Novel Medicines: What is in the Pipeline?
New medicines in development remind me of the “coming attractions” in the movie theatre. They promise something exciting in the future. And just as movie studios hope for blockbusters but cannot predict success ahead of time, so it is with drug development. Many new compounds hold promise, but there are plenty of surprises along the way. Until the FDA has deliberated, pharmaceutical companies never know which drug will actually reach the marketplace and become a hit. (See phases of development on page 254.)
New drugs in the pipeline for treatment of osteoporosis fall into two broad categories: those that are refinements of current medicines and those that are completely novel compounds. Refinement includes modifying the structure of the molecule, inventing a new delivery system, and using new combinations. Examples include an effervescent form of Fosamax that is similar to Alka-Seltzer®, calcitonin in a pill form, and different parathyroid hormone formulations.
FORTEO THAT IS NOT A SHOT
Since Forteo (teriparatide) is an effective medicine that has the drawback of requiring daily shots, other methods of taking the medicine are being investigated. These include nasal spray, topical preparation, tablet, patch, implantable chip, and a tablet that tricks your body into producing its own parathyroid hormone.
Skin applications. Multiple companies are working on delivery of Forteo through the skin. Various methods of skin application are under development. One of the most promising developments is a microneedle patch produced by Zosano Pharma. It is an adhesive patch about the size of a postage stamp that looks like fine sandpaper. It is made up of thirteen hundred miniscule titanium arrowheadshaped needles that are coated with medicine. After the patch is applied to the skin, the medicine dissolves away from the needles. It is virtually bloodless and painless.
Almost two hundred postmenopausal women were recruited for a six-month study to test effectiveness and safety. Three different doses of generic Forteo, called teriparatide, were tested in the patch form and compared with daily Forteo shots and a placebo patch. The patch, which was worn for a total of thirty minutes once a day, caused a small area of redness that resolved quickly.
The medicine from the patches reached the bloodstream faster than from the Forteo shots and achieved a shorter burst of medicine, which is how teriparatide works best. After six months of treatment, the highest dose patch tested, 40 micrograms, showed bone density increases at the spine equivalent to the Forteo shots. A larger trial is planned.
Microchip. The firm Microchips is pursuing a device that is implanted under the skin like a pacemaker. The device is about the size of an Oreo® cookie and contains a battery, wireless antenna, and microchip with the generic version of Forteo. The medicine is released on command for a full year. In addition, the researchers are testing the device as a platform for transmitting health information, possibly even to your smartphone.
Make your own. Rather than focusing on a resource to deliver Forteo, an alternative approach is to give a medicine that stimulates the release of your own parathyroid hormone. This approach focuses on inhibiting the calcium-sensing ability of the parathyroid gland. An oral medicine would stimulate the parathyroid to release a pulse of parathyroid hormone. The most advanced compound in clinical trials was ronacaleret, but it showed insufficient effectiveness in the trials. Other similar compounds are in testing.
ALL NEW AND DIFFERENT
Advances in defining the molecules that regulate bone remodeling have led to the development of medicines that target those molecules. Investigational medicines with novel mechanisms of action may provide benefits beyond those of the current medicines.
Odanacatib. Of all the novel medicines, odanacatib, developed by Merck, is the farthest along in clinical trials. It decreases bone breakdown but at the same time does not decrease bone formation as much as other antiresorptive medicines. Odanacatib blocks an enzyme called cathepsin-K, which is produced by osteoclasts, the bone breakdown cells. Cathepsin-K helps to carve out the pits where bone remodeling happens. Odanacatib works by blocking this action. This leads to shallower bone breakdown pits and greater bone mass but preserves the function of the osteoclasts.
The results of early clinical trials showed increases in bone density with bone formation preserved to a greater degree than bisphosphonates. A large fracture study of women ages sixty-five and older is underway, using two formulations of odanacatib taken once weekly: a 50 mg tablet alone and a tablet combining 50 mg of Odanacatib with 5,600 IU of vitamin D3.
Another cathepsin-K inhibitor compound called ONO-5334, produced by a Japanese company, Ono Pharmaceutical, is also in clinical trials.
REGULATORS OF BONE FORMATION
Since Forteo is the only available medicine for targeting osteoblasts, the bone building cells, the need in the osteoporosis “medicine cabinet” is for more bone formation medicines. Research on how cells communicate with one another led to the identification of a complex system of messengers, called the Wnt signaling pathway, which plays a central role in regulating the growth and activity of osteoblasts. Its discovery has opened the door for development of new compounds that target these messengers and may eventually yield new osteoporosis therapies. Approaches will either use factors that lead to new bone formation or try to block factors that decrease bone formation.
A protein called sclerostin, produced by bone cells (osteocytes), is one of the messengers that sends the signal to apply the brakes in making new osteoblasts. The blocking of sclerostin would allow the rate of bone formation to increase. Amgen is testing a protein that neutralizes the effects of sclerostin. The compound AMG 785 is in clinical trials. A shot given either monthly or every three months is being compared to daily Forteo and once-a-week Fosamax.
Other agents are in earlier stages of development.
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The Bare Bones
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Investigational SERMs:
A Promise of an Ideal Estrogen
An estrogen designed to prevent fractures, breast cancer, heart attack, stroke, and dementia would be perfect. If that's not enough, add the benefits of increasing your sex drive and maintaining your skin's youthful look. Sounds too good to be true, doesn't it? So far, it is.
SERMs, short for “selective estrogen receptor modulators,” hold the promise of being such an ideal medicine. You may also see them referred to as estrogen agonist antagonists (EAAs). These designer drugs have a split personality. They mimic estrogen in some tissues and have the opposite effects in others. Evista was the first drug of this type approved for osteoporosis. Tamoxifen is in the same class, but it is used in patients with breast cancer. Because neither Evista nor tamoxifen is ideal, there is still room for “new and improved” versions.
Although multiple promising SERMs have entered clinical trials, only two medicines, lasofoxifene and bazedoxifene, have made it all the way to filing for FDA approval. However, neither had received FDA approval as of midyear 2011.
FABLYN®
Lasofoxifene was branded originally as Oporia®, then its name was changed to Fablyn. Fablyn was Pfizer's first foray into the bone arena.
Fablyn
(lasofoxifene)
Category
Antiresorptive
Selective Estrogen Receptor Modulator (SERM), also referred to as an
Estrogen Agonist/Antagonist (EAA)
Manufacturer
Pfizer and Ligand Pharmaceuticals
Pivotal Fracture Trial
PEARL
Fracture Reduction
Spine
Nonspine
Indications for Osteoporosis
Not approved
Dose
0.5 mg pill once a day
Additional Information
Lowers risk of invasive breast cancer
Causes uterine polyps
EFFECTIVENESS
PEARL: Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene
In a five-year global study, researchers evaluated the effects of Fablyn on fractures and breast cancer. More than 8,500 women with postmenopausal osteoporosis were given one of two doses of Fablyn or a placebo. The 0.5 mg dose of Fablyn lowered spine fractures by 42 percent and breast cancer by 81 percent. However, it also doubled the risk of blood clots.
Unlike Evista, Fablyn decreased nonspine fractures by 24 percent and reduced the risk for heart attacks and stroke by about a third. Nevertheless, the overall rates of death were higher in the Fablyn groups, which is one of the concerns for the FDA. On further review, only the study sites located in Central and South America showed an increase in lung cancer and deaths. Also, women taking Fablyn needed more procedures for problems like polyps in the uterus and incontinence. In the meantime, European Medicines Agency, the European equivalent to our FDA, approved Fablyn 0.5 mg a day for treatment of osteoporosis.
VIVIANT® AND APRELA®
Another SERM not yet approved by the FDA is bazedoxifene, which has the brand name Viviant. Bazedoxifene is also put into a combination tablet with the estrogen Premarin and is branded as Aprela. The pairing of a SERM and estrogen is categorized as a tissue selective estrogen complex (TSEC). The motivation for adding an estrogen to a SERM stems from the concept that the benefits of each will be achieved with better overall tolerability. Together they are different than either agent alone.
For example, the tendency of SERMs is to cause or worsen hot flashes. If an estrogen is added to a SERM, are hot flashes prevented or relieved? In the series of studies called SMART (Selective Estrogen Menopause and Response to Therapy), Aprela (bazedoxifene 20 mg combined with either Premarin 0.625 or 0.45 mg) was effective in decreasing hot flashes. The combination did not cause breast pain or thicken the lining of the uterus, which is common when estrogen is used alone. This combination also retained the positive features of a SERM. In addition, Aprela prevented bone loss in healthy postmenopausal women. Pairing of a SERM with estrogen in Aprela created a new approach for controlling hot flashes and preventing osteoporosis while protecting the uterus from estrogen stimulation. Although no effect was observed at the breast, long-term safety is not known.
Aprela
(bazedoxifene with Premarin)
Category
Antiresorptive
SERM plus estrogen is called a tissue selective estrogen complex (TSEC)
Manufacturer
Pfizer
(developed in collaboration by Ligand Pharmaceuticals and Wyeth)
Phase III Trial
SMART
Indications
Not approved
Dose
Combination pill once a day
Additional Information
Controls hot flashes
Viviant (bazedoxifene alone) was evaluated for the prevention and treatment of postmenopausal osteoporosis in two large clinical trials. Participants were randomly assigned to take different doses of Viviant, Evista 60 mg, or placebo. This study design allowed direct comparison with the only FDA-approved SERM, Evista, and the study drug. The three-year pivotal fracture trial included approximately 7,500 women and tested 20 mg and 40 mg of Vivant. It was extended for two years without the Evista group for more complete safety information.
More than half of the women had spine fractures at the beginning of the study. The treatment effect was similar for those with and without spine fractures. Evista and the 40 mg dose of Viviant showed the same fracture reduction at the spine (42 percent). The 20 mg dose of Viviant also showed similar fracture reduction at the spine (37 percent). Nonspine fractures were not reduced by any of the medicines. Only an analysis of a higher risk subgroup showed a reduction of nonspine fractures compared with placebo or Evista. Similar to Evista, hot flashes were common side effects of Viviant in about one in ten women. The lining of the uterus (endometrium) did not have a tendency to thicken or develop polyps. Changes in cholesterol were favorable, including increases in good cholesterol. The numbers of strokes and heart attacks were similar in all groups, including the placebo group. Clotting in the legs (deep venous thrombosis) occurred more frequently with Viviant and Evista but was uncommon. The effect of Viviant on breast was neutral.
A two-year prevention study evaluated 10, 20, and 40 mg of Viviant in over 1,400 postmenopausal women with low bone mass (T-score between -1.0 and -2.5 at the femoral neck or lumbar spine). All doses of Viviant and Evista prevented bone loss and had modest gains of less than 2 percent. Bone markers decreased by about 20 percent in all Viviant groups compared to a 27 percent decrease in the Evista group. Overall, Viviant was tolerated well.
The 20 mg dose was approved in Europe in 2009; it is marketed as Conbriza®.
Viviant
(bazedoxifene)
Category
Antiresorptive
Selective Estrogen Receptor Modulator (SERM), also referred to as an
Estrogen Agonist/Antagonist (EAA)
Manufacturer
Pfizer
(developed in collaboration by Ligand Pharmaceuticals and Wyeth)
Pivotal Fracture Trial
Phase III trial for 3 years with 2 year extension
Fracture Reduction
Spine
Nonspine
Indications for Osteoporosis
Not approved
Dose
20 or 40 mg pill once a day
Additional Information
Improves good cholesterol
Does not stimulate the uterine lining
APPROVAL FOR ANY NEW SERMS?
Ten years ago the buzz was designer estrogens. Every pharmaceutical company seemed to have one in development. It looked as if this class of medicines would be a hit for bone and other menopausal health benefits. In early trials, new drugs appeared to be superior to Evista. What a difference a few years make! Evista is still the only choice available. The medicines yet to be approved are all under the Pfizer umbrella, after their acquisition of Wyeth.
Will the FDA ever approve another designer estrogen? Aprela has the best chance. Its unique combination—bone-building effects plus its ability to reduce hot flashes—makes it different. Because it can prevent the undesirable side effects of estrogen in nonbone tissues, it may become a reasonable option for someone with severe menopausal symptoms. Stay tuned.
For now, the perfect SERM remains elusive. There is still room for improvement.
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The Bare Bones
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Other Medicines: Available Elsewhere But Not in the United States
It must be human nature to want something we cannot have. Two bone health medicines fit into that category: strontium ranelate and tibolone. Some patients end up seeking sources for these medicines as alternatives to the current “medicine chest” of FDA-approved drugs for osteoporosis. Strontium ranelate (marketed as Protelos® or Osseor®) and tibolone (brand names Livial® or Xyvion) are available in many other parts of the world. Both have pivotal fracture studies, but neither has been approved for sale in the United States. Strontium ranelate does not even qualify for submissison to the FDA because no US study sites were used in the pivotal fracture trial.
TIBOLONE
The effects of tibolone are similar to combination estrogen and progesterone with a testosterone-like androgen added. Therefore, tibolone has beneficial effect on hot flashes, bone density, and libido (sex drive). The dose used for menopausal symptoms is 2.5 mg a day. Tibolone has no direct biological activity but it is metabolized in the body into active components. These components have different hormonal actions depending on the tissue type. It acts like estrogen in the bone and vaginal tissues, like progesterone in the lining of the womb (endometrium), and like testosterone in the brain.
Tibolone
(Livial or Xyvion)
Category
Both antiresorptive and bone formation
Synthetic steroid
Manufacturer
Organon
Pivotal Fracture Trial
LIFT (using 1.25 mg daily)
stopped early because of strokes
Fracture Reduction
Spine
Nonspine
Indications
Not approved
Dose
2.5 mg pill once a day
Additional Information
Risk of breast cancer and colon cancer reduced by two-thirds
LIFT: Long-Term Intervention on Fractures with Tibolone
Despite widespread use of tibolone, its long-term safety and effects on fracture reduction were not known. The LIFT trial sought to fill the gaps of knowledge about this medicine. More than 4,500 women aged sixty to eighty with low bone density and a spine fracture or osteoporosis by bone density were randomly assigned to tibolone 1.25 mg or placebo pill each day.
The trial was stopped just short of three years because of safety concerns. Women in the tibolone group had an increased risk of stroke. Overall, they were twice as likely to have a stroke. Women over seventy had a fourfold increased risk. Although the numbers of strokes were small, the differences were significant between groups. Interestingly, there was no increased risk of clotting, as is seen with estrogens and SERMs.
Tibolone did reduce spine fractures identified on x-rays by 45 percent and nonspine fractures by 26 percent. Two unexpected findings were that tibolone reduced both breast cancer and colon cancer by two-thirds.
Almost one in ten women had vaginal bleeding. Women in the tibolone group were more likely to have a thickening of the lining of the womb, and four developed endometrial cancer. More women on tibolone stopped taking the study medicine because of vaginal discharge, vaginal bleeding, or breast discomfort.
For these reasons, the benefits of tibolone did not outweigh the risks. Tibolone in half the dose that is used for menopausal symptoms did pass the safety test. Therefore, where approved, tibolone is used in younger post-menopausal women who have a low risk of stroke to treat symptoms of menopause without increasing their risk of breast cancer
STRONTIUM RANELATE
Strontium is a naturally occurring mineral (element number 38 on the periodic table you studied in chemistry). Like calcium, strontium has two positive charges. Your body naturally contains about 320 mg of strontium, most of which is in bone. Strontium can replace calcium in some of its biochemical processes because of the similarity between the two elements. In the bone, strontium accumulates in the active remodeling sites. It is incorporated into the bone mineral and retained in your skeleton. Strontium in the form of various salts has medicinal uses. The compound strontium ranelate is used in other countries for treatment of osteoporosis.
As a medicine, it may have a dual effect on the bone. In animal models, strontium both prevents bone breakdown and stimulates bone formation. However, bone biopsies of women treated with strontium ranelate do not show this dual effect. The biopsies showed less bone breakdown but no evidence of increased bone formation. Bone markers showed only a modest effect on bone metabolism. Bone breakdown decreased by about 10 percent and bone formation decreased by 8 percent.
Using bone density, it is hard to tell if there is an actual increase in bone. Measurements by DXA overestimate the bone density because strontium is denser than calcium. Therefore, much of the bone density effect is a technical artifact due to the replacement of some calcium with strontium. The error in measurement is estimated at 10 percent above the “real” bone density. To get a better estimation of the correct reading, the use of mathematical formulas to adjust the DXA bone density measurements is recommended. However, these calculations are complex and based on multiple assumptions. In addition, because strontium stays in the bones, these adjustments will need to be applied to all future DXA results, even after treatment with strontium ranelate has ended.
Strontium ranelate
(Protelos or Osseor)
Category
Both antiresorptive and bone formation
Mineral
Manufacturer
Servier
Pivotal Fracture Trial
SOTI
TROPOS
Fracture Reduction
Spine
Nonspine
Indications
Not approved
Dose
2 grams in a sachet mixed into water once a day taken at least 2 hours after food, milk products, and calcium supplements
Additional Information
Rare allergic reaction
Two fracture studies have evaluated the effectiveness and safety of strontium ranelate. One was designed to look at spine fractures and the other looked at nonspine fractures. Before subjects were given strontium ranelate, calcium and vitamin D intakes were optimized. This phase was called FIRST (Fracture International Run-in Strontium Ranelate Trial).
After successful completion of FIRST, subjects were randomized to strontium ranelate 2 mg dose daily or placebo. Strontium ranelate comes in a sachet that is mixed in water to form a suspension. Subjects were instructed to drink this suspension as soon as it was prepared. The strontium ranelate suspension cannot be taken at the same time as food or calcium products, such as milk or supplements. The dose is taken at least two hours after eating or consuming these products, usually at bedtime.
SOTI: Spinal Osteoporosis Therapeutic Intervention
The SOTI trial included about 1,600 women with postmenopausal osteoporosis defined either by bone density at the spine or the presence of at least one spine fracture. Almost 90 percent of the participants, average age seventy, had spine fractures at entry. After three years, the reduction of spine fractures identified by x-ray was 38 percent. The study continued, and after four years, the decrease overall was 33 percent for spine fractures.
TROPOS: Treatment of Peripheral Osteoporosis
Only older at-risk women were targeted for this study. Entry criteria limited participation to women older than seventy-four years of age or women older than seventy who also had risk factors and low hip bone density. Over five thousand women participated in TROPOS. After three years, the reduction of nonspine fractures was 16 percent. The numbers of hip fractures were similar in the strontium ranelate and placebo groups.
A later analysis found that a subgroup of women over the age of seventy-four with low bone density (T-score of less than -2.4 at the neck region of the hip) had 36 percent lower risk of hip fracture. Consistent with the SOTI study, spine fractures identified by x-ray decreased 39 percent. However, x-rays were not available for about one-third of the participants. At the end of five years of treatment with strontium ranelate, the nonspine fracture reduction was 15 percent.
The most common side effects were digestive complaints—nausea, loose stools, and diarrhea. These symptoms tend to decrease after three months of use. Mild increases were seen in blood levels of an enzyme found in muscle, but there were no associated symptoms. A small increase in the number of clots in the deep veins was also observed.
After the medicine was approved in other countries, rare severe allergic reactions were reported, which caused several deaths. Patients taking strontium ranelate are advised to discontinue it immediately if any skin reactions appear.
According to my colleagues in other countries who prescribe strontium ranelate, it is reserved for those who could not tolerate bisphosphonates, and for whom tibolone or SERMs are not indicated. Also, it can be challenging to take, since individuals must wait two hours after dinner before they can take it as a drink. Patients often dislike it. Digestive side effects are common; many have to get up during the night to go to the toilet. Some doctors are hesitant to prescribe it both because the mechanism by which it works is still not clear and because it is difficult to measure response by analyzing bone density changes.
The use of other strontium salts is in development. Servier, the French manufacturer of strontium ranelate, has acquired the rights to an investigational drug, strontium malonate, which is also known as NB S101. Unlike the powder form, strontium malonate is in pill form for once-daily use. However, the new formulation does not change the effect strontium has on bone when it replaces calcium.
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The Bare Bones
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