All DRESSed Up With Nowhere To Go

This post was written by several members of the RxISK Team drawing on the work of Jorge Carrasco – see below.  There is a prior RxISK post on DRESS Syndrome – No Way to Treat a Lady.

María Elisa Rangel was 38 and a mother of four children when she signed up for a phase 1 clinical trial in April 2015. They needed the money.

The drug was cenobamate, marketed by SK Life Science which is a subsidiary of SK Biopharmaceuticals, the second largest South Korean conglomerate.

The trial was run by Celerion, a CRO (Contract Research Organization) in Kempe, Arizona, USA.

Thirty-two days into the trial she developed severe side effects and was later admitted to hospital. She collapsed and died 50 days later.

The autopsy showed eosinophilic myocarditis due to DRESS – Drug Reaction with Eosinophilia and Systemic Symptoms.  Cenobamate had previously been linked to DRESS. which has 10% mortality

Rangel’s family were presented with hospital bills for over $26,000.  In March 2022 SK Life Science and Celerion agreed an out-of-court settlement with her family for an undisclosed sum.

Celerion and Cenobamate

The story starts about 2005 when cenobamate, otherwise known as YKP3089, was developed by South Korean company SK Biopharmaceuticals, hoping to develop it as an anti-anxiety drug. It was later claimed to be effective in the treatment of epilepsy, and is now on the market for this.

The only Phase 1 (healthy volunteer) randomised controlled trial, YKP3089C020, was run by Celerion in Kempe, Arizona on behalf of SK Biopharmaceuticals.

Celerion:

“The name Celerion is derived from the Latin celeritas meaning swiftness and speed. Our name reflects our founding principle – to help our clients get their products to the market faster.”

Celerion now has facilities across North America, Europe, and Asia, in 30 countries worldwide, employs more than 1,000 full-time scientific and medical personnel … while upholding the highest standard of ethics. Their facilities offer over 600 beds and are among the most extensive in the industry.

The Chief Principal Investigator (PI) for Celerion was Dennis Swearingen MD, also from Kempe. The research data were analysed by Clario (Philadelphia, Pennsylvania), on behalf of SK Biopharmaceuticals but strangely the results were not submitted for publication until July 2021.

In 2015 – the year of the fatal trial Swearingen earned $915,404.62 associated research payments from Merck Sharp & Dohme LLC and $1,222,158.55 research payments from Quebec-based Valeant Pharmaceuticals International, in addition to his earnings as an employee of Celerion.

(In 2015, in one of the biggest pharmaceutical company scandals, the value of Valeant, which had a reputation for buying up smaller companies and then raising the prices of their products, plummeted when it was revealed that they were illegally running a pharmacy company, Philidor Rx which fraudulently dispensed their products. The remnants of Valeant were rebranded as Bausch Health.)

Principal Investigators: are people who work with private labs, where they do trials.  They have no great medical expertise – their expertise is in not getting in the way of running trials not in diagnosing and treating adverse reactions.

Another player is William Elliot Rosenfeld MD. Seventy year-old Rosenfield of Saint Louis, Missouri, is a neurologist. In 2021 he pocketed $622,351.89, mainly in consulting fees, from SK Life Science – makers of cenobamate, making him their highest paid consultant. Over the last three years he has co-authored thirteen ghost-written articles about cenobamate published in six different journals.

Rikki has been a volunteer for Celerion 99 times. Its worth listening to him Say Hi to Rikki.

The Trial

The trial enrolled 108 subjects for a 65 day study in early 2015 as part of its development as an anticonvulsant.

This was a so-called “Thorough QT study” to assess the effects of therapeutic and supratherapeutic cenobamate doses on the heart rhythm in healthy adult subjects. This was the trial in which Maria Rangel died.

Rangel, a healthy undocumented immigrant from Mexico, had no health insurance. She volunteered in April 2015 and became subject no 95 in the trial. She was one of 54 subjects randomised to treatment arm A.

After taking increasing dosages of cenobamate for 32 days she became unwell. Her illness started with an itchy rash on her face which became widespread. Her clinical course and blood test results are documented María Rangel’s liver enzyme results (page 369 onwards).

She reattended Celerion’s clinic the next day. The rash was more extensive. She was given antihistamine cream and tablets. Her blood tests were abnormal: one of her liver function tests was six times higher than that recorded before she started cenobamate. Her trial medication was stopped.

No action was taken over the abnormal results. She reattended six days later, breathless and with a fever. She was referred to a local emergency department, where a “drug rash” was diagnosed. She was sent home on oral steroids. Over the next five days she attended Celerion’s clinic three times – each time her blood tests showing serious worsening of her liver function.

She experienced several mild to moderate adverse events in the days and weeks after being discontinued from the study, including depressed mood, face swelling, anxiety, back pain, alopecia, ecchymosis, blurred vision, chest pain, dyspnea, palpitations, headache, cough, fatigue, and asthenia. Her depressed mood began 7 days after the last dose of study drug and Dr Swearingen considered it but not the other problems possibly related to study drug.

The remaining events began 25 to 50 days after the last dose and [he] considered them all unlikely or unrelated to study drug.

Two days after a skin biopsy had confirmed DRESS she was finally admitted to hospital for treatment on day 44.

Thereafter she frequently attended the trial centre and hospitals, running up bills for her family totalling over $26,000.

The day before she died, 86 days after she entered the trial, she developed chest pains. She phoned Celerion and was reminded to go the emergency room for chest pain. The clinic staff also suggested relaxation techniques, such as taking a warm bath or listening to music.

The next day she was found collapsed by her husband and she was unable to be resuscitated. Post-mortem examination showed she died from a heart attack caused by “eosinophilic myocarditis due to DRESS, with findings of pleural effusions, pericardial effusion, pulmonary oedema, cardiomyopathy, and necrotizing myocarditis”.

She is one of three people who have been documented as developing DRESS whilst taking cenobamate. A 36-year-old white female with epilepsy entered the same study YKP3089C017 early in 2014. She developed DRESS 24 days into the trial and was admitted as an emergency with a rash and fever. She improved on treatment with steroids, but was lost to follow-up.

SK Biopharmaceuticals would have been aware of this serious event but Rangel was not warned of the probable association.

María’s widowed husband, Cristobal Legarda sued Celerion, SK Life Science and Swearingen in 2016

DRESS Syndrome

DRESS is often disingenuously referred to as a “skin condition” in drug trial adverse events tables.

Seven years ago RxISK carried the harrowing story of a 16 year-old girl’s death from DRESS caused by an antibiotic. Allopurinol and virtually all anticonvulsants are known to cause this condition, as are some vaccines including for Covid.

A review article of 172 patients with DRESS published in the American Journal of Medicine in 2011 had shown that epilepsy drugs were one of the commoner causes. Despite this many doctors are not aware of DRESS.

The DRESS Syndrome Foundation  list the following common Early DRESS Symptoms:

• Fever 38º to 40ºC (100º to 104ºF)
• Skin eruption/rash
• Facial swelling
• Swollen lymph nodes
• Low energy or general sense of feeling unwell

If you have read this far, you will know more about DRESS than most doctors.

DRESS-rehearsal:

If you are taking medication and develop any of the above symptoms:

1. Blame the drug.
2. Seek medical attention immediately.
3. Work with your doctors to stop taking the medication you suspect is causing your reaction.
4. Insist that doctors seriously consider and test for DRESS Syndrome.

DRESS syndrome is evolving. There are an increasing number of conditions linked to meds including Eosinophilic Oesophagitis and Eosinophilic Stomatitis.  The DRESS sydrome foundation recognise variants that don’t show Eosinophilia.  Oesophagitis and Stomatitis affect surfaces of the body – they are not inside the body – and can be thought of as rashes of the mucosal membranes.

Having your oesophagus or mouth affected is less of a problem than having your heart affected and so these conditions are even less recognized but are happening ever more often with the increasing use of anticonvulsants, like lamotrigine, and some antibiotics.

If you have something odd that doctors aren’t recognizing which doesn’t fit the classic DRESS picture – think atypical DRESS and raise it with your doctor.

Cenobamate

Cenobamate is now marketed as Xcopri (US) and Ontozry (EU). In the last three years it has been licenced for the treatment of patients with focal onset seizures, mainly as an add-on treatment for patients whose epilepsy is not controlled by other medication.

Meprobamate, which is related to cenobamate, is one of the most famous drugs in the history of medicine. In the 1950s, marketed as Miltown, it was the first tranquilizer and helped usher in the psychopharm era.  It was also recognized to have anti-seizure activity.

Felbamate is another closely related drug which has been marketed for anti-seizure effects from the 1980s onwards but is rarely used now.

All the bamates and related drugs like retigabine and flupirtine are weakly anti-seizure and come with risks of suicide and DRESS and related syndromes.  Nobody talks about these problems with meprobamate – there is silence about its eclipse.  It was the best-selling psychotropic drug in the mid to late 1950s but by the early 1960s it had vanished – replaced by Librium and Valium.

The other angle on the Cenobamate story is that for three decades companies have bought drugs like lamotrigine, pregabalin and gabapentin on the market as anti-convulsants but with a view to encourage their leakage into the treatment of anxiety, or anxiety rebranded as bipolar disorder – which is where the money is.

This rebranding helps get regulatory approval for another reason. A straight-up anxiolytic that caused problems like DRESS syndrome would never be approved but lamotrigine gets approval for the treatment of a serious disorder like epilepsy because much more risks can be tolerated for epilepsy than for anxiety.  The marketing then leads to a leakage into other much more lucrative areas.  Shipwreck of the Singular has a lot more on this strategy.

How do you Solve a Problem Like Maria?

The “Thorough QT study” was performed as a requirement of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Guidance 14 states:

“If not precluded by considerations of safety or tolerability due to adverse effects, the drug should be tested at substantial multiples of the anticipated maximum therapeutic exposure.”

The plan was for Rangel to take up to 500mg daily of cenobamate, whereas the normal therapeutic dose is 200mg.

Is it justifiable that any drug should be tested in volunteers “at substantial multiples of the anticipated maximum therapeutic exposure”?

Was Celerion’s founding principle: “to help our clients get their products to the market faster” part of the problem as the cenobamate dosage was increased over a rather short timescale, saving money.  In later clinical practice, doctors have been told to increase the dose slowly – as they are told with lamotrigine.

Poverty impacts on many clinical trial volunteers in two ways. Many volunteers can’t afford medical insurance – which may not cover participating in trials. This likely inhibits the investigating clinicians from referring them for specialist care when it is needed.

If they are admitted to hospital volunteers will struggle to pay their bills. It is well recognised that trial sponsors will not cover illness arising during a trial unless the trial drug can be proved to be responsible.

There are a few clues in the FDA narrative (p376+) suggesting that María Rangel had financial problems.

“She again reported feeling sad due to being homebound, and concern over finances”

“She stated that she had increased stressors in her home life and finances over the past few days”

“She also reported ongoing stress with regard to family finances and the need to find childcare for her return visits.”

Despite being “undocumented”, see Celerion’s website March 2015, she was allowed to participate in the trial.

The family were unable to afford a headstone at Greenwood Memory Lawn Cemetery in Phoenix, Arizona, where she was buried on August 19 2015.

Epilogue

Jorge Carrasco is an award-winning Digital Journalist at NBC Universal Telemundo Enterprises in Miami Beach. In 2017, he won the Gabriel García Márquez Award for Journalism in the Text category. He was a Health Journalism Fellow at University of South California: see for instance “Latinos in need turn to paid clinical trials as full-time jobs”. As an investigative journalist he has exposed some of the issues associated with clinical trials in Florida. He published the story of María Rangel  in Spanish.

On March 1, 2022, the family lawyer Daniel Treon confirmed that Celerion and SK Life Science, Inc. had reached an out-of-court settlement with Maria’s husband Cristobal Legarda, citing terms of confidentiality. This settlement happened a few weeks before going to trial.

Celerion said in an emailed statement that the case had been “settled by mutual agreement of the parties” and that its mission is “to help our customers get their medicines to market quickly and safely so that they have an effect on lives of our families, friends and people in need around the world.”

Citing the settlement with the Legarda-Rangel family, SK Life Science Inc. declined to answer questions about the case, but a company spokesman explained in an email that the drugmaker’s “top priority” is “the safety of patients and participants in our clinical trials”.

Before reaching the settlement, Celerion, SK Life Science Inc. and the study’s investigators declined multiple interview requests during the Noticias Telemundo investigation, claiming that the six-year litigation prevented them from commenting on the case.