I am long OPKO Health Inc. (OPK) because of Rayaldy Capsules, OPKO's new vitamin D drug. I am not a stock analyst; my qualifications are listed on my Seeking Alpha profile. For the last eleven years, I have been reading, writing, and speaking about vitamin D as the the director and founder of the public interest, non-profit Vitamin D Council. My peer-reviewed publications in scientific journals are listed here.
In an earlier article, I speculated on possible additional indications for Rayaldy above and beyond the initial indication for which Rayaldy is currently being developed - secondary hyperparathyroidism (SHPT) in patients with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency. SHPT is characterized by chronic elevation of blood parathyroid hormone (PTH) levels, and it develops in these patients primarily as a consequence of vitamin D insufficiency. These Rayaldy trials are important as elevated PTH is associated with significant increased cardiovascular mortality in these patients. However, in this article, I will concentrate on just one potential additional indication for Rayaldy: the prevention of falls in the elderly.
Rayaldy is a first-in-class modified-release product that treats SHPT by correcting the underlying vitamin D insufficiency, a condition characterized by low blood levels of a prohormone known as 25-hydroxyvitamin D (25D). Rayaldy steadily boosts the blood 25D levels in a physiological manner due to its unique modified-release formulation.
Rayaldy will directly compete with nutritional vitamin D (vitamin D3 or vitamin D2), which requires comparatively high doses to increase blood 25D. Vitamin D2 is available over-the-counter (OTC) or by prescription, and vitamin D3 is available OTC only. For unclear reasons, nutritional vitamin D has been found to be ineffective in treating SHPT in CKD patients.
Rayaldy will also compete with prescription vitamin D hormone therapies, such as Hectorol Capsules (Sanofi (SNY)), paricalcitol capsules or calcitriol capsules. These therapies effectively lower PTH when administered in sufficiently high doses, but fail to correct the underlying vitamin D insufficiency. They often cause hypercalcemia (too much calcium in the blood), which can accelerate CKD progression via calcification of the kidneys, a risk that causes most physicians to prescribe these therapies with caution (usually at sub-therapeutic doses). Physicians understand that vitamin D hormone therapies are not effective or indicated for correcting vitamin D insufficiency.
In discussing Rayaldy's possible role in preventing falls, one needs to know Rayaldy's relationship to nutritional vitamin D. Rayaldy is a modified-release formulation containing the form of 25D that is normally made in the body from vitamin D3, namely 25-hydroxyvitamin D3 (25D3). OPKO's Phase 2 trials have shown that Rayaldy effectively increases blood 25D3 levels and effectively lowers blood PTH; the Phase 2 effect size was substantial.
The administered 25D3 is subsequently metabolized into calcitriol, which is a steroid hormone similar to cortisol or testosterone. The body can only make adequate calcitriol when blood 25D3 levels are sufficiently high (at least 30-40 ng/mL). All of vitamin D's health benefits are thought to depend on sufficiently high 25D3 levels.
Falls among the elderly are costly, both financially and medically. In 2010, falls among older adults cost the U.S. health care system $30 billion. By 2020, the annual direct and indirect cost of fall injuries is expected to reach $54.9 billion. Of people over age 65, one in three fall every year. In 2011, emergency departments treated 2.4 million nonfatal fall injuries among older adults; more than 689,000 of these patients had to be hospitalized.
Doctors are at a loss as how to prevent falls. There is no drug approved by the U.S. Food and Drug Administration (FDA) to prevent falls. Multiple prescription medications are often cited as the cause of falls, but doctors find it difficult to reduce the dose of these medications lest the treated disease or symptoms return. Regular exercise helps prevent falls, as does vision correction, but the effect size is modest. It helps to try to "fall proof" a home, but such efforts are usually problematic. Modern medicine would quickly embrace any prescription medication that helped to prevent falls.
To the best of my knowledge, all studies of daily OTC vitamin D3 in significant doses point to effective prevention of falls in the elderly. For example, a 2001 German study of elderly women found vitamin D3 caused a 46% reduction in falls. A 2003 Swiss study of elderly women found 800 IU/day of vitamin D3 plus calcium reduced the risk of falling by 49% compared with calcium alone. A 2009 German study of the elderly found 800 IU vitamin D3 reduced falls by 27% and reduced body sway by 28%. In fact, at least 10 university-based randomized controlled clinical trials have shown daily vitamin D3 prevents falls, and higher daily doses (> 800 IU/day) work when lower doses do not.
A meta-analysis is a study that combines the results of multiple independent clinical trials. Four rigorous meta-analyses (2004, 2009, 2010 and 2011) all concluded that vitamin D3 prevents falls. The U.S. Preventive Services Task Force recommends vitamin D to reduce falls in the elderly. The Centers for Disease Control and Prevention make the same recommendation. The American Geriatrics Society states, "vitamin D supplements of at least 800 IU per day should be considered for people... who are otherwise at increased risk for falls."
Vitamin D's effect size in preventing falls is substantial, with the four meta-analyses showing a 13%, 14%, 20% and 24% decreased risk of falling with vitamin D3. However, those meta-analyses included studies using only 400 IU/day, an almost meaningless dose. When studies using at least 800 IU/day are combined, the effect size was no less than 24%.
The mechanism by which vitamin D3 prevents falls is fairly well understood. It increases blood levels of 25D3 and thereby corrects vitamin D insufficiency, which increases muscle strength and restores balance in the elderly. Higher 25D3 levels are associated with better balance in the elderly. Surprisingly, blood 25D3 levels of 50 ng/mL were associated with better balance in the elderly than levels of 30 ng/ml, a level widely thought to be adequate. The same study showed vitamin D3 reduced body sway in the elderly by 28%. It also improved choice reaction time in the elderly, a crucial capability to prevent falls.
More recently, a study from Tufts University showed 4,000 IU/day of vitamin D3 increased muscle fiber diameter in mobility-limited elderly vitamin D deficient women. So, vitamin D improves muscle strength, balance, body sway, reaction time and muscle fiber size in vitamin D deficient elderly, thus preventing falls.
By the way, in 2009, my colleagues and I found convincing evidence that these same mechanisms are operative in improving athletic performance in vitamin D deficient athletes. We concluded that the reason the Russians and East Germans dominated world sports between 1955 and 1985 was because trainers from these two countries routinely irradiated their elite athletes with vitamin D-producing ultraviolet light during those 30 years.
Rayaldy may or may not be more effective than OTC vitamin D3 in preventing falls in the elderly. The active ingredient in Rayaldy is 25D3, the substrate that the body needs for fall prevention. Studies indicating that nutritional vitamin D3 has health benefits, such as prevention of falls in the elderly, clearly imply that Rayaldy will have the same or better benefit, since Rayaldy is at least five times more potent in boosting blood 25D3 levels than is OTC vitamin D3.
As evidence of the unsatisfactoriness of OTC vitamin D3 to prevent falls, consider the fact that vitamin D3's efficacy in preventing falls has been recognized for at least a decade and that nutritional vitamin D3 has been available for decades. Despite widespread recommendations, how many of the elderly currently take vitamin D3 to prevent falls? How many doctors routinely recommend OTC vitamin D3 to prevent falls? No one knows for sure, but ask some older people that you know and I suspect you will find that few take daily vitamin D3 to prevent falls despite a strong rationale and widespread recommendations by respected organizations that they do so.
Besides OTC vitamin D3, Rayaldy will compete with vitamin D2 which is available OTC in low doses or in 50,000 IU capsules with a prescription. Vitamin D2 is not human vitamin D and does not normally have a role in human physiology since dietary sources (other than supplements) are rare. Studies have shown vitamin D2 is inferior to vitamin D3 in raising blood 25D levels. Prescription vitamin D2 is administered in supraphysiological intermittent doses, not physiological daily doses. One study showed that high intermittent doses actually increase the risk of falls, and I am unable to find any convincing studies showing that administration of prescription vitamin D2 significantly reduce falls.
There remains some risk with Rayaldy. Enthusiasm over vitamins in the past, such as vitamin E and C, has waned when negative data emerged from appropriately designed clinical trials. Current Phase 3 trials of Rayaldy in CKD may fail. While four meta-analyses have all shown vitamin D3 reduces falls, phase 2 or 3 studies with Rayaldy may not bear this out. Furthermore, Rayaldy and vitamin D3 are not identical compounds; it is possible that vitamin D3 may have some presently unknown and unique benefits. Also, OPKO may elect not to develop Rayaldy for the indication of preventing falls in the elderly. Finally, competitors (currently there are none) may beat OPKO to the new falls indication.
My educated guess is that Rayaldy will eventually be approved by the FDA to prevent falls in the elderly. While I think OTC vitamin D3 in adequate doses will prevent falls as well as Rayaldy, it may be decades before such comparison studies are done. However, if OTC vitamin D3 would be an effective market competitor, it would already be widely used to prevent falls, as it has been available for decades. An effective prescription drug to prevent falls, like Rayaldy, would be rapidly embraced by the medical profession.
A good example is the prescription sleeping pill Rozerem, a melatonin receptor agonist. It has been known for years that OTC melatonin improves sleep. However, that did not prevent a melatonin mimic from being approved by the FDA. Rozeram did not have to beat melatonin in FDA trials, only beat placebo. There are many other similar examples. The same will be true of Rayaldy and OTC vitamin D3.
The FDA clinical trials necessary to approve Rayaldy to prevent falls will only include elderly patients with vitamin D insufficiency who have fallen twice or more during the most recent six months (frequent fallers). This will make the effect size greater than 24% and thus more likely to be found statistically significant in phase 2 and phase 3 trials. In addition, Rayaldy will not be under dosed; it is being administered in doses of 1 or 2 capsules per day in the currently ongoing Phase 3 trials; each 30 microgram capsule is approximately equivalent to 5,000 IU of vitamin D3.
Finally, the potential good that a prescription for Rayaldy could do in preventing falls in the elderly is immense. Everyone over the age of 65 is at an increased risk for falls. According to Wikipedia, the number of senior citizens in the U.S. was about 35 million in 2010. By 2020, more than 50 million Americans will be 65 years of age or older.