I have always been jealous of the vast amount of money and research that has gone into Alzheimer’s research. I figured if Sanfilippo had a tenth of the funding that Alzheimer’s research had, that we could have created a cure for all 4 Sanfilippo subtypes in a matter of years. But with all that money why didn’t Alzheimer’s have a ‘cure’ or at the very least a half dozen treatments on the market? It terrified me that a treatment had not been developed for Alzheimer’s. What did that say for Sanfilippo?
I realize now that Alzheimer’s shares the same problem that Sanfilippo does, it is a slowly progressing neurological disorder that lacks measurable endpoints. Meaning it is very difficult to prove that a drug has a visible effect on a patient. You can’t reverse brain damage (yet) but you can stop or slow the progression. But how do you know that the drug has halted the progression of the disease when the neurological decline is slow to progress? Sanfilippo syndrome has one very important edge over Alzheimer’s. In Alzheimer’s there are several genes associated with the cause of the late onset version of the disease, making it harder to treat. For Sanfilippo we know the exact single gene defect that causes each Sanfilippo subtype, this allows us to zero in on that one specific disease-causing gene.
The FDA has taken a leap of faith and approved Aduhelm under its Accelerated Approval program. Instead of rejoicing this monumental approval, critics are gasping and calling for the resignation of FDA officials, including my personal hero, Janet Woodcock.
I read this editorial by Dr. Kakkis yesterday, which led me to binge read 6 articles over the raging controversy of the approval . I took away three points that the critics had against the approval of Aduhelm.
First point was that the critics didn’t think the drug was effective enough to grant approval.
That it was too expensive, and the applications were too broad, concerned that Medicare would go bankrupt.
Critics suggested that a friendship between an FDA director and top Biogen exec, inappropriately swayed the FDA to not only approve Aduhelm but use the Accelerated Approval program to do so.
For those that have been with us since diagnosis you must remember my obsession with the Prescription Drug User Fee Act PDUFA and The Food and Drug Administration Safety and Innovation Act FADASIA and the work that the EveryLife foundation was doing with their ULTRA and TREAT acts. Any of these acronyms ring a bell? This was back in early 2012.
I begged all of you in numerous email blasts from JJB to call your members of congress and implore them to include language from the ULTRA and TREAT acts advocating for 'Accelerated Approval'. I hope you remember because this blog is all about Accelerated Approval. The language that we advocated our members of congress for was included in FADASIA and signed into law by President Obama on July 12th 2012, this law was used to approve Aduhelm. You helped us get there. This is the language that we asked for:
The Secretary shall consider how to incorporate novel approaches to the review of surrogate endpoints based on pathophysiologic and pharmacologic evidence in such guidance, especially in instances where the low prevalence of a disease renders the existence or collection of other types of data unlikely or impractical. -PDUFA V sec 506 pg. 94
I took the liberty of cutting and pasting the FDA’s definition of Accelerated Approval AA. To make the most of my blog please read the definition word for word.
When studying a new drug, it can sometimes take many years to learn whether a drug actually provides a real effect on how a patient survives, feels, or functions. A positive therapeutic effect that is clinically meaningful in the context of a given disease is known as “clinical benefit”. Mindful of the fact that it may take an extended period of time to measure a drug’s intended clinical benefit, in 1992 FDA instituted the Accelerated Approval regulations. These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint. Using a surrogate endpoint enabled the FDA to approve these drugs faster.
In 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint.
A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).
The FDA bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint. Studies that demonstrate a drug’s effect on a surrogate or intermediate clinical endpoint must be “adequate and well controlled” as required by the FD&C Act.
Using surrogate or intermediate clinical endpoints can save valuable time in the drug approval process. For example, instead of having to wait to learn if a drug actually extends survival for cancer patients, the FDA may approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real clinical benefit. In this example, an approval based upon tumor shrinkage can occur far sooner than waiting to learn whether patients actually lived longer. The drug company will still need to conduct studies to confirm that tumor shrinkage actually predicts that patients will live longer. These studies are known as phase 4 confirmatory trials.
Where confirmatory trials verify clinical benefit, FDA will generally terminate the requirement. Approval of a drug may be withdrawn, or the labeled indication of the drug changed if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug (e.g., show a significantly smaller magnitude or duration of benefit than was anticipated based on the observed effect on the surrogate).
In Alzheimer’s patients’ researchers have found that the protein, beta-amyloid builds up in the brains of patients. In this case beta-amyloid is the surrogate biomarker.
In comparison, researchers have found that the protein Heparan Sulfate builds up in the brains of Sanfilippo patients. For Sanfilippo Heparan Sulfate (HS) is the surrogate biomarker.
Unfortunately for our kids the FDA has not given HS the nod yet, but they just let beta-amyloid through so there is hope for us! Which gives me so much hope four our children. I would be over the moon excited if the FDA would grant the sponsors working on treatments for Sanfilippo syndrome Accelerated Approval for the lowering of Heparan Sulfate in cerebrospinal fluid.
BTW biomarker and endpoint are often interchanged don’t confuse yourself.
AA is here for disease like Sanfilippo syndrome and Alzheimer’s. Try and picture what it would take for a drug to show clinical benefit in a Sanfilippo child, you might be able to picture this in an Alzheimer’s patient instead. Other than brain damage and death, there isn’t a significant hallmark of Sanfilippo that is consistent throughout the Sanfilippo patient population.
Some of the common hallmarks of Sanfilippo are behavioral issues, sleep problems, diarrhea, hyperactivity, loss of speech, vision, mobility, and hearing. In the last stage children lose all their motor and brain functions and slowly succumb to death.
These main hallmarks are not consistent throughout the patient population, children might not suffer from all these symptoms, the degree of severity differs, and the timeline of presentation and decline is variable. Our patient population is considered heterogenous. Now add to it the rarity of the disease. Take Sanfilippo type C, I know of 20 patients in the United States, the youngest child is 6 and the oldest is in their mid-thirties, the rest of the kids are spread unevenly through this age range. No two kids are in the same place in the disease.
At this point we can’t use brain damage as an endpoint, our children that could never read are not going to start reading, the brain damage has been done. An attenuated child’s brain MRI might look worse off than a severely affected Sanfilippo child’s MRI. Death isn’t a good endpoint because we don’t have a definitive timeline of death, it could happen in the first decade of life or the third decade. Same goes for hearing, mobility, vision, and speech. We can’t have a trial that last 40 years.
Side note- there are nearly 7,000 rare disease, half of those affect children and one third of these children will not live long enough to see their 5th Birthday. There are only 400 treatments for these 7,000 diseases. Think about that. It’s not because we can’t treat them. The science is here, but the incentive to produce a drug is not.
If the majority of Sanfilippo children died by 5 then we would have a good endpoint for our clinical trial. Most Sanfilippo children are not always diagnosed before the age of 5. Furthermore, the validated assessments currently used in clinical trials are not sensitive enough to see the change in our kids. The old gold standard tests that the FDA relies on are not designed for patients like ours. For instance, for mobility and endurance trials, sponsor use a test called the 6min walk test. It is exactly as it sounds; a patient walks up and down the hall trying to stay in a straight line for 6 minutes. You can’t explain to a Sanfilippo child to walk down to a cone and back for 6 minutes. They literally do not understand, they might be able to hear you and can still walk but they don’t understand the message. Perhaps you could model it, but it’s not sustainable for 6 whole minutes. The child will undoubtably become distracted and run in the other direction or take off their shoe and throw it at you. Go ahead and laugh at the vision, but it is not funny. We have a major problem.
Hearing and vision tests can’t be done unless the kids are sedated even if we could get an IRB to approve sedation for hearing and vision assessments, we don’t have anything to compare it to. Sleep disturbances is another major issue for our kids, but extremely hard to measure during a trial. I’m hoping you have gotten the point. To summarize, Sanfilippo is a slowly progressing, ultra-rare, heterogenous disease. And that is the root cause of the pain in the pit of my stomach and the heartbroken voice in my head that whispers: You’re wasting your time, give up and enjoy Jonah while you still can.
To answer the question forming in your head about what we are going to do to address these hurdles in the clinic. Well, we’re getting creative and designing tools and measures that will be sensitive enough to capture change in areas that we think we can show change in. This is a massive undertaking, it is costing us huge sums of money, time, and resources. All things we don’t have on our side. You know what we do have on our side? Accelerate Approval! Will the FDA grant us AA? Unfortunately like my colleague says, that question is as clear as mud.
What does a clinically meaningful change mean? That is for the patient to decide and when a patient can’t communicate, it is for the family to decide, with the patient’s best interest at heart. Meaningful change is not something that a critic with no experience in a situation like ours has any business commenting on. For me a clinically meaningful change for Jonah would be stopping his diarrhea. I’m not making a joke.
For another Sanfilippo parent it might be that they could walk out of the room for 5 minutes without their child opening the front door and running into the street. This is something that I imagine is consistent to what an Alzheimer’s patient caregiver would consider as a meaningful change as well.
If I can take Jonah to the playground without fearing that he might shit his pants that is meaningful change. For transparency’s sake it’s not that Jonah is incontinent, he can get to the bathroom in time if he is so inclined. Jonah often gets consumed by what he’s doing that he doesn’t want to stop to use the bathroom. If he were to need to use the bathroom at church he’d get up and go, but if he’s at the playground having fun, he might not leave, and no one can hold diarrhea back very long.
Jonah has defiled public bathrooms from coast to coast. When
Jonah lets loose it’s usually before his butt cheeks meet the toilet seat. His
pants are down around his ankles before he reaches the stall, leaving a slick,
stinking, disgusting trail behind him. Like Pavlov’s dog hears the can opener and starts salivating. Jonah senses the cool
toilet bowl behind his legs and instantly releases the rest of the contents of his bowels.
Spraying all shades of brown soup down the wall as his butt closes in on the
toilet seat. The runoff penetrates every crevice of the toilet. Picture walking
into a Starbucks bathroom after Jonah has done his thing and tell me that
diarrhea isn’t a meaningful endpoint worth a few of your taxpayer bucks. Frankly that shit effects you too. You just don't realize it until you step in it.
My company Phoenix Nest is making an enzyme replacement therapy (ERT) for Sanfilippo type D and gene therapy for Sanfilippo type C. The other comparable ERT’s on the market run between $350-700 thousand a year. ERT is a monthly or bimonthly infusions for a patient’s lifetime. Gene Therapy is onetime procedure, other comparable diseases have priced the procedure at a million dollars. Aduhelm, is priced at $54,000 a year, which is nothing in comparison to how much families pay out of pocket to care for their cognitively impaired parents or children. We must bring assistants into our homes, send our kids to private schools, our parents to assisted living homes, we buy medical equipment, all kinds of palliative care therapies and over the counter regiments. For many families one of the parents must quit their job to stay home with their child or parent. That’s at least $50,000 right there. Not to mention the strain it puts on families emotionally and financially.
EveryLife Foundation released a study analyzing the financial and emotional burden on families caring for rare disease patients: Economic Burden of Care Disease Study The report found that in 2019 $966 Billion dollars were spent out of pocket, representing 379 rare diseases made up of 15.5 million Americans.
The FDA did the right thing by using Accelerated Approval for Alduhyme. Alzheimer’s ticks off all the requirements for the AA pathway. Furthermore, I don’t see any crime in an FDA employee knowing a Biogen employee, people in our space run in the same circles. Knowing someone across the isle and seeing that person at a conference or speaking on the same panel can’t be helped. Lastly, the FDA is supposed to be our partners in developing treatments. Their job is to help us find a regulatory path forward, if at the end of the trial the data shows that no meaningful benefit has been met, then the drug isn’t approved. In the case of AA, if after Biogen's phase 4 confirmatory trial shows no meaningful benefit, then Alduhyme will be pulled. I get the feeling that the uproar in the news is to sell papers and give people something to complain about. It has become our National past time to throw our regulators and policy makers under the bus.
I admit I was a bit skeptical about Biden’s decision to replace Dr. Janet Woodcock with Dr. Patrizia Carazzoni, I didn’t know anything about her, and I really like Dr. Woodcock. I am delighted that Dr. Carazzoni has come out strong, straight out of the gate and right on top of the COVID crisis. Impressive! Now if Biden would hurry up and confirm Dr. Woodcock as the White House official FDA commissioner.
Another great new piece of legislation coming out of the EveryLife Foundation the STAT act. STAT is asking that the Federal Government to create a Center of Excellence for rare diseases. Please sign on and spread the word.
