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Histone Deacetylase Inhibitor (HDACi) ~ vorinostat

Niemann-Pick Disease Clinical Trial Updates:

  • Cyclodextrin (NPC ~ pediatric)
  • Vorinostat (NPC ~ adult)
  • Enzyme Replacement Therapy (ASMD ~ pediatric)

Niemann-Pick Disease Research “In the News”:
Penn Vet Researchers Identify Effective Treatment for Niemann-Pick Disease Type C

Dr. Forbes D. Porter, MD, PhD
Senior Investigator, PDEGEN, NICHD
Program Head, PDEGEN, NICHD
Clinical Director, NICHD

Dear NNPDF Families and Friends,

In tandem with World Rare Disease Day 2015 and in support of our NPD families WORLD-WIDE, the National Niemann-Pick Disease Foundation (NNPDF) is pleased to share the most recent research and clinical trial updates within the Niemann-Pick Disease Community.

The NNPDF central offices received the following clinical trial updates from Dr. Forbes D. Porter at the National Institutes of Health (NIH) to share with the NPC membership with regards to recent developments in the Cyclodextrin and Histone Deacetylase Inhibitors (HDACi ~ vorinostat) clinical trials.

Click here to read the latest press release from National Institutes of Health (NIH) February 27th 2015

[Feb 27th, 2015 ~ blg]


National Institutes of Health
HDACi ~ vorinostat Clinical Trial Update for NPC Adult Patients
Dateline:  NIH/Bethesda, Maryland ~ Friday, September 12, 2014

Update from Dr. Forbes D. Porter, MD, PhD
Senior Investigator, PDEGEN, NICHD
Program Head, PDEGEN, NICHD
Clinical Director, NICHD

The NNPDF central offices received the following update from Dr. Forbes D. Porter to share with the NPC community with regards to recent developments in reference to the Histone Deacetylase Inhibitors (HDACi) ~ vorinostat clinical trials for NPC adults.

We are pleased to inform the NPC community of an upcoming clinical trial at the NIH to study the safety and tolerability of vorinostat in adults with Niemann-Pick disease, type C1. We plan to begin enrolling patients in September 2014.

This clinical trial is an open label study for 12 patients. “Open label” means that every patient will get vorinostat. There is no placebo, or sugar pill, in this study. Patients will come to the NIH for a total of 3 visits – at baseline, 3 months and at 6 months for this trial. Each visit will last for about 7-10 days. Patients will start taking the study drug while they are at the NIH and will continue taking the study drug when they return home. They will also need to have blood drawn for safety labs every two weeks between visits while they are at home. After the 6 month visit, they will stop taking the study drug and they will be done with the trial.

Vorinostat is a pill that is taken by mouth. The purpose of this study is to test the safety and tolerability of vorinostat when it is given to adults with NPC1. Patients will have blood drawn and will have a lumbar puncture (spinal tap) to collect spinal fluid at each visit to measure how much of the drug is absorbed. Patients will also have tests of hearing, speech, swallowing and movement.

Who is eligible to participate?
To participate in this study, specific “inclusion” and “exclusion” must be met. Participants will be screened first over the phone, to try to establish eligibility for this trial before traveling to the NIH.

To be eligible for this study, patients:

  • Must be between 18 years and 60 years of age
    Have a documented diagnosis of NPC1 either by fibroblast testing or NPC1 mutation testing
  • Must have their skin fibroblasts treated with vorinostat, and the cells must exhibit a reduction in the filipin lysosomal storage
  • Have at least one neurological symptom of NPC1
  • Must be healthy enough to travel to the NIH and to be able to comply with the requirements of the protocol
  • May be on miglustat, but may not start miglustat or change the dose of miglustat during the trial
  • Must be willing to stop all non-prescription supplements, except an age-appropriate multivitamin
  • May not be taking another drug in the HDAC inhibitor family, including valproic acid, unless stopped at least two months before starting the trial
  • May not be taking more than two medications to control seizures
  • May not take anticoagulants (blood thinners) or have a history/presence of a bleeding disorder
  • May not have active lung disease, oxygen requirement or clinically significant history of decreased blood oxygen saturation, respiratory therapy, or requiring active suction.
  • May not have a history of taking any form of cyclodextrin in an attempt to treat NPC1

Please note!
If an interested patient passes the phone screening, their fibroblasts (skin cells) will need to be tested to make sure their cells respond to the drug. This will help us predict if the person is likely to have a response to the study drug during the trial. Skin cells are taken by a skin biopsy, which many people with NPC have had before. We will help families schedule the skin biopsy to have the skin cells shipped to the lab for testing. If an individual has already had a skin biopsy at the NIH for the Natural History Study, they probably do not need to have another biopsy for this trial.

What are the risks of this study?
The use of vorinostat in NPC1 is experimental, and the purpose of this protocol is to determine the safety of the drug in this patient group. Vorinostat is approved for use in adults with certain types of cancer. It is not approved for use in children.

Based on prior clinical studies, the most common serious drug related adverse reactions are pulmonary embolism and thrombocytopenia (low platelets). Other side effects include anemia (low red blood cells), nausea, vomiting, diarrhea and high blood sugar. Patients will be monitored for signs and symptoms of these problems during the trial.

This effort is being supported by Notre Dame College of Science and the Ara Parseghian Medical Research Foundation and represents collaboration among investigators from Notre Dame, Broad Institute, Mayo Clinic, Weill Cornell Medical College, Washington University, and the National Institutes of Health.

The assistance of the whole NPC community has been essential in getting this trial started. We appreciate your continued support to work toward our goal of making safe and effective therapies accessible to all individuals with NPC1.

Please email nichdnpc1@mail.nih.gov if you would like more information about the study or if you are interested in participating.

Click Here to View the Press Release

Dateline: September 12th, 2014
Ara Parseghian Medical Research Foundation (APMRF):

The FDA has granted an Investigational New Drug exemption to the APMRF that will allow us to study the safety and potential biochemical efficacy in adult patients with NPC1. The study will enroll 12 NPC1 patients. Although the IND exemption does not allow us to test vorinostat in children with NPC1, this exemption will save significant time and expense in obtaining proof of concept data. Working together, this collaborative group hopes to advance our understanding of the potential of an HDACi to treat individuals with NPC. Greg Crawford, Dean of the Notre Dame College of Science, in conjunction with APMRF have raised $500,000 to facilitate this work.  Merck has graciously agreed to provide the drug supply for the trial.

[Sept 12th, 2014 ~ blg]


National Institutes of Health  
Clinical Trial Updates for Niemann-Pick Type C Disease
June 27th, 2014
*Cyclodextrin and HDAC Inhibitor*

Update from Dr. Forbes D. Porter, MD, PhD
Senior Investigator, PDEGEN, NICHD
Program Head, PDEGEN, NICHD
Clinical Director, NICHD

The NNPDF central offices received the following update from Dr. Forbes D. Porter to share with the community in regards to recent developments in both the Cyclodextrin and new Histone Deacetylase Inhibitors (HDACi) clinical trials.

The TRND team continues to work to determine if cyclodextrin is a safe and effective therapy for children and young adults with Niemann-Pick Disease, type C1. This trial was initially started in January 2013 using Ommaya reservoirs; however, after three patients we had to stop the trial due to complications.  The trial was revised to administer the cyclodextrin by lumbar intrathecal infusion (spinal tap).  We were able to resume the trial in September of 2013 and to date we have enrolled twelve patients in whom we have studied cyclodextrin doses between 50 and 400 mg.  Some of the initial biomarker results look promising and we expect to obtain results from additional biomarker testing over the next few months.   From a safety perspective we are still concerned about ototoxicity (hearing loss) and we are working to try to better understand this issue.  Concurrent with this first trial we are working on a number of options that would support a phase II/III trial that would try to show that cyclodextrin has clinical benefit.    This second trial will need to be multisite and multinational.

For more information about the Cyclodextrin Clinical Trial, visit the Cyclodextrin page.

In addition to cyclodextrin, we are also exploring the potential use of histone deacetylase inhibitors (HDACi) to treat NPC1. The Maxfield and Sturley research groups showed that HDACi can reduce cholesterol storage in cells that have been cultured from NPC1 patients.     Over the past year we have been working to establish a proof of concept clinical trial of HDAC inhibition in NPC1.  A proposal to evaluate HDACi in NPC1 was awarded one of the first U01 grants (Drs. Maxfield, Ory and Porter) designed to promote extramural utilization of the NIH Clinical Center (http://www.nih.gov/news/health/mar2014/nichd-13.htm).  This collaboration has now been expanded this intramural/extramural collaboration to include investigators from Notre Dame (Drs. Helquist and Wiest), Broad Institute (Dr. Holson) and Mayo Clinic (Dr. Patterson).   This effort is being supported by Notre Dame College of Science and the Ara Parseghian Medical Research Foundation. The initial drug to be tested will be vorinostat.  Vorinostat is approved by the FDA for the treatment of cutaneous T-cell lymphoma.  Since this is a proof of concept trial and the safety of this drug in NPC subjects is not likely to differ significantly from patients with cutaneous T-cell lymphoma who have failed alternative chemotherapy, we were able to obtain a waiver of the requirement for an Investigational New Drug application for the testing of vorinostat in adult subjects with NPC1.  The NICHD Institutional Review Board (IRB) has approved a protocol to test the safety and efficacy of vorinostat in a cohort of 12 adult NPC1 subjects and we are currently working on IRB approval for a second site at the Mayo Clinic.  This will be a phase I proof of concept trial that will focus on safety of HDACi in NPC1 subjects and determine if HDAC inhibition has a desirable biochemical effect in white blood cells.  Although we still have a number of issues to resolve, it is our goal to initiate this protocol this fall.

[Jun 27th, 2014 ~ blg]


Ara Parseghian Medical Research Foundation Announces:
HDACi Drug Trial Expected to Start in 2014!

An article from the the Spring 2014 Ara Parseghian Medical Research Foundation Newsletter:

Tremendous progress has been made to initiate a new, two center drug trial later this year at the Mayo Clinic and NIH Clinical Center. To reach this goal a major collaborative effort is underway to determine if a histone deacetylase inhibitor (HDACi) can be used to safely treat patients with Niemann-Pick Disease, type C1 (NPC).

This collaboration includes investigators Drs. Paul Helquist and Olaf Wiest, (University of Notre Dame), Dr. Fred Maxfield (Weill Cornell Medical College), Dr. Dan Ory (Washington University School of Medicine), Dr. Forbes Porter (National Institutes of Health). Dr. Ed Holson (Broad Institute) and Dr. Marc Patterson (Mayo Clinic). This effort has been assisted and coordinated by the Ara Parseghian Medical Research Foundation (APMRF), the University of Notre Dame College of Science, and Translational Drug Development, Inc.

The discovery of the use of HDACi for the treatment of NP-C was first made in the labs of Paul Helquist and Olaf Wiest and they soon collaborated with Dr. Maxfield who helped confirm their hypothesis. Recently, the Maxfield laboratory found that treatment of human NPC1 mutant cells with certain HDACi leads to clearance of excess cholesterol and other lipids from certain parts of the cells and it corrects the overall defect in cholesterol regulation. This metabolic correction was associated with increased expression of the NPC1 protein. Based on this preliminary data, the HDACi treatment could result in a benefit to NPC1 patients.

The initial trial will use the HDACi drug vorinostat which has been approved by the FDA to treat a type of cancer known as cutaneous T-cell lymphoma. Vorinostat was shown by the Maxfield laboratory to be effective in cells from NPC1 patients collected as part of the NPC Natural History trial at the NIH.

Drs. Ory, Maxfield and Porter have received a U01 grant from the NIH to support the clinical trial work to be performed at the NIH Clinical Center.

The FDA has granted an Investigational New Drug exemption to the APMRF that will allow us to study the safety and potential biochemical efficacy in adult patients with NPC1. The study will enroll 12 NPC1 patients. Although the IND exemption does not allow us to test vorinostat in children with NPC1, this exemption will save significant time and expense in obtaining proof of concept data. Working together, this collaborative group hopes to advance our understanding of the potential of an HDACi to treat individuals with NPC.

Greg Crawford, Dean of the Notre Dame College of Science, in conjunction with APMRF have raised $500,000 to facilitate this work and to allow for a second clinical trial site at Mayo Clinic. Merck has graciously agreed to provide the drug supply for the trial.

To view the announcement in the newsletter format, you can see it on page 2 of the APMRF Spring 2014 Newsletter or visit their website.

[June , 2014 ~ blg]


Ara Parseghian Medical Research Foundation Announces HDACi Clinical Trial
Dateline: 12/10/2013

Dear Families and Friends,

We received an update from Cindy Parseghian, President of the Ara Parseghian Medical Research Foundation, in reference to a clinical trial planned in 2014 for Histone Deacetlase Inhibitor (HDACi).

“We are pleased to announce a clinical trial in a Histone Deacetylase Inhibitor (HDACi) for the treatment of NP-C disease in the summer of 2014. A group of dedicated researchers are collaborating closely to move a HDACi to trials. To read more about the trial please visit the Ara Parseghian Medical Research Foundation web page at www.parseghian.org or the Foundation Facebook page.  More information will be forthcoming as the details of the trial are determined. Patient enrollment will be announced after the trial is approved by the FDA.”

~ Cindy Parseghian

Hope for NPC Patients

A clinical trial is expected to begin in the summer of 2014 using a Histone Deacetylase Inhibitors (HDACi). The goal of the Phase 1 clinical trial will be to establish the safety and tolerability of an oral HDACi as a treatment for NPC1 disease. To meet this objective, researchers at the National Institutes of Health, Mayo Clinic, Washington University and Cornell will develope a phase 1, first-in-human, open label, multi-center, dose escalation study of a HDACi in late adolescents and adults with NPC1 disease. Results from this study will lay the foundation for future clinical trials to assess the effectiveness of an HDACi in slowing disease progression, and may lead to the first FDA-approved drug for the treatment of this devastating disorder. The trial is dependent on an approval of an Investigational New Drug Application (IND) by the Food and Drug Administration (FDA).

The secondary objectives of the trial will be to determine biochemical efficacy of the HDACi to increase the expression of the NPC1 protein and normalize lipid and protein biomarkers. A team of researchers will examine data on plasma and cerebrospinal fluid markers to use as potential clinical endpoints. These outcome measures can potentially serve as surrogate outcome measures in future Phase 2 and Phase 3 HDACi trials.

Twelve NPC1 patients (18 years and older) will be recruited for the study. Eligible patients will demonstrate at least one neurological manifestation of NPC1 (e.g., hearing loss, vertical supranuclear gaze palsy, ataxia dementia, dystonia, seizures, dysarthria, or dysphagia). Symptoms cannot be so severe that they interfere with the patient’s ability to comply with the requirements of this study. Testing will be performed on patient fibroblasts to establish in vivo responsiveness to the HDACi. The safety of HDACi in pediatric populations has not been established. Children under 18 years old are thus currently excluded due to FDA comments, in a pre-IND meeting, suggesting that safety and tolerability first be established in adults. Potential participants will be admitted to the NIH Clinical Center or Mayo Clinic for determination of eligibility and baseline clinical evaluations. Patients who have received any form of cyclodextrin or an HDACi in the past in an attempt to treat NPC1 will not qualify for the trial.

Clinical sites will be overseen by Dr. Porter at the National Institutes of Health Clinical Center and Dr. Marc Patterson at the Mayo Clinic in Rochester, MN. Dr. Ory will oversee performance biomarker analysis of clinical samples at Washington University while Dr. Maxfield will supervise personnel in his laboratory who will perform quantification on NPC1 protein expression and histone acetylation in the clinical samples. Dr. Maxfield and his personnel will also test fibroblasts from prospective trial participants to confirm that their cells respond to HDACi treatment.

The discovery of the use of HDACi for the treatment of NP-C was first made in the labs of Paul Helquist and Olaf Wiest at the University Of Notre Dame. They soon collaborated with Dr. Fred Maxfield’s lab at Cornell who helped confirm their hypothesis. Recently, the Maxfield laboratory found that treatment of human NPC1 mutant cells with certain HDACi leads to clearance of excess cholesterol and other lipids from certain parts of the cells and it corrects the overall defect in cholesterol regulation. This metabolic correction was associated with increased expression of the NPC1 protein. Based on this preliminary data, the HDACi treatment could result in a benefit of NPC1 patients.

Funding for the Phase 1 trial has been provided by a grant from the National Institutes of Health, funds raised by Greg Crawford, Dean of the College of Science at the University Of Notre Dame and the Ara Parseghian Medical Research Foundation (APMRF).

The APMRF has been instrumental in funding the labs of Helquist, Wiest, Maxfield, Ory and Dr. Steven Sturley, at Columbia University, in the investigation of HDACi, providing the found work for the Phase 1 trial. In addition, the APMRF has been a major supporter of the Natural History Study conducted by Dr. Porter at the NIH which has focused on fathering of clinical data and establishing biomarkers for use in clinical trials.

To view the announcement in the newsletter format, you can see it on page 2 of the APMRF Winter 2013 Newsletter, or visit their website.

[Dec 11th, 2013 ~ blg]