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.
Accelerated
Approval
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.
My hero, Dr. Woodcock photo taken October 2013 at the EveryLife Foundations Abbey Award ceremony. Both Dr. Woodcock and I received an Abbey that year. I received mine for the advocacy work that I put into getting the Accelerated Approval language added to FADASIA. I was extremely honored and proud to win an Abbey and to be standing by Dr. Woodcock's side.
