Three clinical trials are underway; two others are being planned

April, 2019

Possible treatments for two NBIA disorders are being tested in clinical trials that are either in progress or being planned for the near future.

The best known of these is the Retrophin Inc. trial for Pantothenate Kinase-Associated Neurodegeneration, or PKAN, now underway at 20 sites in the U.S., Canada and Europe. It is the first trial of a medication that targets the underlying causes of this disorder.

Fort Study logoRetrophin, based in San Diego, finished enrolling patients in December 2018, with approximately 82 PKAN patients between the ages of 6 and 65 years. The Fosmetpantotenate Replacement Therapy, or FORT study, is being conducted under a Special Protocol Assessment agreement. That means the U.S. Food and Drug Administration believes that the trial’s design is adequate to support the filing of a New Drug Application, assuming the results are favorable.

This 24-week Phase 3 clinical trial is designed to test the safety and effectiveness of Retrophin’s drug, fosmetpantotenate, also known as RE-024. It follows the gold standard for a clinical trial: It is randomized and double-blind, meaning that neither the patients nor the doctors know who is getting the drug and who is getting a placebo (sugar pill).

The main result of the study, called the primary endpoint, is to determine the extent to which individuals improve over the 24-week trial, based on a scale that measures activities of daily living specifically created for PKAN individuals. After the initial six months of testing, all study participants will have the chance to take the drug.

Retrophin expects to have preliminary data from the primary endpoint during the third quarter of 2019. If the results are positive, the company will submit an application to have fosmetpantotenate approved by the FDA in the US and by the European Medicines Agency in Europe.

Two Studies for INAD

Retrotope Inc., of Los Altos, Calif., has a combined Phase 2/Phase 3 clinical trial underway to assess the effectiveness and safety of a new drug, RT001, in individuals with Infantile Neuroaxonal Dystrophy (INAD), the most severe form of PLAG26-Associated Neurodegeneration (PLAN).

Retrotope logoThe clinical trial started enrolling in November at USCF Benioff Children’s Hospital in San Francisco and Goryeb Children’s Hospital in Morristown, N.J..

In this type of “single arm, open-label” study, all participants get the drug, so there is no placebo control group with which to compare results. The drug is a patented, chemically modified polyunsaturated fatty acid that the company believes can protect against and recover function from the cell damage that is a hallmark of numerous neurodegenerative diseases. Enrollment is by invitation, and the researchers are selecting 15 INAD individuals to take part. The estimated completion date is July 2020.

The primary endpoint is a change in score involving activities of daily living and vital functions tailored for INAD. Six other outcomes are secondary measures, such as gauging spasticity and motor function.

The company also is funding a two year prospective observational study of INAD in multiple centers outside of the U.S. This study will consist of a sufficiently large enough number of infants and children with INAD to allow for age and severity of disease matching with the subjects enrolled in the U.S. RT001 study. The objective of the study is to better understand and define the course of the disease in infants and children with INAD.

The National Organization for Rare Disorders (NORD) is offering assistance with ground transportation to study participants. NORD will book and pre-pay expenses for ground transportation between an airport and lodging, as well as the study site, for one visit to the site.

Another trial involving INAD individuals is a smaller, open label Phase 4 clinical trial of an FDA-approved drug being used off-label. It started in January.

Three participants with INAD who are capable of swallowing tablets are being invited to use desipramine in the project, “Novel Off-label Use of Desipramine in Infantile Neuroaxonal Dystrophy: Targeting the Sphingolipid Metabolism Pathway to Reduce Accumulation of Ceramide.”

An October 2018 paper in Cell Metabolism, “Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to a-Synuclein Gain,” reports that a fruit fly model of PLAN is associated with an accumulation of ceramide, a fat molecule associated with metabolic syndrome and other disorders, when it accumulates. The FDA-approved drug, desipramine, used to treat depression, can block ceramide accumulation and its downstream consequences in the fly model.

This is a research study proposed by Dr. Yong-hui Jiang, at Duke University Health Center in Durham, N.C., to find out if desipramine can improve INAD symptoms and slow disease progression.

“Participants will receive an initial oral dose of study drug once a day,” according to the study description on the website. “This dose may be changed, depending on response. Clinically collected data will be recorded for up to 5 years. Investigators will also ask for participant permission to obtain a sample of child's skin biopsy from unused clinical sample previously collected for standard of care.”

Phase 4 studies look at drugs that have already been approved by the FDA. The drugs are available for doctors to prescribe for patients, but phase 4 studies might still be needed to answer important questions.

For more information on all of these ongoing clinical trials, see

Other PKAN Trials Planned

Spoonbill logoSpoonbill logoDrs. Penny Hogarth and Susan Hayflick from Oregon Health & Science University, along with the nonprofit Spoonbill Foundation, are collaborating with Dr. Ody Sibon from University Medical Center of Groningen in the Netherlands and a sister nonprofit, Stichting Lepelaar, to study CoA-Z for treating PKAN.

CoA-Z corrects the metabolic process in PKAN mice. The OHSU + UMCG team plan to start testing it in humans soon. As of February 2019, the researchers were waiting to receive final approval for the clinical trial plans from the FDA and the OHSU Institutional Review Board (IRB), among other steps. They also plan to work with regulatory authorities in other countries to enable CoA-Z to be tested worldwide. Hogarth will be updating families on this work at our family conference in May.

Hogarth, Hayflick and Sibon said that their work was made possible by families who have worked hard to raise the funds. As of Feb. 25, the two foundations had reached $1,358,399 of their $2 million goal.

CoA LogoSeparately, Dr. Suzanne Jackowski at St. Jude Children’s Research Hospital in Memphis, Tenn., is working on another PKAN treatment involving CoA. She has been studying CoA synthesis for decades and has been working since 2010 on ways to boost CoA levels in patients with PKAN, which is caused by mutations in the PANK2 gene that reduce CoA levels. CoA is necessary for proper energy production that fuels neurotransmitter function in the brain.

An October 2018 paper with Jackowski as senior author, “A therapeutic approach to pantothenate kinase associated neurodegeneration” in the journal Nature Communications, describes the discovery and development at St. Jude of a pantazine compound that treats a new mouse model with brain CoA deficiency. The pantazines are unique synthetic molecules that can rescue the movement disorder and substantially extend the shortened lifespan of the mouse model. The molecules activate the other PANK proteins to compensate for missing CoA.

“It’s a brand new mechanism of action that’s never before been described,” says Jackowski.

“We are still figuring out the best dosing schedule and modifying the compound to optimize its metabolism for human use in pill form,” Jackowski says. “Extrapolation of the mouse dosing experiments to larger animals is challenging since this drug is following non-conventional parameters. This is quite exciting scientifically - it is really a first-in-class drug. Nevertheless, we are keeping our eyes on the ball to move as fast as possible toward a promising therapeutic. The pre-IND meeting with the FDA was successful and the neuroscience FDA representatives were very interested and encouraging in their review of our data to date.”

Jackowski notes that the pantazine compounds are completely different from pantothenate, pantethine, acetyl-phosphopantetheine and CoA. They were named ‘pantazines’ because these compounds modulate pantothenate as it’s converted into CoA. Because the pantazines are new, St. Jude Children’s Research Hospital is patenting them. In addition, St. Jude has filed a patent covering their use as therapeutic agents for the treatment of PKAN.

A company collaborating with Jackowski’s team, CoA Therapeutics, Inc., a subsidiary of BridgeBio, is developing drugs to correct imbalances in CoA metabolism. PKAN is the company’s first target. It has licensed the technology and patents from St. Jude and is working on translating the laboratory results into a drug for PKAN therapy.

Jackowski will also be presenting this work at our family conference in May.



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