Fight For Treatment

The disease progression can be very different from one child to the next.  Some have liver complications from birth, some start showing significant neurological presentations by the age of 2, others grown normally until school age then start to show signs of clumsiness or lose developed abilities.  Even siblings with the same gene mutations have been seen to have years of difference between the onset of severe symptoms.  Some of the experimental drugs are more effective than others dependent on the gene mutation combinations.  It is a near impossible task to know what is the best action parents can take to give their child the longest and best quality of life possible.

The news of Liam's Niemann Pick Type-C diagnosis in August of 2021 devastated Jen and I.  Our world was darkened, swarming in fear and uncertainty, everything felt hopeless.  We had no understanding of what Niemann Pick was, only that a cure did not exist and it would take our only child at a very young age.  We were numb for weeks trying to sort out the range of emotions that flooded over us.  

Slowly, we started being able to tolerate reading about NPC and began researching the disease we had given to our son.  NPC is an autosomal recessive disorder, which means that Jen and I both carry one mutated NPC1 gene and Liam received both of them.  Jen & I have at least a 1 in 4 chance of having a child with NPC.  The more we learned about NPC, the more it hurt.

One thing became clear; The disease has been building up in Liam since birth and it will only get worse with time.  We urgently need to get Liam on any and all treatments that could help slow the progression of the disease down as soon as possible to buy him as much time as we can.  Then pray that a cure is discovered soon. 

As a lysosomal storage disorder, Niemann Pick Type-C causes the build up of cholesterol in cells of the body because the mutated NPC1 genes do not produce enough of the proteins needed to break down and remove the cholesterol.  The cells inevitably die from swelling up and cellular stress.  The brain, nervous system, liver & spleen are the crucial parts of the body that are impacted but there is no order or pattern to which systems will show severe symptoms of the disease first.

Learning that our infant son has NPC, has been a traumatic and devastating experience. The process of accepting this reality was incredibly difficult and emotionally taxing. However, connecting with other families who had gone through similar challenges was a source of strength and support. These families provided information, knowledge, insight, and friendship that is helping us navigate the difficult journey. Though it wasn't easy for these families to open up about their experiences, as talking about it can be emotionally difficult and reopen old wounds, we are grateful for their willingness to share and connect with us. Through these connections, we found comfort in knowing we were not alone in our struggle.

With no FDA approved treatments for NPC in the United States, our doctors looked into clinical trials for whitch Liam might qualify.  Jen & I researched all we could about NPC, it's history, the experimental drugs, and clinical trials.  We scrambled for anything we could hold onto for hope.  

By talking directly to the families, we gained an in-depth understanding of the treatments their children were receiving, the difficulties they encountered, and the varying outcomes they experienced. The type of treatment available to families depended on the severity of their child's symptoms, whether or not there were any clinical trials available at the time, and the ever-changing regulatory environment. Over the past 15 years, families have gone from being able to test out treatments at home to being required to participate in placebocontrolled trials. For instance, Hydroxypropyl-beta-cyclodextrin (HPBCD), one of the most impactful treatments discovered so far, is a sugar molecule commonly used to make drugs and other active ingredients more soluble, stable, and absorbable. It is used in pharmaceuticals, dietary supplements, food, beverages, cosmetics, and other personal care items. Now can only be administered to NPC patients through IV (through veins) or IT (through spinal fluid) transfusions within the protocols approved by the FDA, if you meet specific criteria. 

Two drugs that recently went through clinical trials that use the HPBCD sugar molecule are  Cyclo-Theraputic's Trappsol  and  Mando's Adrabetadex.  Trappsol is only administered through IV and has predominantly shown to improve organ tissue, like the liver and spleen, when administered at a young age.  It is unknown how much of the drug passes though the blood-brain barrier to help with neurological symptoms.  Adrabetadex has been tested being administered though both IV and  IT.   Administration into the spinal fluid (IT) allows the drug to directly reach the brain and has shown to have most significant impact in affecting the course of the disease and it's symptoms.  IT administration also requires the use of anesthesia for children who are not able to remain still while the drug is given.  IT Adrabetadex has risks of side effects that impact sensory functions, like hearing loss.  IT Adrabetadex is only accessible through compassionate use or an expanded access program.

A third experimental drug, KemPharm's Arimoclomol (previously owned by Orphazyme), is a much less invasive method as an oral medication that tries to use heat shock proteins to rescue any protiens that the NPC1 genes may produce.  It has not proven to be as impactful as the cyclodextrin based drugs but has shown in some cases to have as much as a 67% reduction in the rate of progression of the disease when paired with Miglustat.  Unfortuantely, results are not consistent across patients of different mutation combinations.  Arimoclomol only works if the patient produces some protein from the NPC1 genes.  Patients need to have at least 1 missense mutation and hope that creates enough protein for Arimoclomol to be able to rescue.  There also aren't any good test to know how well a patient might respond before taking the drug.  Their is no way to ensure Arimoclomol will work for Liam.

Once Jen and I learned about the various experimental treatments, we started to push for all three.  At the time Liam was diagnosed, only 2 NPC clinical trials were accepting patients, Arimoclomol and Trappsol.    The Arimoclomol study required patients to be at least 2 years old, and for the Trappsol study, patients needed to be at least 4 years old.  Both trials had the chance of giving Liam a placebo.  21 months felt like an eternity for our son to have to wait to get treatment for a continually progressive fatal disease that was already adversely impacting Liam's life.    

Compassionate Use and Expanded Access Programs are both additional ways for patients to access experimental drugs that are still in the clinical trial process.

Compassionate use refers to the use of an investigational drug outside of a clinical trial for a patient with a serious or life-threatening condition who has exhausted all other treatment options and is unable to participate in a clinical trial. The decision to grant compassionate use is made on a case-by-case basis by the FDA and the drug manufacturer.

An expanded access program (EAP) is a program that allows patients with serious or life-threatening conditions to access investigational drugs before they are approved by the FDA. EAPs are typically established by the drug manufacturer and may be open to a larger group of patients than compassionate use. The goal of an EAP is to provide earlier access to potential therapies for patients who have no other treatment options.

In both cases, the drug is not yet FDA approved and the patient is not part of the clinical trial.

Our doctors informed us about the stricter criteria the FDA had placed on getting early access to IT Adrabetadex in March of 2021.  Liam would only be able to qualify for IT Adrabetadex if he showed major presentations of severe neurological onset of the disease.  To qualify, Liam would need to be having seizures, have difficulty swallowing, show signs of Vertical Gaze Palsy, or not be able to walk by the age of 2.  Vertical gaze palsy usually is the first perceptible symptom that the FDA will accept.  Despite that with every passing month, Liam became more developmentally delayed and clearly was being impacted by the disease, he would have to wait to get treatment.  We made it a point to get Liam assessed regularly and seen by specialist who were experinenced with vertical gaze palsy, to give us the best chance to catch it early.

We pushed for months to get Liam access to any of the treatments through compassionate use or an EAP.  Initially, we felt that Liam's 2 missense mutations had a good chance at responding well to Arimoclomol and we could try to help Liam's genes to work more natually while he was so young.  But in January of 2022 Arimoclomol was not an option because Liam was only 6 month old.   Doctors attempted to get Liam access to either of the IV treatments since Liam's liver and spleen were so enlarged and IV was the most the logical treatment to treat the organs.  Jen and I were ok with starting Liam off with IV Adrabetadex, then once the disease begins to present with more severe neurological symptoms we could add Adrabetadex administered through IT without having to go through prolonged washout period (up to 6+ weeks)  while the disease continued unimpeded to wreck havoc in Liam's body and brain.  

The discussions, meetings and evaluations between the doctors and drug companies dragged on for months.  By April of 2022, we were no closer to getting Liam started on one of the experimental drugs than when we first learned of his diagnosis.  

A burst of hope came when news spread that Orphazyme, the owners of Arimoclomol at that time, was planing to open enrollemnt for a sub-study of their Arimoclomol trial for children between the ages of 6 months and 3 years to test the safety and tolerability of the drug.  We were estatic, Liam qualified for a clinical trial! We quickly reached out to the company, researchers and doctors over the trial's sites to get Liam enrolled as quickly as possible.  

Of couse, it couldn't be that easy.  Liam would be the first and only NPC kiddo in the United States on this sub-study.  The sites that were conducting the clinical trial had not yet gone thorugh the IRB/FDA approval process and had to start that process once we made our interest known to enroll Liam.  

To make matters worse, in June of 2022, Orphazyme was bought out by KemPharm.  This made KemPharm the new sponsor for the clinical trials of Arimoclomol and added to the complexity of getting through all the necessary regulatory approval processes before a trial could be started.  We went from looking like Liam would start Arimoclomol mid-June, to worrying that the study would be scrapped entirely, to waiting for months in uncertainty due to a lack in communication.

With no garuantee that the pathway to getting Liam enrolled in the Arimoclomol trial would materialize, we continued to persue Adrabetadex.  By the end of the summer, Mandos had agreed to allow Liam to use Adrabetadex, a local doctor agreed to administer the drug to Liam and began working on the application to the FDA for approval.   However, before the application could be submitted, the doctor who would be administering the Adrabetadex announced his plans to retire causing another review of the application to transfer the care to a new doctor that was taking over.  This triggered doctors and Mandos to re-evaluate Liam's current condition and reconsider the treatment plan. 

 As time went on, Liam's spleen remained enlarged but his liver's condition did slowly improve.  The doctors became less confident that IV Adrabetadex would benefit Liam and did not think FDA would approve its use.    Liam would have to wait to qualify for an open clinical trial or start presenting