PDCD FDA Listening Session - September 8, 2023
The Voice of the
Pyruvate Dehydrogenase Complex Deficiency
(PDCD) Patient Community
Patient-led Listening Session
with the U.S. Food & Drug Administration
September 8, 2023
PDCD FDA Listening Session - September 8, 2023
Objective of session
The PDCD patient community seeks to establish deeper relationships with the FDA reviewers to foster
dialogue for future regulatory deliberations. We believe the sharing of patient and caregiver
experiences and preferences will provide FDA staff with a better understanding of PDCD and
demonstrate the community’s urgent unmet medical need.
About Pyruvate Dehydrogenase Complex Deficiency
Pyruvate dehydrogenase complex deficiency (also known as PDC deficiency, or more commonly PDCD)
is a rare mitochondrial disorder that causes impaired carbohydrate metabolism. This impairment
results in neurological problems and the buildup of a chemical called lactic acid in the blood.
PDCD is caused by mutations in the genes that make up or affect the activity of the PDC. The PDC is
located in the mitochondria, the cell’s “powerhouse” that makes almost all the energy we need to
survive. The PDC is vital in converting the carbohydrates we eat into adenosine triphosphate (ATP),
which act as the “currency” to our cells. Thus, when the PDC is defective, our cells suffer from a lack of
ATP to spend on energy, and the signs and symptoms of PDCD reflect such energy failure. An estimated
85% of cases of PDCD are caused by a mutation in the PDHA1 gene. Other genes that have been linked
to PDCD include DLAT, DLD, PDHB, PDHX, and PDP1. Although mutations that cause PDCD can be
inherited, the majority appear by chance.
The age of onset and the severity of the symptoms of PDCD vary widely among affected individuals.
The disorder can present before birth, as brain abnormalities detected by routine ultrasound; during
infancy or early childhood, as developmental delay and chronic neurologic symptoms, including
seizures; or rarely, in late childhood as a movement disorder such as ataxia. In general, individuals with
PDCD symptom onset before birth or in infancy die during childhood, sometimes from lactic acidosis.
Those that present later may survive into adulthood.
The frequency of the disease is estimated to be 1 in 50,000.
There is no U.S. Food and Drug Administration-approved treatment or cure for PDCD. As such,
clinicians traditionally recommend symptom management and general supportive care such as a
ketogenic (keto) diet for developmental delay, seizures, and incoordination and physical and
occupational therapy to help with muscle function.
Summary
Seven caregivers - including one caregiver who was also an affected adult - to PDCD patients
participated in the Listening Session via videoconference, along with clinician Dr. Rebecca Ganetzky of
Children’s Hospital of Philadelphia. Patients represented ranged in age from 1 to 32.
Outlined below are summaries for each speaker, along with some key themes from the session,
including direct quotes about the burden of living with PDCD, current treatments, tolerance for risk in
trying new treatments, and the most valued outcomes for potential treatments.
PDCD FDA Listening Session - September 8, 2023
Summary: Father to a 25-year-old son affected by PDCD
The first sign something was wrong was low activity early on in life. He would also sleep through the
night in the exact same place he was placed in the crib. The family's pediatrician assured them children
develop at different rates, but after a few months without progress, their child was diagnosed with
PDCD. The family was told he would not live past his teens.
At age 17, the patient developed psychosis and mental health issues. The family believes this is related
to PDCD, with most patients simply not living long enough to develop such symptoms.
Today, the patient is relatively stable health-wise thanks to the ketogenic diet but has a mild physical
disability and is cognitively impaired, which limits his ability to work.
They hope this session will enhance potential treatments.
Summary: Father to a 19-year-old daughter affected by PDCD
The father shared anecdotes from his daughter’s childhood: age 2, severe weakness meant the family
had to feed her via syringe every 15 minutes; age 4, she was in and out of hospitals due to recurrent
fevers, loss of mental status, and acidosis, and they were told to prepare for her to die; age 6, required
intensive support just to sit up, which would leave her winded; age 8, still non-verbal and able tolerate
only a few hours of school a day; age 10, faced severe hip dysplasia and unable to take even 20 steps
with support; age 14, worsened developmental disability with additional diagnoses of autism and
anxiety; age 19, sturdier, but unable to speak or care for herself.
Early access to treatments is critical. He encouraged the FDA to recognize that a successful treatment,
even with only incremental improvement, could have had a profound impact later in her life. Given the
disease's devastating impact, the family is willing to accept treatment risk with even small benefits.
He noted that despite medical advances since her diagnosis nearly 20 years ago, not much has changed
in the way her disease and symptoms are managed that would give her a better quality of life.
Summary: 32-year-old mother affected by PDCD and caregiver to a 4-year-old son affected by PDCD
Other than gait issues as a child, the speaker considered herself healthy. She had gastric bypass surgery
approximately 10 years ago so she could one day have children, which seems to have kick-started
issues. After the surgery, her body began eating her muscles and organs to survive. She lost the ability
to walk or stand and had severe nerve pain and stroke-like episodes.
After four years with no answers, she found out she was pregnant. The child was born with low blood
sugar, jaundice, and an under-formed lung, but otherwise healthy. Three years later, at the mother's
age of 31, and the son age 3, both received an official diagnosis of PDCD.
The mother was diagnosed with dysautonomia and postural orthostatic tachycardia syndrome (POTS)
which causes her autonomic nervous system to malfunction, leading to temporary vision loss and
passing out. She also reported sharp nerve and muscle pain which worsens at night, perforated
PDCD FDA Listening Session - September 8, 2023
intestine which required surgery, gastroparesis, esophageal dysmotility, hypo-hidrosis, diminished
temperature sensation, along with many vitamin deficiencies. All issues are worsened by stress. Both
patients are on the ketogenic diet.
She urged FDA staff to ensure access to clinical trials to all age groups, noting that her son was eligible
for a PDCD trial and she was not. She also encouraged better labeling of sugar-free products, noting
that her son only can have 10g of carbohydrates per day but, due to a rounding loophole, many items
can claim to be sugar-free when they are not which creates severe health risks for PDCD patients. She
also advocated for more carbohydrate-free over-the-counter medicines, vitamins, and prescriptions.
Summary: Mother to a 15-month-old daughter affected by PDCD
Her daughter was one of the first children to be diagnosed with PDCD in utero. At her 12-week
ultrasound, doctors observed fetal brain abnormalities, which led to a PDCD diagnosis 19 weeks into
the pregnancy.
PDCD impacts her daughter's brain and muscle development, hearing, vision, speech, and motor skills.
Her daughter cannot sit up by herself, crawl, walk, talk, and struggles with energy levels.
She credits early intervention and the ketogenic diet for improving her daughter's outlook but worries
about the lack of treatments that could improve her obstacles and quality of life.
The patient currently receives physical, occupational, vision, and feeding therapies, in addition to
therapeutic "mito cocktail" medications such as acetylcysteine, riboflavin, and thiamine in hopes of
defending against the degenerative nature of the disease.
She worries most about the development of seizures and consumption of carbohydrates or sugars that
would risk lethal metabolic acidosis.
Given the grim prognosis of PDCD patients, the family is hopeful for a treatment quickly. They feel gene
therapy and early diagnosis are promising, with hopes that a small molecule therapy - like the clinical
trial their daughter is currently enrolled in - could help bridge the gap while things progress.
Summary: Mother to a 19-year-old daughter affected by PDCD
She reports her daughter, who was diagnosed at 18 months of age and is now age 19, is totally
dependent upon others for her survival, including to feed, dress, move, medicate, and bathe her.
Pain is a major aspect of the disease. Her daughter has constant muscle pain, but her lack of speech
keeps her from communicating what’s hurting. Such pain also keeps her from sleeping more than a few
hours a night, allowing for almost no regenerative sleep.
The disease leaks into almost all aspects of the family's day. A good day is when pain medication
controls muscle pain and the patient can participate in school activities. Bad days - which she reports
are more frequent now - mean 2-3 hours of uncontrollable, severe pain. The pain is frequently joined
by "low energy" days, where the patient loses nearly all motor function.
PDCD FDA Listening Session - September 8, 2023
The degenerative nature of the disease has also meant the loss of function that existed at younger
ages, such as walking and speaking. The family lives in "crisis mode" daily, worried about greater
mental and physical regression or even death.
The patient uses a ketogenic diet to provide cellular energy, but it has contributed to severe
osteoporosis. She has had 52 orthopedic surgeries and several fractured bones. She has also been
hospitalized hundreds of times for respiratory illness, because her body cannot fend off minor viruses.
She takes sodium bicarbonate to avoid acidosis, a cocktail of supplements for bone health, fat
processing, along with narcotics and muscle relaxants for pain, but it does nothing to stop progression.
The family is looking for something that would improve energy output, increase function, and inhibit
cellular death, thus creating a better quality and quantity of life such as stronger muscles for tone,
speaking, eating, and breathing.
Given that a slow and painful death seems the only other option, the family is open to assuming risk
for a new treatment. They would like to see the rapid approval of repurposed FDA-approved
treatments as well as streamlined approval of studies for novel, promising therapies and therapeutics.
Summary: Mother to a 3-year-old daughter with PDCD
Despite a few small issues at birth such as failing a hearing test, the family left the hospital with a
seemingly healthy baby girl. Over the next few months, hearing loss was confirmed but now with
developmental issues and atypical muscle tone.
At age four months, an MRI showed the child's brain was severely underdeveloped. After additional
issues arose, whole exome sequencing led to a PDCD diagnosis at 10 months old.
The family immediately began a ketogenic diet and feels that the delayed diagnosis - the 10 months
with a non-ketogenic diet - made the disease progress, which could have been avoided if PDCD was
included on newborn screening.
Today at age three, the hardest symptom to manage is seizures. She was diagnosed with infantile
spasms, which are managed with medications - but focal seizures are a large part of her life. She has
had a positive reaction to medical CBD, but they have not found any medications that work without
major side effects. On good days, the patient may only have a few seizures. On bad days, it could be up
to 20.
Despite this, the child's personality and interactions with her surroundings have blossomed. She
cannot walk or talk, but she finds ways to communicate. The family is trialing an adaptive
communication device and reports positive results.
PDCD FDA Listening Session - September 8, 2023
They continue to work on mobility due to worries around losing milestones and skills. She attends
physical, occupational, feeding/speech, and aquatic therapies. Before her diagnosis, she attended
daycare but was pulled out due to inability to fight common viruses without a hospital visit.
The family believes the best chance at extending life for patients is via gene therapy and small
molecule therapy.
Summary: Mother to a 3-year-old daughter affected by PDCD
For nearly two years, the family desperately tried to find an explanation for their daughter's
developmental delays, seizures, aspiration, choking episodes, and kidney stones. At 21 months, she
was diagnosed with PDCD.
At this time, the child was referred to a dietician and placed on a ketogenic diet, which brought
immediate results. She went from an unsteady toddler, who could only scoot a few inches before
tiring, to crawling and standing within a week. The family feels this extended diagnostic journey - and
lengthened period without any treatment and special diet - worsened their daughter's PDCD
symptoms and believe PDCD should be added to newborn screening.
At age two, they started a clinical trial and report positive results, including new movement - what they
call "new joy and lightness," as well as relief from pain, exhaustion, and gastrointestinal issues. They
also noticed additional mental acuity, including new words, interest in complex toys, and
consciousness of her surroundings.
With that said, the family still needs more from future treatments. Even with the ketogenic diet and
trial, their daughter struggles with energy levels, gastrointestinal issues, and choking events where she
abruptly stops breathing.
She urged the FDA and drug developers to consider the needs of PDCD patients when considering
flavor additives to treatments, mentioning aspartame flavoring in a trial as a cause of major issues for
her child.
They are interested in pursuing small molecule therapies, gene therapies, and advancements in
managing a keto diet and are willing to take a risk for improved quality of life.
Follow-up Questions
James Valentine of Hyman, Phelps & McNamara helped moderate the session and asked several
follow-up questions.
Putting aside a complete cure for PDCD, what would be valuable in future treatments for PDCD?
Caregiver: Something to improve hypotonia and weakness. Her world is very small because of muscle
fatigue. She gets worn out from just a few minutes of physical therapy. She has very weak core
PDCD FDA Listening Session - September 8, 2023
strength.
Patient (and caregiver): Something that would allow myself and my son to consume more
carbohydrates and not limit him to 10 carbohydrates per day. Sleep improvement would greatly help
with other areas of life.
Caregiver: More flexibility in what we could feed our son. Something labeled keto on a store shelf can’t
be fed to him. Something that could stop the progression of the disease, prevent organ decline, and
neurodegeneration.
Caregiver: What gets lost is that carbohydrates are life-threatening and scary. Anything that would
provide energy to the cells would be life-preserving.
Caregiver: My daughter is very severe. We work hard just to maintain her status quo. Slowing the
progression of the disease is my biggest concern. We’d want something to help hit more physical
milestones and to continue doing speech therapy. Keeping her muscles strong is very important and
will play a huge factor as the disease progresses.
Caregiver: The number one thing is slowing or stopping the progression of symptoms. On the trial, we
have seen significant improvements since our daughter has been able to stand and bear weight. Her
gastrointestinal symptoms, her aspiration, and her sleep have all improved. Before she was able to
crawl, the reflux and aspiration were very bad.
Caregiver: Stability and incremental gains in function would be great. A lot of unknowns about him
decompensating from a virus or changing things.
Question: How do you determine improvements?
Caregiver: Moving her body more, less constipation, eating more by mouth. Step-by-step benefits.
Caregiver: Looking for stability and increment improvements. We are concerned about stability. Is he
one good virus away from decompensation? When is the other shoe going to drop?
A clinician’s view
Dr. Rebecca Ganetzky of Children’s Hospital of Philadelphia (CHOP) joined the session to talk about her
experience treating approximately 50 patients with PDCD. These patients span a wide range of ages -
the oldest is currently 47 - and severity. She estimates she diagnoses 10 new patients a year, who are
often local to her hospital. She believes PDCD is underdiagnosed and much more common than
estimated. She encouraged more research into gene therapy, enzyme replacement therapy, and drug
screening for PDCD treatments.
PDCD FDA Listening Session - September 8, 2023
FDA follow-up questions
FDA’s Division of Clinical Outcome Assessment asked several follow-up questions.
Question: The use of augmentative and alternative communication (AAC) devices was mentioned
earlier. Has anyone used them?
Caregiver: Yes, we have an AAC device. Honestly, it is progressing with speech. We spent a long time
setting up the device while she was progressing. We have high hopes for using it with more complex
needs.
Caregiver: Our child used an AAC device starting at age 5 or 6. Its accuracy used to be a lot better. With
the progression of the disease and her ataxia being so much worse it became difficult to push buttons
as she ended up dragging her hand. It became frustrating for her. She uses vocalizations and gestures
instead.
Question: Can you give some examples of how symptoms can fluctuate?
Caregiver: He has bilateral brain lesions, so on bad days the lesions have a greater effect. On a very
mild day, he can walk and talk. If it's a bad day, he'll just fall over. You never know what he'll fall into.
His legs will be wobbly. Ataxia kicks in. On a good day, he goes to preschool and has a good vocabulary.
On a bad day, you can tell. It's night and day.
Caregiver: The thing we look out for is lethargy. Weak and low-toned. That’s an indication when we
need labs drawn or new meds. Even when they can't communicate, it's present.
Caregiver: My son can communicate and can talk, but the psychosis takes over and disconnects him
from reality. We use drugs like Ativan, sometimes it works, but sometimes we have to just sit with him
for hours. Our belief is that’s a symptom of mitochondrial disease.
PDCD survey
A survey, which was distributed by participating patient advocacy groups a few months prior to the
session, was taken by 57 patients affected by PDCD and their caregivers. Results from this survey were
presented during the session and are cited several times below.
Survey Results & Direct Quotes from Patients and Caregivers
During the session, FDA staff heard participants describe PDCD as a disease that progresses with
remarkable speed to severely affect the ability to eat, walk, talk, breathe, and sleep - and, ultimately,
to continue living. These concerns largely mirror survey results.
Muscle weakness:
As with most mitochondrial diseases, severe muscle weakness is one of the most common
symptoms reported by PDCD patients. More than 84% of survey respondents cited muscle
PDCD FDA Listening Session - September 8, 2023
weakness as one of the three most impactful symptoms, making it the most common response.
Such weakness has drastic outcomes for many patients such as a struggle to walk, stand, talk,
or eat. Below are some quotes from listening session participants regarding these struggles.
She used to walk with assistance. Eventually she lost the ability to support her weight at
age 8. Now, she must be lifted and carried and propped when not using her wheelchair.
Because of PDCD, (she) will never walk, or talk, or care for herself.
My body started to eat my own muscles to survive, and my organs were shutting down.
Over a matter of days, I lost the ability to stand or walk.
(She) is 15 months old and cannot feed herself, sit up by herself, crawl, walk, talk - all
things typical children her age can do.
Will she ever be able to walk? Or talk? Will she be able to attend school? And if so,
develop socially age-appropriate friendships?
They say that only when we have walked in the shoes of another, can we begin to fully
understand their journey of fear, sorrow, doubt, fatigue, and even laughter and dreams.
We have not walked in (her) shoes because (she) has never been able to walk on her
own. But, (we) have, however, walked beside her, literally step by step for 19 years.
In the first year of her life, we were not sure if she would be able to ever smile
intentionally or interact with loved ones. Although she cannot walk or talk, she certainly
can communicate with those who know her best.
She suffers from terrible daily pain, but the lack of speech inhibits her ability to tell us
what is hurting.
We haven’t heard a discernable word from her since she was about 9 years old. Now,
she just has vocalizations. She cannot advocate for her wants and needs and thus we
have watched her spirit dim without the ability to communicate with those around her.
She was 2 and could barely swallow due to severe muscle weakness, requiring around-
the-clock small high-caloric feeds and daily PT on her tiny facial muscles. This literally
meant feeding her by mouth via a 10 cc syringe every 15 minutes in order to avoid
dependence on a g-tube, in addition to daily passive motion exercises to support the
development of her weak tiny facial muscles.
PDCD FDA Listening Session - September 8, 2023
Energy and fatigue:
Nearly 56% of survey respondents reported chronic fatigue - including tiredness, excessive
sleeping, brain fog, or mental fatigue - as one of the three most impactful symptoms of PDCD.
During the listening session, participants commented similarly.
Just sitting upright for a while left her fatigued as if she had just run a mile.
(She) struggles to maintain enough energy to get through the day. She can walk with her
walker for short distances, but any rough terrain or longer outings cause her to tire
quickly and needs to be carried or pushed in a stroller.
We still see (her) struggle with her energy levels. Some may say she is a great sleeper,
but as parents we know the metabolic reason behind her multiple naps throughout the
day. “Low energy” days can trigger a complete loss of muscle function, no ability to hold
her head or body up, or even to make her eyes focus.
She does not have friends because she doesn’t have the stamina nor the ability to
participate in social activities.
I have poor endurance and need frequent rest periods.
“Low energy” days can trigger a complete loss of muscle function, no ability to hold her
head or body up, or even to make her eyes focus.
Developmental disabilities and delays:
In the survey, 52% of survey respondents described PDCD as causing a high level of impairment,
meaning profound developmental or cognitive delay and significant support to do age-
appropriate activities and tasks.
(He) has a mild physical disability, but he is cognitively impaired. Essentially, he is a
cognitive 9-year-old in a 25-year-old body. This limits his ability to work, and he attends
day programs.
At age 14, (her) developmental disability worsened so much that she got additional
diagnoses of autism and anxiety. Another diagnosis compounding the underlying
metabolic defect, inability to walk, communication challenges, developmental delay,
fatigue, muscle weakness and fragility that is every day while living with PDCD.
PDCD FDA Listening Session - September 8, 2023
The beginning seems like a logical place to start, but unfortunately, we don’t have time
to cover the months of hopeless searching, desperately trying to find an explanation for
my daughter’s development delays, seizures, aspiration and choking episodes, kidney
stones, and a host of other symptoms.
She is now 15 months old and has brought us more joy than we could have ever
imagined. However, she has been impacted with both brain and muscle development,
hearing loss, vision impairment, speech and motor delay, all that comes with a PDCD
diagnosis.
On top of such delays, caregivers on the session frequently reported related struggles such as
autism, anxiety, and mental health issues.
At age 14, when the fatigue of caregiving became so profound that my wife and I felt we
could barely go on, and (her) developmental disability worsened so much that she got
additional diagnoses of autism and anxiety.
At age 17, (he) developed psychosis. Mental health issues are not well understood as
they relate to Mitochondrial Disease and the ability to control these symptoms in
conjunction with the keto diet and other treatments has posed a challenge that we have
yet to conquer. Our belief is that the issue is that many of the PDCD children don’t live
long enough to develop these symptoms and/or those that live past their teens may be
mildly affected and either misdiagnosed or not diagnosed.
More severe symptoms:
While weakness, fatigue, and developmental delays were some of the most common issues,
they were not always the most concerning. Both session testimony and the survey showed,
despite lower incidence, greater concern for more life-threatening symptoms, including acidosis
and seizures. Nearly all patients or caregivers who had experienced such issues rated them as
causing “significant worry.”
Acidosis:
The risk of acidosis is constantly prevalent, and we must closely monitor her ketones
several times a day.
Any improvement over time to her chronic metabolic acidosis and metabolic stress
may have diverted metabolic strokes so there would be less ataxia and perhaps she
could draw or write.
PDCD FDA Listening Session - September 8, 2023
If she were to consume carbohydrates and sugars, dangerous levels of lactic acid
would present and increase the risk of painful and lethal metabolic acidosis.
Seizures:
Regarding seizures specifically, a good day for (her) might consist of her only having
a couple, whereas on a bad day, she could have upwards of 20 or more.
Our biggest worry is her chance of developing life-threatening seizures and/or
metabolic crisis. (She) is at risk for organ decline and neurological degeneration
which would result in a limited life span.
Fear of death due to these symptoms:
As a family, we have lived in a crisis mode for the past 20 years. Constantly worried
about death. We have already watched her regress medically and physically and we
fear that every illness will be the one that ends her life. Even minor illnesses can be
catastrophic, so we live all day every day in fear.
When she was 4, the hospital emergency room was a revolving door for us with
recurrent fevers, loss of mental status, and acidosis; watching her go limp with a
mere virus and us fearing additional severe cerebellar strokes which had left her with
permanent severe ataxia. While the diagnostic tools were abundant - MRI, blood
tests, muscle biopsy - the suggestions on how to help her improve were next to
nothing. We were told to prepare for her to die.
Every drive, every single drive, would result in a choking event where we would
frantically pull over, rip her out of her car seat and suction her airway. Although a
choking event while driving is terrifying, it pales in comparison to a choking event
during sleep. I live in constant fear that I won’t wake up for the next one.
Existing Treatments for PDCD
No FDA-approved treatment exists for PDCD. Current options for symptom management and general
supportive care mainly focus on a ketogenic diet, often with physical or occupational therapy to help
with muscle function. When asked what efforts patients or caregivers are taking to improve quality of
life, survey results showed the most frequently utilized options as a ketogenic diet (79%), physical
therapy (67%), and the use of adaptive mobility devices (67%). Every participant on the session noted
the importance of diet - often with a caveat, that while helpful, it was not a cure.
Ketogenic diet:
PDCD FDA Listening Session - September 8, 2023
Currently, her lactic acid levels are managed by the ketogenic diet but there is
currently no cure for this disease.
The ketogenic diet remains the main treatment for the disease to bypass the citric
acid cycle to provide cellular energy. But it is not enough. We also treat her
symptomatically; sodium bicarbonate to fend off acidosis, a cocktail of supplements
for bone health, and fat processing, narcotics and muscle relaxers for pain and spam.
We are grateful for the symptomatic treatments we have. But every day we see our
daughter slipping away without better treatments and modalities for PDCD.
Even with the therapeutic ketogenic diet, we still see (her) struggle with her energy
levels.
The ketogenic diet has had a significant impact as the change we observed was
almost immediate, but it does not address the cognitive deficit or the mental health
issues.
The ketogenic diet has essentially saved her life; however, it is not without
challenges. She has severe osteoporosis, in part due to the diet. She has had 52
orthopedic surgeries and several fractured bones. She has endured hundreds of
hospitalizations for respiratory illness because she is not always strong enough to
fend off even minor viruses.
Due to the positive impact a ketogenic diet can have on outcomes, several participants brought up
adjacent regulatory issues, such as the need for better carbohydrate labeling and the desire to add
PDCD to newborn screenings.
Sugar-free labeling and medicine:
The only treatment we have right now for PDCD is a ketogenic diet. Thankfully, I am
fairly intelligent and know how to not just read but understand nutrition labels. But
there comes a point where even understanding them is not enough. Now, we have to
question them too. My son’s daily allotment is 10g of carbohydrates. As if that is not
hard enough, due to a loophole in the FDA rounding rules, companies … can make
false claims that they are a sugar-free candy and have 0g of carbs.
As you know by now, sugar and carbohydrates are toxic to people with PDCD, but
most medications have carbohydrates in them. Access to acetaminophen and
NSAIDs (non-steroidal anti-inflammatories) that do not contain sugar is limited to
suppositories or crushing adult pills and finding safe OTC medications for cough,
PDCD FDA Listening Session - September 8, 2023
congestion and constipation are almost impossible. It would be very helpful to have
access to more carb-free multivitamins, OTC medications, and prescription
medications.
Adding PDCD to newborn screening:
We feel gene therapy and early diagnosis through newborn screening are the
promising routes to give any child with PDCD a fighting chance.
Early implementation of the ketogenic diet is of the utmost importance for PDCD
patients, and for the first ten months of her life, Piper’s regular diet could have been
progressing her disease. This could have been entirely avoided if PDCD was included
on the newborn screening.
Desired outcomes for potential treatments
When asked “Which outcomes would be meaningful to you for a possible drug treatment?” via survey,
patients and caregivers prioritized gains in developmental/cognitive ability (91%) and gains in function
such as energy, strength, mobility, and dexterity (91%) as the top two outcomes, followed by
slowing/stopping the progression of the disease (81%) and prolonging life (79%). Participants on the
session were asked a similar question, largely mirroring the survey, with the addition of improving diet
flexibility.
Improve energy/muscle tone:
She has weak core strength. So that limits where she can be. Playing or doing a
learning activity. Anything that improves muscle and fatigue. They look like they just
ran a mile.
In an ideal world, treatments for PDCD would improve energy output, increase the
PDCD function and inhibit cellular death. Treatments focused on quality AND
quantity of life, that would create stronger muscles for tone, speaking, eating, and
breathing.
It is important to recognize that a successful treatment even with small incremental
improvements in the devastating symptoms of PDCD could have profound benefits
later in the course of this disease. An incremental improvement with (her) muscle
weakness during childhood and infancy could have improved her ability to weight
bear, perhaps avoid severe hip dysplasia, avoid heaps of durable medical equipment,
and perhaps even walk.
PDCD FDA Listening Session - September 8, 2023
Slow/stop the disease’s progression:
Anything that can stop the progression of the disease. Stopping or slowing organ
decline or nerve deceleration.
Get her through the progression and degradation of the disease.
Our priority would be slowing or stopping the progression of symptoms.
Improve diet flexibility:
Something that would allow more carbs. (His) daily limit is 10 grams. Almost
impossible. He's mild, he's doing great. But it's also not practical to sustain.
Something that will allow his body to process some carbohydrates.
Flexibility on what we could feed our daughter. Every day we struggle with her
metabolism.
It’s not just a want to consume carbohydrates. Carbs become scary and life-
threatening. Anything that would provide energy to the cells. To provide muscle tone,
increase energy to all the muscles and organs. Muscle strength to breath.
Openness and risk assessment regarding new treatments
Given the poor outcomes associated with the disease, not surprisingly, participants were open to
trying a variety of treatment options - even those with some risk.
We feel gene therapy and early diagnosis through newborn screening are the
promising routes to give any child with PDCD a fighting chance. Our hope for gene
therapy is to give her body a chance to eat a more normal and sustainable diet and
help eliminate the scary degenerative end of life situation we may be facing. We are
also hopeful for small molecule therapy to also bridge the gap, for example, a trial
for therapeutic treatments while we are in the early phases of gene therapy
research.
During the Covid pandemic, the FDA granted emergency authorization for
treatments and vaccines because it was the right thing to do. PDCD is our
emergency. I would like to see rapid approval of repurposed FDA approved
medication to treat PDCD as well as streamlined approval of studies for novel,
PDCD FDA Listening Session - September 8, 2023
promising therapies and therapeutics. Our loved ones do not have a lifetime to wait.
As a family, we would be willing to assume a moderate amount of risk when it
comes to this process. When a slow and painful death is the only other option, the
risk associated with new treatments becomes miniscule.
Although my son and I are part of the Natural History study for PDCD, we
unfortunately missed the deadline for (him) to participate in a clinical trial offered to
him by one week. It was then suggested he try a few new experimental treatments
when available which we are so excited about given there are no treatments
available for PDCD. But do you know who was not offered those treatments? Me, the
adult. I am also willing to trial small molecule therapies and would allow gene
therapy to be performed on me. I also know I am not alone. There are more
symptomatic moms and adults with PDCD just like me who are willing to go to
extreme lengths to find treatments for ourselves and our children.
We understand that the best chance at extending lifespan and improving quality of
life for patients is through gene therapy and small molecule therapy. We did have
the opportunity to participate in a clinical trial but declined due to travel
requirements, with the closest hospital being an 11-hour drive. I am also a parent
board member for a PDCD foundation fighting to give our kids a chance at a better
life through gene therapy research. As her parents, we struggle with protecting her in
a bubble but also wanting to give her fun childhood experiences. Managing this fear
weighs on our hearts daily. The reality of our situation is that eventually degradation
of her body and the progression of the disease will take (her) life.
My husband and I are willing to accept risk because we are out of time. PDCD is a
progressive disease and every day we wait on new treatments could mean more
damage or loss of function that she will not get back. We are willing to take risks
because (she) deserves a chance at a future. A future filled with less pain and a little
more joy.
PDCD FDA Listening Session - September 8, 2023
FDA divisions represented
Office of the Commissioner (OC) - 2 offices
OC/OCPP/PAS - Office of Clinical Policy and Programs/Patient Affairs Staff (organizer)
OC/OCPP/OPT - Office of Clinical Policy and Programs/Office of Pediatric Therapeutics
Center for Biologics Evaluation and Research (CBER) - 3 offices/divisions
CBER/OCD - Office of the Center Director
CBER/OCD/PS - Office of the Center Director/Policy Staff
CBER/OTP/OCE/DCEGM/GMB1 - Office of Therapeutic Products/Office of Clinical
Evaluation/Division of Clinical Evaluation General Medicine/General Medicine Branch 1
Center for Drug Evaluation and Research (CDER) - 6 offices/divisions
CDER/OND/ODES/DBIRBD - Office of New Drugs/Office of Drug Evaluation
Sciences/Division of Biomedical Informatics, Research, and Biomarker Development
CDER/OND/ODES/DCOA -Office of New Drugs/Office of Drug Evaluation Science/Division
of Clinical Outcome Assessment
CDER/OND/ON/DNII - Office of New Drugs/Office of Neuroscience /Division of
Neurology II
CDER/OND/ORDPURM/DRDMG -Office of New Drugs/Office of Rare Diseases, Pediatrics,
Urology and Reproductive Medicine/Division of Rare Diseases and Medical Genetics
CDER/OTS/OB/DBIV - Office of Translational Sciences/Office of Biostatistics/Division of
Biometrics IV
CDER/OTS/OCP - Office of Translational Sciences/Office of Clinical Pharmacology
Partner organizations
Partner organizations that helped identify and prepare patient community participants include:
United Mitochondrial Disease Foundaon
For more than 25 years, the United Mitochondrial Disease Foundaon (UMDF) has built a global
network of paents, researchers, clinicians, instuons, and industry partners dedicated to fighng
mitochondrial disease. Together with the mito community, UMDF is commied to a mission of funding
the best science no maer where it is found in the world while at the same me providing crical
educaon, advocacy, and support-focused programs and services to paent families. Learn more at
umdf.org.
MitoAcon
Since 2005, MitoAcon has transformed the lives of families affected by mitochondrial disease. Our
mission is to improve the quality of life for children, adults, and families living with mitochondrial
disease through support, educaon, outreach, advocacy, clinical research iniaves, and granng
wishes for children affected by mitochondrial disease. Commied to making the largest impact
possible, MitoAcon serves individuals in the U.S. and worldwide through support, educaon,
PDCD FDA Listening Session - September 8, 2023
outreach, advocacy, and clinical research iniaves. The programs and services MitoAcon provides
connue to be a lifeline for families impacted by mitochondrial disease. Learn more at mitoacon.org.
The Elizabeth Wa PDCD Research Fund
Through outreach, philanthropy and advocacy, The Elizabeth Wa PDCD Research Fund will support
research for Pyruvate Dehydrogenase Complex Deficiency, by promong small molecule research,
advocang for adding PDCD to the Newborn Screening Test, providing essenal educaon to
caregivers, and travel grants to families seeking specialized PDCD care. Learn more at
pdcdresearchfund.com.
Hope for PDCD
Hope for PDCD was founded in 2022 with an urgent mission: to cure Pyruvate Dehydrogenase Complex
Deficiency. Hope for PDCD’s core values are: 1) to empower PDCD patients and families, 2) to promote
solidarity among the PDCD community and 3) to build a better future for PDCD. All financial gifts are
invested wisely and 100% of every dollar donated goes to research and advocacy efforts for PDCD.
Hope for PDCD has quickly grown into a collective of volunteer parent and patient board members,
scientific advisors, and industry partners. Hope for PDCD aims to fund a multi-million-dollar research
project into AAV9 gene replacement therapy for PDHA1 mutations while pursuing equitable access to
diagnosis, care and treatments for PDCD patients. Find out more at hopeforpdcd.org.
Disclaimer
Discussions in FDA Patient Listening Sessions are informal. All opinions, recommendations, and
proposals are unofficial and nonbinding on FDA and all other participants. This report reflects the
United Mitochondrial Disease Foundation’s and MitoAction’s account of the perspectives of patients
and caregivers who participated in the Patient Listening Session with the FDA. To the extent possible,
the terms used in this summary to describe specific manifestations of PDCD, health effects and impacts,
and treatment experiences, reflect those of the participants. This report is not meant to be
representative of the views and experiences of the entire PDCD patient population or any specific group
of individuals or entities. There may be experiences that are not mentioned in this report.
