Who better to point me in the right direction then the teachers on the front lines administering these tests to kids like Jonah. His therapists gave me a list of tests, which I then requested to view from the owners. My guy chuckled when he pulled them for me. He said he wasn’t even aware that they owned the assessments, they were so old. On that note… I finally had something we could work with. The ALL-127 protocol is now finished and back with the hospitals Internal Review Board (IRB). We anticipate approval to be coming in a few weeks. Our site initiation visit is set for October 14th. Our goal for first patient in is end of October early November. We will make our first milestone and be able to bring the rest of the participants in for screening and baseline after the new year. After that the participants will come in for two more annual visits. Meanwhile the ERT mouse toxicology studies for ALL-027 will wrap up and we will head back to the FDA. If all goes smoothly the ALL-127 patients will proceed into the interventional trial. Truth be told I’d like to extend the study for at least a third year, sadly we don’t have the budget for it.
The study is extraordinarily expensive. Our hope is that once we start accumulating the natural history data that we will garner more pharma interest and find a financial partner. I have a feeling that once the study is published on clinicaltrials.gov that we will have more patients wanting to participate. It would be amazing if we could include all the San D kids that wanted to come. The participants are coming from around the world, over half of them don’t speak English. We must translate all the consents and other patient facing documents to their native languages and bring in translators to help them throughout the study. ALL-127 doesn’t just include cognitive assessments, there are numerous physical and clinical tests as well. Labs, sedation for x-rays and MRI. It’s no walk in the park for the children or their parents. Their commitment to the study and desire to help bring forth a treatment is nothing less than heroic.
The ALL-127 protocol is going the extra mile by including a video collection of daily living activities (ADLs) shot at home by the children’s caregivers. There will be a retrospective portion as well, all the patients’ medical records will be reviewed for the onset of disease symptoms. All the data gets imputed by the site coordinator into a controlled data base. It took our team (Labcorp) almost a year just to design the database, in their defense I did keep making changes to the protocol.
I’m extremely proud of the video portion of the study, we’re
working with Aparito, a company that has licensed HIPPA and GDPR compliant
software program to manage patient data. With the help of our patient community
our team came up with several activities that we hope will capture the participants
real-time real-world experiences. Caregivers will video children performing daily
activities in a natural setting, within standardized parameters for video capture
which will hopefully cause minimal disruption in their daily routines. The video
activities compliment the assessments performed in the clinic. The idea is to visualize,
describe and score the children’s behavior, movement, communication abilities, and
yes smiles that are hard or even impossible to capture in the clinic. Remember
our young kids are always on the move, they can’t sit still and tend to run
away. Our advanced kids smile if we're lucky, they're cared for 247. I'm hoping that our video tasks will capture a few smiles and any incremental improvements seen by families after intervention.
These videos are taken on a smart phone using an app, the families are given a secure QR code where they download the app, which has been designed and translated to walk them through all the activities and questionnaires. The videos will be taken within 14 days of the clinical visits and at 6mo time points in between the clinic visits. We named the app RARE Recording Application for Real-world Evidence. The San C version is called C-RARE, get it? Sri came up with the acronyms.
When supporters donate to medical research, the primary thought is the cost and time of drug discovery in the lab. This is the tangible portion that can be visualized. It’s the behind the scenes and back-end work that you don’t see that takes just as much time and funding resources as the laboratory research. The contracts, study design and quality checks are sucking up all my time. Everything that goes into drug discovery must be meticulously collected, scored, and stored for FDA review.
In between reviews I have been working on new quality of life and clinical outcome questionnaires tailored to absorb as much as we can out of the Sanfilippo patient experience. These types of questionnaires are called Clinical Outcome Assessments (COAs) the cognitive assessments also fall under the COAs. Over the past ten years I have been told on numerous occasions that it is too hard to design and validate syndrome specific COAs. That I’d be wasting time to even try because the FDA wanted the ‘gold standard’ validated assessments that have been used in thousands of trials. It later occurred to me that the advice was coming from people that didn’t have a full understanding of the progression or phenotype of Sanfilippo syndrome or that the FDA had extremely little experience with Sanfilippo. It’s only been 10 years since the very first San A trial started. The FDA is just now wrapping their brains around the data coming from these trials. They have had a steep learning curve.
A few months ago, the FDA came out with a new guidance that
states if there is not an assessment available that is sensitive enough to
measure your target endpoint, then make a new assessment, they go on to walk
you through how to do it. I had already started to create a COA to measure
behavior when this guidance came out. The FDA guidance was the push I needed to
create a series of Sanfilippo specific COAs. The Sanfilippo families have been
guiding us on the development of these COAs, patiently walking through every question
and giving their feedback and suggestions for improvement. It has been an extremely
rewarding experience for all of us. My
team engsged a couple of expert clinical assessment designers to help us with the
scoring and wording of the questionnaires. When finished we’re going to pilot
the COAs on the C-RARE app. We didn't finish the new COAs in time for the ALL-127 launch. They will however be done by the ALL-027 intervention trial.
The JLK-347 clinical protocol is being scrubbed by Labcorp’s quality control team right now! Labcorp is the CRO managing our studies and storing the data. We’re planning 2 sites, one in France and the second in the US. While the NHS for San C gets underway, we will finish up the tox and biodistribution animal studies (contingent on the grant coming in). The plan is for JLK-347 participants to transition straight into the interventional trial, JLK-247 and become their own controls.
PN has been working on a third program that is suitable for all Sanfilippo subtypes, AVP6. It’s a peptide administered nasally which increases synaptic function. It’s an option that will pair nicely with gene therapy and ERT interventions.
I have taken the time to give you all an extra-long blog as
I plan on being too busy to write again for another year! Tomorrow we will win the
JLK-247 grant and begin our next chapter. Watch for the press release on Linkedin.Fingers crossed.
Quick Jonah update, he is doing great! He's still smiling and still
learning. He just started his freshman year! Jeremy and I are so incredibly
proud of him. This kid is fighting his fate like, Batman, his favorite superhero and he doesn't even know it.
I gave a few talks this year:
ADVANCE Sanfilippo syndrome workshop Cure Sanfilippo Foundation
https://www.youtube.com/watch?v=UbtxDl20TyQ&t=3s
My talk is on the ALL-127 program and RARE app. It starts at 1:30ish. Phoenix Nest had three other talks. Srikanth Singamsetty discusses JLK-247, Tsui-Fen Chou speaks about ALL-127 and Alexey Pshezhetsky gave a talk on AVP6. The AVP6 talk and it's data were not published for wide distribution. You will have to wait until we publish.
NINDS Nonprofit Forum 2022
https://videocast.nih.gov/watch=45549
My talk starts at 2:17ish on day 1. Please watch the talk right after mine with Emily Caporello, NINDS and put a face with my "program director".
Decision Vision Podcast
I spoke on my experience with applying for NINDS SBIR/STTR grants
RDLA- Rare Disease Week 2022- Policy Deep Dive: Speeding Therapy Access Today (STAT)act
https://www.youtube.com/watch?v=btB0cCzWoM8
Spoke to how federal funding helps the ultra-rare disease community! My talk starts at 1ish
Check out the new FDA fit-for-purpose clinical outcome assessment guidance.
https://www.fda.gov/media/159500/download
