Finding Solutions in Combating Mitochondrial Diseases

Clinical trials are proving positive with Dichloroacetate (DCA)

Mitochondria are the intracellular "powerhouses" of our cells. They are responsible for generating the energy needed by every tissue and organ in our bodies to perform their normal functions. Energy is essential to life and, when energy production is compromised, disease results. PDC is a key enzyme for maintaining the body's energy supply. The scientific team lead by Dr. Peter Stacpoole at the University of Florida in Gainesville, Florida, has connected a number of disease states to their potential treatment with the drug dichloroacetate (DCA). DCA stimulates PDC, increasing its ability to promote cellular energy production. DCA has shown promise in treating several life-threatening diseases, including cancer, pulmonary arterial hypertension and congenital PDC deficiency (PDCD) in children.

Solutions are needed to deliver the fruits of science to patients for whom they are intended. With DCA, Dr. Stacpoole's team has developed a uniquely acting compound that is a prototype of new class of drugs to increase the efficiency of normal metabolic processes essential for cell survival. Indeed, the story of DCA is a striking example in which the basic scientific questions have been answered and animal studies and even early stage clinical trials have been conducted. Yet, DCA is too simple a molecule to be patented. This problem has prevented traditional pharmaceutical support for conducting human trials with DCA in diseases in which currently approved therapy is either inadequate or nonexistent.

  • Dr. Stacpoole and his team at the University of Florida are among the few researchers in academia whose efforts in drug development have advanced to the stage of human trials. They have worked with the FDA to design a definitive clinical trial of DCA for children with congenital PDC deficiency, a currently fatal disease for which no approved therapy exists. Most children with congenital PDC deficiency suffer and die within the first months or years of life because their cells are starved for energy and their lactic acid levels are too high. Dr. Stacpoole has treated several children with PDC deficiency for up to 22 years with oral DCA, which controls their lactic acid levels, has few, if any, side effects and may improve the children's quality and quantity of life.
  • In DCA, Dr. Stacpoole and his team have developed an oral treatment for congenital PDC deficiency that will not require surgery or complicated medical procedures. They have already conducted early clinical trials that show DCA to be safe and well-tolerated. Now, the team is nearing FDA approval to conduct a definitive phase 3 trial in ~24 children with congenital PDC deficiency to determine the long-term efficacy of DCA. If the trial results are positive, they can lead to the first FDA-approved drug for any mitochondrial disease.
  • The ability of DCA to stimulate energy production by mitochondria has also been shown to be therapeutic in animal models of pulmonary arterial hypertension (PAH), a life-threatening disease affecting the heart and lungs of adults. In animal models of this disease, DCA stimulates PDC activity, decreases the abnormal growth of cells lining the blood vessels of the lungs, reverses heart failure and improves survival. Dr. Stacpoole's team has FDA-approval for a phase 1 trial in 30 adults with PAH to determine DCA's safety and tolerability and to begin to evaluate its therapeutic efficacy.
  • DCA can also aid in treating cancer. Whereas normal cells rely on a normal PDC to obtain their energy, PDC is inhibited in cancer cells, which derive their energy through the breakdown of carbohydrates to lactate acid. Dozens of publications from cancer researchers throughout the world have documented DCA's anti-cancer effects in human tumors studied in tissue culture or in animal models. By re-activating PDC in mitochondria, DCA causes tumor cells to self-destruct and animal survival increases. Dr. Stacpoole and others have already conducted 2 early phase clinical trials in adults with recurrent brain tumors, including patients with glioblastoma multiforme (GBM), the most deadly brain cancer. Several patients received the drug for over 1 year. DCA was well-tolerated and generally safe. In some of the patients treated for the longest time, the brain tumors regressed in size. These findings are very encouraging, because GBM is a highly aggressive tumor, with only about a one and a half year survival after initial diagnosis.

Because DCA is unpatentable, there is no pharmaceutical funding to help undertake further steps. Dr. Stacpoole has submitted a well-reviewed grant to the Orphan products Division of the FDA to conduct a phase 3 trial of DCA in children born with PDC deficiency throughout the U.S., but the budget ceiling of such awards is too low to allow the DCA to be purchased, formulated for oral use and distributed to the children who would be entered into the trial. An additional $250,000 is needed to accomplish these tasks and ensure the trial can move forward. For an in-depth look at the process of conducting and funding clinical trials, please read Dr. Stacpoole's personal account in the Dive Deeper section.


Dr. Stacpoole’s federally-sponsored research is broadly focused in two areas: intermediary metabolism and new drug development. He conducts patient-oriented research in the Shands Hospital Clinical Research Center (CRC) at the University of Florida and collaborates with investigators across North America into the causes and treatment of genetic mitochondrial diseases, due to nuclear DNA or mitochondrial DNA mutations in genes that encode enzymes of carbohydrate metabolism or oxidative phosphorylation. These studies also engage collaborators with expertise in neurology, neurobehavior, clinical pharmacology, pulmonary medicine, oncology and cell and molecular biology.

Related research by Dr. Stacpoole includes mechanistically-oriented laboratory studies on the molecular and biochemical consequences of loss-of-function mutations in the mitochondrial pyruvate dehydrogenase complex (PDC) and therapeutic interventions for PDC deficiency. He also collaborates with other faculty at the University of Florida to investigate the regulation of amino acid metabolism in humans in response to different genetic or nutritional perturbations.

With regard to new drug development, Dr. Stacpoole and his colleagues have developed, in DCA, a prototype for a novel class of investigational drugs for the treatment of acquired or inborn errors of mitochondrial energy metabolism and lactic acidosis. Its sites and mechanisms of action are being further explored by in vitro and in vivo laboratory studies employing cell and molecular techniques and mass spectrometry.

In his own words, Dr. Stacpoole has drafted the following in-depth document regarding what it takes to conduct and fund a clinical trial:

What Does it Take to Conduct and Fund a Clinical Trial?

I am asking your help in making three clinical trials of DCA a reality for the treatment of children and adults with three life-threatening diseases: pyruvate dehydrogenase complex deficiency (PDCD), pulmonary arterial hypertension (PAH), and brain cancer. Everyone's heard of clinical trials, but here is what they mean to the further development of DCA and to the patients who would participate in DCA trials.

1. How long is the preparation time for a clinical trial?

It generally takes years of preclinical studies of tissue preparations and animals to determine whether a drug is possibly safe and effective for human use. Because DCA is unpatentable, lack of pharmaceutical support has meant that the time to clinical development has been slower and has relied exclusively on grants from the National Institutes of Health (NIH) and other funding agencies.

2. What is the goal of a clinical trial and how many are needed before an investigational drug can be approved?

Trials are usually conducted in 3 phases. A Phase 1 trial is typically the first time the drug is given to humans. It is usually conducted in healthy volunteers to determine safety and to understand how the drug is metabolized by humans. The next step is a Phase 2 trial, which is what we are attempting to conduct in patients with PAH or brain cancer. Here, we are basing the rationale for trying DCA on two principles: (1) that much preclinical and Phase 1 data indicate that DCA will be both safe and effective in these conditions; and (2) that both PAH and brain cancer are life-threatening diseases with high mortalities, despite current FDA-approved treatments. Thus, there is great need for new therapeutic approaches to both diseases. Phase 2 trials are usually conducted in only a few patients to establish some evidence of safety and efficacy in that target population. Finally, based on promising results from Phase 1 and 2 studies, a Phase 3 trial is developed, the goal of which is to definitively determine chronic safety and efficacy of a drug in a larger sample of the target population so that, if the results are positive, they can be submitted to the FDA for approval of the drug for the specific indication. This is the stage we are at with PDCD. After many years of research, including Phase 1 and 2 trials, we have scientifically compelling reasons to think that DCA may be the first specific treatment for this devastating childhood disease. We have worked directly with the FDA over the past 2 years to develop an FDA-approved Phase 3 trial protocol that can be used to study approximately 30 PDCD children over a 4-year period to demonstrate conclusively DCA's potential safety and efficacy for lifelong administration to these patients.

3. Why do some trials get funded while others do not?

Most trials are funded primarily by the sponsor (i.e., industry) who holds the patent on the drug and most trials involve treatment of common diseases, such as diabetes or hypertension where there can be a huge return to the company on its investment in drug development. However, rare diseases historically fall into a fiscal "Valley of Death," either because potential therapies, like DCA, can't easily be patented or because pharmaceutical companies can't reap the financial profits by investing in small markets that may involve only a few hundred patients. In order for us to reach the current stages of DCA development, we have had to rely on federal grants, which are very competitive (currently, only ~10-15% of NIH grant submissions are funded!); take a long time between submission and funding; and often have limited funds available for rare disease trials. Consequently, many promising therapies for rare diseases, such as PDCD and PAH, never reach the stage of Phase 2 or 3 trials.

4. What are the resources needed to conduct a Phase 2 or Phase 3 trial?

Trials require teams of professionals with complementary expertise, including physicians, to recruit patients and oversee their evaluation and treatment; research-oriented nurses and dieticians, to assist physicians in such tasks and maintain close communication with patients throughout the trial; laboratory technicians to analyze patient samples; pharmacists to formulate, test and distribute drugs; and data managers and biostatisticians to collect, manage and analyze large amounts of clinical and laboratory data. Also needed is equipment with which to prepare drugs and analyze samples. Thus, a clinical trial is usually the most complex and expensive medical research that is conducted in the U.S. or elsewhere, because funds must cover fractions of investigators' salaries, supplies, patient care and drug manufacture.

5. What will the DCA trial cost?

The 2 year Phase 2 cancer trial in 20 adults with recurrent brain tumors will cost approximately $650,000 or about $325,000 per year. The 4 year Phase 2 PAH trial in 20 adults with chronic disease will cost approximately $1.4 M or about $355,000 per year. The 4 year Phase 3 PDCD trial in up to 30 children with this disease will cost approximately $4 M, or about $1 M per year.

These trials may seem expensive, when compared to the cost of conducting tissue culture, animal or other non-human laboratory studies, however, they are exceedingly inexpensive, compared to the average pharmaceutically-sponsored clinical trials for common diseases. Furthermore, they will accomplish a common purpose: to move forward DCA's development to eventual FDA approval and marketing.

6. How can you help?

We are extremely grateful for any donations towards these trials. However, no trial can commence unless all the required funds to complete the study are in hand. Otherwise it would be both scientifically irresponsible and unethical to recruit collaborators, and especially patients, to a trial that we could not promise would be seen to its completion. Everyone-- donors, researchers and patients' expect and deserve answers from these trials and there are no shortcuts to conducting them from start to finish. Funding a clinical trial is not like turning a rheostat; it is flicking a toggle switch from "off" to "on." Please help us switch on these trials of DCA. Partner with us, allow us to keep you updated on our progress, and share in the hope that your contribution accelerates the pace of DCA treatment for children and adults with these life-threatening diseases.

On behalf of myself, my colleagues and my patients, thank you.

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