Coenzyme Q10 treatment does not slow the progression of Parkinson’s disease (PD). This was the disappointing conclusion of a Phase 3 clinical trial designed to test the disease-modifying potential of the drug. CoQ10 is an antioxidant that supports mitochondrial function. The results, published March 24 in JAMA Neurology, come on the heels of a promising Phase 2 study, but also amid negative outcomes from other small trials of this compound. The large, multicenter trial, called "QE3," likely puts an end to hopes of using coenzyme Q10 to treat sporadic PD, said Flint Beal of Weill Cornell Medical College in New York, the trial’s lead investigator. “We are quite disappointed, but we can’t argue with the data,” he told Alzforum.
No Brakes on Parkinson's Progression: Treatment with coenzyme Q10 failed to curb PD in a phase 3 clinical trial. Parkinson’s progression scores climbed at an equal pace in treatment groups (blue) and placebo group (orange) over the 16-month trial period. [Copyright © 2014 American Medical Association. All rights reserved.]
Also called ubiquinone, coenzyme Q10 is a component of the electron transport chain that drives the generation of ATP in mitochondria. CoQ10 accepts electrons from Complex I, a 46-subunit machine that pumps protons across the inner mitochondrial membrane, and hands the electrons off to the next member of the respiratory chain. Thus reduced, CoQ10 acts as a powerful antioxidant and has been shown to counteract oxidative damage, a form of injury associated with neurodegenerative disease. Researchers hoped that the coenzyme would stave off damage to dopaminergic neurons in people with PD. Animal studies suggested the approach held promise (see Spindler et al., 2009).
QE3’s smaller predecessor trial, QE2, gave researchers reason for optimism, as well. In that North American multicenter Phase 2 trial, 80 people newly diagnosed with Parkinson’s disease received one of three daily doses (300, 600, or 1200 mg) of CoQ10 or a placebo. All groups also took Vitamin E, owing to previous reports that the lipophilic vitamin may enhance CoQ10 uptake and have synergistic antioxidant effects. The participants were monitored for signs of disease progression for 16 months, or until their PD had progressed to a point where they had to start dopaminergic therapy. In this small trial, treatment appeared to correlate with slowed disease progression in a dose-dependent manner, a finding that stimulated researchers to move forward with the larger QE3 trial (see Schults et al., 2002).
The QE3 trial spanned 67 treatment centers that together enrolled 600 patients. The larger trial followed the same protocol as QE2 but upped the dose; the participants were given either 1200 mg or 2400 mg. At both these higher doses, CoQ10 was generally well tolerated and triggered minimal adverse events, the scientists report. However, disease symptoms progressed just as quickly in both CoQ10 groups as in the placebo group. The investigators concluded that CoQ10 showed no evidence of benefit in early PD patients.
“I’m really puzzled by it—the QE2 trial looked so good,” said David Simon, the lead trial investigator at Beth Israel Deaconess Medical Center in Boston. “But there’s a reason why we do not move directly from small Phase 2 studies into clinical practice. They don’t always replicate."
Despite the QE2 trial results, two other studies completed after the initiation of the QE3 trial had already begun to temper expectations. In 2007, the National Institute of Neurological Disorders and Stroke Neuroprotection Exploratory Trials (NET-PD) consortium tested 2400 mg CoQ10 in PD patients (see NET-PD, 2007). A primary analysis of the results, which relied on historical controls, deemed CoQ10 worthy of moving into a larger trial. However, a secondary analysis using controls that more closely resembled the treatment group found that continuing with the drug would be futile. By this point, the QE3 trial had already been funded, Simon said. Another recent trial tested MitoQ, a chemically modified version of CoQ10 designed to efficiently cross cellular membranes and target the mitochondria. This study was negative, as well (see Snow et al., 2010).
In spite of the rash of failures with CoQ10, Simon still believes that targeting the mitochondria is a solid approach to treating PD. “The data implicating mitochondrial dysfunction as a cause of PD is overwhelming,” he said. Simon added that the variety of causes that underlie sporadic PD, and the lack of biomarkers available to stratify them, may make it difficult to identify the patients most likely to benefit from such treatments.
For example, a recent study found that mutations in PINK1, which are known to cause PD, prevented the ability of Complex I to pass electrons off to CoQ10 in the respiratory chain (see Mar 2014 news story). The transfer is necessary to drive the proton gradient that generates ATP. “If you were to give CoQ10 to patients with PINK1 mutations, it would not bind or receive electrons from Complex I, so it would not help,” said that study’s leader, Bart De Strooper of the University of Leuven in Belgium. However, De Strooper added that patients with different mitochondrial defects theoretically could have benefitted from the treatment. “I don’t think the trial is definitive. It only shows that the treatment won’t work in the broad population of sporadic PD patients,” he said.
The QE3 study investigators were unable to determine whether CoQ10 reached its target in the brain. They also do not know if whatever fraction of CoQ10 that did get into the brain improved mitochondrial function there. An analysis of blood mitochondrial activity in the QE2 trial indicated that CoQ10 enhanced respiratory chain function, however, that analysis was not done in the QE3 trial. “We think of CoQ10 as a mitochondrial drug, but what it really does and where it actually goes is not clear,” said Russell Swerdlow of the University of Kansas Medical Center, Kansas City. If it does make it to the brain and into the mitochondria, “does it prevent oxidative damage, enhance the respiratory chain, or perhaps do neither of those things?” Swerdlow asked. In Alzheimer’s disease, most clinical trials in the past decade were negative, and many of those trials did not rigorously quantify drug exposure and target engagement.
Swerdlow added, however, that the QE3 trial was a reasonable attempt to treat mitochondrial dysfunction, which he sees as a major cause of sporadic PD. Swerdlow has his sights set on other ways to improve mitochondrial function, such as treatment with oxaloacetate, a bioenergetic intermediate that changes the redox balance of the mitochondria and promotes respiration.
CoQ10 is commercially available as a food supplement. Flint agrees that though QE3 has dashed hopes of treating PD with CoQ10, enhancing mitochondrial function still holds promise. “There are a lot of creative approaches being developed,” he said. For example, Flint and colleagues have treated animal models with mitochondrial-targeted peptides that protect dopaminergic neurons from death (see Yang et al., 2009). On this point, Anthony Schapira and Sandip Patel of University College London pose a rhetorical question in an accompanying editorial: “Is this the end of the road for targeting mitochondria for neuroprotection in PD? Our answer to this would be an unequivocal ‘no.’”—Jessica Shugart
- Spindler M, Beal MF, Henchcliffe C. Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr Dis Treat. 2009;5:597-610. PubMed.
- Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M, . Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50. PubMed.
- A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology. 2007 Jan 2;68(1):20-8. PubMed.
- Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O'Sullivan JD, Fung V, Smith RA, Murphy MP, Taylor KM, . A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov Disord. 2010 Aug 15;25(11):1670-4. PubMed.
- Yang L, Zhao K, Calingasan NY, Luo G, Szeto HH, Beal MF. Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Antioxid Redox Signal. 2009 Sep;11(9):2095-104. PubMed.
- Chaturvedi RK, Beal MF. Mitochondria targeted therapeutic approaches in Parkinson's and Huntington's diseases. Mol Cell Neurosci. 2012 Dec 5; PubMed.
- Schapira AH, Patel S. Targeting mitochondria for neuroprotection in Parkinson disease. JAMA Neurol. 2014 May;71(5):537-8. PubMed.
- Beal MF, Oakes D, Shoulson I, Henchcliffe C, Galpern WR, Haas R, Juncos JL, Nutt JG, Voss TS, Ravina B, Shults CM, Helles K, Snively V, Lew MF, Griebner B, Watts A, Gao S, Pourcher E, Bond L, Kompoliti K, Agarwal P, Sia C, Jog M, Cole L, Sultana M, Kurlan R, Richard I, Deeley C, Waters CH, Figueroa A, Arkun A, Brodsky M, Ondo WG, Hunter CB, Jimenez-Shahed J, Palao A, Miyasaki JM, So J, Tetrud J, Reys L, Smith K, Singer C, Blenke A, Russell DS, Cotto C, Friedman JH, Lannon M, Zhang L, Drasby E, Kumar R, Subramanian T, Ford DS, Grimes DA, Cote D, Conway J, Siderowf AD, Evatt ML, Sommerfeld B, Lieberman AN, Okun MS, Rodriguez RL, Merritt S, Swartz CL, Martin WR, King P, Stover N, Guthrie S, Watts RL, Ahmed A, Fernandez HH, Winters A, Mari Z, Dawson TM, Dunlop B, Feigin AS, Shannon B, Nirenberg MJ, Ogg M, Ellias SA, Thomas CA, Frei K, Bodis-Wollner I, Glazman S, Mayer T, Hauser RA, Pahwa R, Langhammer A, Ranawaya R, Derwent L, Sethi KD, Farrow B, Prakash R, Litvan I, Robinson A, Sahay A, Gartner M, Hinson VK, Markind S, Pelikan M, Perlmutter JS, Hartlein J, Molho E, Evans S, Adler CH, Duffy A, Lind M, Elmer L, Davis K, Spears J, Wilson S, Leehey MA, Hermanowicz N, Niswonger S, Shill HA, Obradov S, Rajput A, Cowper M, Lessig S, Song D, Fontaine D, Zadikoff C, Williams K, Blindauer KA, Bergholte J, Propsom CS, Stacy MA, Field J, Mihaila D, Chilton M, Uc EY, Sieren J, Simon DK, Kraics L, Silver A, Boyd JT, Hamill RW, Ingvoldstad C, Young J, Thomas K, Kostyk SK, Wojcieszek J, Pfeiffer RF, Panisset M, Beland M, Reich SG, Cines M, Zappala N, Rivest J, Zweig R, Lumina LP, Hilliard CL, Grill S, Kellermann M, Tuite P, Rolandelli S, Kang UJ, Young J, Rao J, Cook MM, Severt L, Boyar K. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 2014 May;71(5):543-52. PubMed.