From the Desk of Paul Gordon, MD

Clinical Research Gains Momentum

One of the main goals of the Eleanor and Lou Gehrig MDA/ALS Research Center is to find better treatments for ALS. As a consequence, at any given time, we have multiple ongoing research projects, both in the basic and clinical sciences. Clinical trials are an integral part of our research, and they offer patients the opportunity to help in the battle to find better treatments. Not only do clinical trials expose patients to the latest state-of-the-art therapies, but the frequent monitoring involved in participation seems to help, as does the emotional aspect of making a contribution to research and to other patients with the illness.

Our research team chooses trials that we think will be safe for the participants, have a high likelihood of helping and that are designed in a rigorous way so that the data will be valid and make a contribution to the body of knowledge about ALS. We are currently enrolling in the following clinical research projects for patients in measures of disease progression (the Markers Study), pulmonary assistance (the Vest Study), and clinical therapeutics (the Minocycline Trial). Upcoming projects will include a phase II trial of CoQ-10, and a pilot trial of a novel vaccination strategy. More information will be forthcoming on these and other trials in future newsletters.

While we at Columbia take great pride in designing excellent trials, patients will be able to read about various trials on the Internet and in advertisements. If a patient decides that participation in a trial is a good idea, it may be difficult to decide on which one. The best trials choose medications that have a solid scientific rationale for use (through animal testing before human trials), have undergone early phase human trials to test safety, and have gone through independent review by agencies such as the NIH and FDA to ensure that the trial is safe, morally sound, and designed to answer the hypothesis being tested. All trials must be approved by the institution’s research review board (IRB), which requires that patients sign a consent form before participation. IRB oversight ensures that scientists and laypersons independent of the research have reviewed the trial, and that they consider the trial to be well-designed, safe, and free from bias.

In the next paragraphs I will shift gears and focus on our current study of minocycline in ALS, as an example of a trial with an excellent scientific rationale, previous early phase human testing, independent funding, and institutional approval from the NIH, FDA and IRB.

The nation-wide phase III trial of minocycline in ALS is now underway and enrolling patients at 28 centers across the United States. At study completion, the minocycline trial will be one of the largest investigator-initiated clinical trials in ALS conducted to date; it will provide data not only on the effectiveness of the treatment, but also on the course of ALS, and on measures of progression. The trial is currently one of only 3 NIH-funded clinical trials for ALS. It has several innovative aspects including use of a medication with extensive pre-clinical testing, a large simple trial design, and sound statistical planning to ensure valid data. This trial is the final important step in determining whether minocycline improves the course of ALS.

What is Minocycline?

Minocycline is a second-generation, long-acting tetracycline. It is indicated in the treatment of a variety of bacterial infections, including brain and meningeal infections; it is ten times better able to enter the brain than other tetracycline antibiotics.

Minocycline may inhibit both apoptosis (a type of enzyme-controlled cell death) and inflammation, which contribute to cell death in ALS. It reduces the activation of apoptosis-promoting caspase enzymes, and its anti-inflammatory properties include prevention of glutamate-induced activation of inflammatory cells and reduction of interleukin (inflammation promoting proteins) production in cell culture. It has neuroprotective effects in animal models of neurodegenerative disorders marked by caspase-regulated and inflammatory cell death. Minocycline has now been tested and shown to protect nerve cells in many scientific experiments. It reduces cell death and prolongs survival in animal models of ALS, stroke, trauma, Huntington’s disease, and Parkinson’s disease.

Minocycline has been shown to be beneficial in multiple different animal experiments of ALS, conducted in Europe, Canada and the United States. In ALS, minocycline probably acts by inhibiting the enzymes involved in cell death pathways. From the ALS animal model, there is evidence that minocycline protects mitochondria, which produce the cells energy supply, reduces inflammation and down-regulates pro-apoptotic caspase enzymes.

Results of Animal Studies

Several laboratories have shown that minocycline delays disease progression in the ALS mouse model. In one laboratory, injections of 5 mg/kg/day provided an increase in lifespan of approximately 11% compared to placebo-treated mice in a blinded study of 20 rodents.

In an independent laboratory, minocycline also prolonged life in the ALS model. Mice injected with 10 mg/kg per day beginning at five weeks of age had delayed onset of impaired motor performance and had statistically significant extended survival compared to saline-treated control mice. Pathologically, minocycline reduced the activation of caspase enzymes, and inflammatory enzymes secondary to upstream effects on mitochondria. The authors detected these effects using ALS mice, neuronal cells and isolated mitochondria.

In a separate study in the ALS mouse model, minocycline improved survival and reduced inflammatory cell activation. In this study, transgenic mice were treated every weekday with an injection of saline or minocycline starting at 70 days of age. Two different minocycline doses were used: 25 mg/kg and 50 mg/kg. Minocycline dose-dependently delayed decline in exercise performance, which met statistical significance between high dose minocycline and saline-treated mice. Minocycline also delayed the onset and slowed decline in muscle weakness in a dose-dependent manner. Both minocycline concentrations delayed mortality to a significant degree. Mice treated with the higher dose had a prolonged life span of 16%.

In a Canadian study, minocycline administered in the food of ALS mice delayed the decline in muscle strength and significantly increased longevity. There was reduced inflammation in the mice treated with minocycline compared to control mice.

Minocycline also provides benefit in models of other diseases with similar mechanisms of cell death to ALS. In a rodent model of stroke, minocycline reduced stroke size by 63%. Animals received minocycline at 45 mg/kg twice the first day and 22.5 mg/kg for the subsequent 2 days. Pathologic studies indicated that minocycline inhibited activation of inflammatory cells and induction of inflammatory enzymes.

In a study of experimental spinal cord injury in rodents, administration of minocycline improved neuron survival and functional recovery. The authors reported that 90 mg/kg injections one hour following spinal cord injury provided significant improvement in motor function when compared to control animals. Those animals that received minocycline had reduced neurodegeneration and apoptosis in the spinal cord.

Minocycline also prevents neurodegeneration in the mouse model of Parkinson’s disease. In this controlled study, mice received doses of minocycline ranging from 60-120 mg/kg/day orally. Minocycline inhibited neurodegeneration and neuronal depletion, and was associated with marked reductions in inflammation.

In a blinded study using the Huntington disease mouse model, survival was prolonged following injections of minocycline at 5 mg/kg/day. Daily minocycline treatment beginning at 6 weeks of age significantly delayed the characteristic decline of exercise performance and extended survival by 14% when compared to saline-treated mice. In this model there was reduction of caspase and inflammatory enzymes. There was no effect of tetracycline, which does not cross the blood-brain barrier, on performance or survival.

Results of Preliminary Human Studies

Two early phase placebo controlled pilot studies in human ALS were completed in 2003. The first was a randomized trial of the tolerability of minocycline in combination with riluzole in patients with ALS. There were nineteen subjects, 11 men and 8 women, enrolled in the 6-month study. There were no statistically significant differences in occurrence of side effects between placebo and active drug groups.

A second pilot study of minocycline, a dose escalation study, is also completed. There were 23 patients enrolled in this randomized, placebo-controlled, 8-month crossover study. The common side effects encountered were largely gastrointestinal, and dyspepsia occurred more often while taking minocycline (5:1 minocycline: placebo). There were no statistically significant differences between groups in occurrence of other adverse events. Laboratory studies of kidney and liver function were elevated to a statistically significant degree while taking minocycline, though the elevations were not considered clinically significant. The majority of patients could tolerate higher than standard doses in Trial 2.

The small sample size and limited duration of these human trials renders it premature to draw conclusions regarding efficacy and, because of the abnormalities detected in liver and renal function while taking minocycline in combination with riluzole, we do not yet consider it appropriate to recommend prescription of minocycline for treatment of ALS. The tolerability of minocycline in these trials was acceptable, however, which supports proceeding to a larger phase III trial in ALS.

We Need Your Help

Despite recent advances in partial understanding of molecular events leading to motor neuron degeneration, there is no cure for ALS. The therapeutic benefit of minocycline on survival and motor function in ALS mice and in animal models of Huntington disease and Parkinson disease provides further evidence it may act as a neuroprotective agent.

It is only through well-designed clinical trials that more effective treatments will be found. Clinical trials are entirely dependent upon the participation of patients with ALS. The Phase III Trial of Minocycline in ALS offers patients across the nation the opportunity to participate in the final important step in determining whether minocycline improves the course of ALS.