US is first to approve PTH ‹ Lilly's teriparatide

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Nov 28, 2002

US is first to approve PTH ‹ Lilly's teriparatide

Rockville, MD - The US FDA has finally approved teriparatide (Forteo®;

Lilly), for the treatment of osteoporosis in postmenopausal women who are at

high risk for having a fracture. This is the first approval of a parathyroid

hormone product anywhere in the world (teriparatide is awaiting approval in

the European Union).

However, the indication in the USwhich also includes men with primary or

hypogonadal osteoporosis at high risk of fractureis narrower than the

company had hoped for.

The FDA notes that teriparatide is the first agent approved for the

treatment of osteoporosis that stimulates new bone formation. It will be

supplied in a disposable pen device that can be used for up to 28 days, and

is administered once a day by subcutaneous injection in the thigh or

abdomen, at a recommended dose of 20 µg and at a cost of $20 US per day

wholesale (according to Dow Newswire). Forteo should be taken for a

period of up to 24 months, Lilly says, noting that the approval is based on

24 clinical trials involving more than 2800 postmenopausal women and men,

including a pivotal Phase III study published in the New England Journal of

Medicine in May 2001 [1].

Dr Felcia Cosman (US National Osteoporosis Foundation) told ABC News:

" [Teriparatide] dramatically increases bone density. It increases the

diameter of bone and it reconnects the disconnected pieces of bone. " Dr

(FDA division of metabolic and endocrine drug products) commented to

Associated Press: " We feel this is an important drug. It is the first

approved that stimulates bone formation instead of slowing the breakdown of

bone. "

Approval delayed due to manufacturing problems and label negotiations

An FDA advisory committee recommended teriparatide for approval more than a

year ago, in July 2001, but approval was delayed because of problems with

Lilly's manufacturing plant in Indianapolis. Safety concerns were also

raised at the advisory committee meetingthe experts were worried about

osteosarcomas that developed in large numbers of test rodents. Although no

osteosarcomas were reported in the human studies, the FDA says, " the

possibility that humans treated with teriparatide may face an increased risk

of developing this cancer cannot be ruled out. " The agency has thus required

that the product carry a black box warning in the label for health

professionals and that this safety issue is explained in a " Medication

Guide " for patients.

The advisory committee was also worried about the duration of clinical

trials. Although originally planned to last 3 years, the trials were cut

short when the rodent tumors were discovered. Thus, the median duration of

the postmenopausal women studies was 19 months; median exposure for men was

11 months. Noting this shortened testing period, as well as the osteosarcoma

question, only 4 committee members recommended the drug for first-line

therapy; 5 felt it should be reserved for second-line therapy. The panel was

also less than enthusiastic about the use of teriparatide by men with

idiopathic or hypogonadal osteoporosis.

Hence the narrow indication approved by the FDA: those who will qualify for

treatment are patients with a history of osteoporosis-related fracture, or

who have multiple risk factors for fracture, or who have failed or are

intolerant to previous osteoporosis therapy, based upon physician

assessment. The agency seems to have overlooked the concerns of its advisory

panel with regard to men.

Prospective studies of fracture rates at different sites needed

In a review of parathyroid hormone treatment of osteoporosis published

recently in the Archives of Internal Medicine [2], Dr Caroline Crandall

(UCLA School of Medicine, Los Angeles, CA), raised some unresolved issues

about the therapy.

She searched MEDLINE and the Cochrane database and retrieved 20 randomized

controlled trials of PTH in humans. Anti-fracture efficacy is the single

most critical efficacy outcome for osteoporosis treatment, and fracture

reduction data " are not robust for PTH, especially at nonvertebral sites, "

she noted. Although PTH decreases vertebral fractures and increases spinal

bone density in women with postmenopausal osteoporosis and in those with

glucocorticoid-induced osteoporosis, it does so " at the expense of a

decrease in radius bone density. "

Crandall explains that there are 2 main types of bonecortical and trabecular

bone. The peripheral skeleton is predominantly cortical bone but the axial

skeleton (eg the spine) is a combination of cortical and trabecular bone.

Metabolism and rates of bone loss differ in the 2 types of bone, and

diseases often differentially affect the 2 types. " The suggestion in several

studies of a decrease in radius bone mineral density (BMD) in association

with PTH use parallels the recognized differing effects of

hyperparathyroidism on trabecular versus cortical bone, " she said. Thus, " we

need to directly determine fracture rates site by site in prospective

studies [of PTH] with adequate statistical power. "

No increased cancer risk seen in humans so far

Crandall noted that treatment with PTH should be restricted to less than 2

years " given the lack of long-term safety and efficacy data, " and that PTH

treatment should be followed by antiresorptive therapy " with the goal of

maintaining BMD gains. " Because of this uncertainty regarding long-term PTH

effects, " optimal duration of therapy is not clear. " Also, it has taken up

to 12 months after stopping PTH therapy for maximal anabolic effects to

manifest at the hip, she notes. However, on a positive note, she says that

although concerns have been raised from animal research " published trial

results indicate that cancer risk is not increased by PTH use in humans. "

Another area that may prove problematic is the route of administration of

PTH, Crandall believes. Although a few studies supported the intranasal

route of PTH administration, most data available refer to the subcutaneous

route. But this " is associated with decreased compliance, " she notes,

particularly in older patients who " may have difficulty with injections. "

At the recent American Society of Bone and Mineral Research meeting, it was

suggested that once-weekly injections of PTH may offer the same therapeutic

effect as once-daily subcutaneous injections. This may address some of the

concerns about compliance, and also over the cost of the therapy. However,

the researchers exploring this approachDr Dennis Black (University of

California San Francisco) and Dr Clifford Rosen (Maine Center for

Osteoporosis, Bangor, ME)stressed that this is still a hypothesis until they

can compare the 2 dosing schedules in a head-to-head clinical trial. They

are currently applying to the NIH for funding to perform such a study.

Other issues that require further investigation are the use of PTH in

combination with other therapies, such as the bisphosphonates, Crandall

concludes.

Nainggolan

Sources

1. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone

(1-34) on fractures and bone mineral density in postmenopausal women with

osteoporosis. N Engl J Med 2001;344:1434-41.

2. Crandall C. Parathyroid hormone for treatment of osteoporosis. Arch

Intern Med 2002;162:2297-2309.