Status: approved; marketed

Organizations involved:

Lilly, Eli & Co. – R&D; Tech.; World mark.

Lilly France S.A. – Manuf.

Cross ref.: See also the entry below for Preos containing full-length recombinant parathyroid hormone.

Description: Fortéo is an aqueous formulation of recombinant teriparatide or human parathyroid hormone (1-34), the amino acid sequence 1-34 of the 84 amino acid full-length human parathyroid hormone (hPTH), expressed by Escherichia coli (E. coli) bacteria. This peptide has a sequence identical to the 34 N-terminal amino acids (a biologically active region) of endogenous hPTH. Teriparatide has a molecular weight of 4117.8 Daltons (4.1178 kDa), and the amino acid sequence H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Phe-Asn-Phe-OH.

Teriparatide has been shown to be an effective anabolic, bone formation agent for treatment of osteoporosis in postmenopausal women and men. Teriparatide is the first approved agent for the treatment of osteoporosis that stimulates new bone formation.

Synthetic teriparatide, rather than recombinant teriparatide, was used in most of the clinical and animal studies of parathyroid hormone (1-34) reported in the literature. With such a molecule (small, linear, not glycosylated, not cross-linked, not folded) , there have been negligible or no concerns that the synthetic and recombinant versions of the same molecule exhibit different activity or bioavailability. There are no amino acid substitutions or chemical modifications, and recombinant teriparatide essentially differs from synthetic human PTH(1-34) only in its method of production and purification. Thus, for essentially all practical (not regulatory) purposes, synthetic and recombinant teriparatide may be considered generic equivalents.

Fortéo is packaged as a sterile isotonic solution in a glass cartridge which is pre-assembled into a disposable pen device for subcutaneous injection. Each prefilled delivery device is filled with 3.3 mL to assure delivery of 3 mL. Each mL contains 250 µg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.10 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3.0 mg metacresol, in Water for Injection. Hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may be added to adjust the product to pH 4. Each cartridge pre-assembled into a pen device delivers 20 µg of teriparatide per dose per day for up to 28-days. Fortéo is stored at 2-8°C (refrigerated).

A biogeneric version (copy) of Forteo was launched in Aug. 2008 in India by Ranbaxy Laboratories Ltd., acquired by Daiichi Sankyo in mid-2008, in collaboration with Virchow Biotech Pvt Ltd., under the trade name Bonista for treatment of osteoporosis. With this, Ranbaxy/Virchow became the first worldwide to market a biogeneric version of Forteo.The Dep.t of Science and Technology, India, assisted in development.

Nomenclature: parathyroid hormone (1-34), rDNA [BIO]; teriparatide (rDNA origin) [FDA]; Fortéo [TR; pronounced for-TAY-o]; Bonista [TR in India; assigned to Ranbaxy Labs.]; LY333334 [SY]; parathyroid hormone (1-34), recombinant [SY]; PTH [SY]; Forteo [SY; commonly used in place of trademark]; Forsteo [TR in Europe]; rhPTH(1-34) [SY]; NDC 0002-8971-01 [NDC]

Biological.: Human parathyroid hormone (hPTH) is a key regulator of calcium homeostasis. The hormone is produced as a 115 amino-acid prepro-peptide. Before secretion, the prepro peptide poriton is cleaved off, yielding the mature 84 amino acid hormone (hPTH). Through its action on target cells in bone and kidney tubuli, teriparatide, whether human or recombinant, increases serum calcium and decreases serum phosphate, and decreases urinary excretion of calcium and phosphate.

Teriparatide is equivalent to the active portion 34 amino acid N-terminal portion of endogenous 84-amino-acid PTH, while Preos [rhPTH (1-84); see related entry] contains the full 84 amino acids of hPTH. Unlike therapeutics previously available for the prevention and treatment of osteoporosis, all of which slow bone destruction by reducing the activity of osteoclasts, Fortéo (and Preos) work by inducing hyperparathyroidism, which increases the number of bone-forming osteoblasts. Daily injections stimulate new bone formation leading to increased bone mineral density and bone strength. Once daily subcutaneous injection of teriparatide stimulates osteoblasts to synthesize new bone on trabecular, endocortical, and periosteal surfaces.

hPTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH (and teriparatide) include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of hPTH [and and rhPTH (1-34) and rhPTH (1-84)] are mediated through binding to specific high-affinity cell-surface receptors. hPTH, teriparatide [rhPTH (1-34)], and rhPTH (1-84) (active agent in Preos) bind to cellular PTH receptors with much the same affinity and have the same physiological actions on bone and kidney. The biologic activity of teriparatide is very similar or identical to synthetic human PTH(1-34) in most in vitro and in vivo assays. Teriparatide [and rhPTH (1-84] does not accumulate in bone or other tissues. Both rhPTH (1-34) and rhPTH (1-84) have much the same effects on bone tissues in rats. As discussed in the Preos [rhPTH (1-84)] entry below, its manufacturer notes differences in biological effects between rhPTH (1-34) and rhPTH (1-84), with the full-length hormone increasing osteoclast apoptosis, unlike rhPTH (1-34) and other PTH analogs lacking the N-terminal amino acid sequence.

The skeletal effects of teriparatide [and rhPTH (1-84)] depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide are manifested as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. Continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation.

The nonclinical development program for teriparatide consisted of acute and chronic studies conducted in rodents, rabbits, and monkeys. Teriparatide increased bone mass and resistance to fracture (bone strength), and improved skeletal architecture (e.g., cortical thickness and trabecular connectivity, number, thickness, and volume) in rats, monkeys, and rabbits. These effects resulted from activation of osteoblasts, which increased apposition of new bone at trabecular, endocortical, and periosteal surfaces, with minimal effect on bone resorption. Increases in trabecular bone mass did not occur at the expense of cortical bone. In short- and long-term studies in species that have cortical remodeling (monkeys and rabbits), teriparatide increased cortical bone thickness and had beneficial effects on cortical bone strength in parallel with an increase in haversian remodeling. In ovariectomized monkeys administered doses of 1 or 5 µg/kg/day for 18 months, teriparatide increased bone mineral density (BMD) and resistance to fracture of the proximal femur (hip) and vertebra, increased bone formation with normal mineralization, and improved bone architecture. Increased trabecular connectivity was observed at all trabecular bone sites examined. No abnormal bone was observed.

Teriparatide caused osteosarcoma in a dose-dependent manner in a two-year rat study. About half of the male rats and a third of the female rats developed and died of this bone cancer at the highest dose (75 mg/kg per day) after near-lifetime treatment. About 5% of the rats of both sexes developed bone cancer at the lowest dose (5 m g/kg per day). Lilly’s recommended human dose for Forteo is 20 mg/day. At the time (Dec. 1998), Lilly halted all ongoing clinical studies, and reported, “After extensive discussions with external experts and the FDA, these findings in rats were considered unlikely to be predictive of an increased risk of skeletal neoplasms in humans treated with teriparatide because of important differences between the rat carcinogenicity model and the intended clinical use of teriparatide in the treatment of osteoporosis.” Lilly reported that no patient in its clinical trials and none of the monkeys in a simian trial developed osteosarcoma. The prolonged exposure of the rats to teriparatide started at a young age, unlike the drug’s short-term use in older people in a therapeutic setting, and teriparatide is not a considered a carcinogen based on standard laboratory tests. Osteosarcoma in humans is a serious but very rare cancer, occurring in about 4/1,000,000 adults each year. It is not yet known, if humans treated with Forteo have a higher risk for osteosarcoma.

Companies.: Teriparatide was developed and is marketed worldwide by Eli Lilly & Co. It is manufactured by Lilly France S.A. (Fegersheim, France).

FDA class: Drug NDA

Approvals: Date = 20021126; NDA 21-318

Date = 20040602; NDA supplement; Indication = insert/labeling changes concerning the Pen administration devic

Date = 20090228; NDA supplement; Indications: = revisions to the Post-Marketing Reports Subsection of the Adverse Events Section of the product insert/lableing to include muscle spasms of the leg and back.

Date = 20090722; NDA supplement; Indication = treat glucocorticoid-induced osteoporosis (GIO) in adult patients at high risk for fracture

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling; 10/2010]:

1.1     Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture

FORTEO is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, FORTEO reduces the risk of vertebral and nonvertebral fractures [see Clinical Studies].

1.2     Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture

FORTEO is indicated to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy [see Clinical Studies].

1.3     Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture

FORTEO is indicated for the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy [see Clinical Studies].

Status: On Oct. 9, 2003, Lilly received European Union approval for Forsteo for treatment of treat osteoporosis in postmenopausal women at high risk of a fracture. In 2007, the EU granted approval for the treatment of osteoporosis in men at increased risk for fracture.

On Nov. 25, 2002, Forteo received FDA approval. The Forteo label has included a boxed warning concerning the potential risk of osteosarcoma (bone cancer) since its approval.

In Feb. and June 2007, Lilly filed applications with the FDA and EMEA/EU, respectively, for a supplemental indication for teriparatide for the treatment of men and women with osteoporosis associated with glucocorticoid therapy and who are at high risk for fracture. Chronic glucocorticoid therapy is the most common cause of secondary osteoporosis.

On April 5, 2008, the European Union granted supplemental approval for the treatment of osteoporosis associated with sustained, systemic glucocorticoid therapy in women and men at increased risk for fracture.

In June 2008, received FDA approval for a new Forteo delivery device in the U.S. The device was designed specifically for Forteo patients to help them self-administer their treatment on a day-to-day basis. In Oct. 2008, Lilly launched the product.

On July 22, 2009, FDA approved a new indication for Forteo, treatment of glucocorticoid-induced osteoporosis (GIO) in adult patients at high risk for fracture. Because patients with GIO may be younger than those currently receiving Forteo, the language in the boxed warning has been updated to emphasize that Forteo should not be used in pediatric and young adult patients with open epiphyses (developing bone). Also, a voluntary Forteo Patient Registry was implemented to collect information about the possible risk of osteosarcoma in patients who have taken Forteo..

Tech. transfer: The Orange Book reports 6,770,623, "Stabilized teriparatide solutions," expiring Dec 8, 2018; 6,977,077, "Method of increasing bone toughness and stiffness and reducing fractures," expiring Aug 19, 2019; 7,144,861, "Stabilized teriparatide solutions," expiring Dec 8, 2018; 7,163,684, "Method of increasing bone toughness and stiffness and reducing fractures," expiring Aug 19, 2019; 7,351,414, Method of reducing the risk of bone fracture," expiring Aug 19, 2019 and; 7,550,434, "Stabilized teriparatide solutions," expiring Dec 8, 2018,

Despite the multiple patents claimed by Lilly as relevant (reported in the Orange Book), it is commonly reported that recombinant parathyroid hormone, presumably PTH(1-34), is now off-patent. No U.S. patents assigned to Lilly or others were found concerning teriparatide’s sequence or recombinant E. coli manufacture.

EP 1059933 B1, "METHOD OF INCREASING BONE TOUGHNESS AND STIFFNESS AND REDUCING FRACTURES, assigned to Lilly, expires in 2019.

In April 2006, in the case of Eli Lilly & Co. vs. Emisphere Technologies, Inc., a U.S. District Court judge ruled that Lilly does not have any rights to a patent application it filed concerning oral delivery of PTH and other drugs. Lilly had an option to exclusively license this technology from Emisphere, but breached its contract by setting up its own “secret” R&D team and filing its own patent application on the same technology and refusing to assign ownership to Emisphere for technology ruled to be covered by the companies’ licensing agreement. In Sept. 2008, Lilly and Emisphere settled their dispute. Terms were not disclosed.

Disease: An estimated 10 million persons in the U.S., 80% women and mostly elderly, have osteoporosis. Osteoporosis is a disease in which the bones become thin and weak, increasing the chance of bone fracture. Osteoporosis usually causes no symptoms until a bone fracture happens. The most common fractures are in the spine (backbone), which can shorten height and without causing pain. Over time, the spine can become curved or deformed and the body bent forward (which can be readily observed in some elderly women). Fractures from osteoporosis can also happen in almost any bone in the body, for example, the wrist, rib, or hip. Once someone has a fracture, the risk for more fractures greatly increases.

Currently available osteoporosis medications, such as bisphosphonates (Fosamax; Actonel), are antiresorptives that work to slow or stop bone loss by reducing the number and limiting the action of bone-removing cells (osteoclasts). In contrast, Forteo increases the number and stimulates the action of bone-forming osteoblasts.

Each year, osteoporosis leads to more than 1.5 million fractures in the U.S. alone, resulting in direct medical costs of $17 billion. This is comparable to the direct costs of other chronic conditions, e.g., asthma and congestive heart failure. Although the risks and costs associated with osteoporosis are significant, less than 50% of the prevalent population is diagnosed. This low diagnosis rate is partially due to the perception that osteoporosis is a normal consequence of aging, and is not a preventable or treatable disease. Forteo and other bone-forming agents are expected to shift this paradigm.

Trials: The clinical program for teriparatide consisted of 25 clinical studies (16 Phase 1, 1 Phase II, and 8 Phase III) enrolling over 2,800 men and postmenopausal women. The four Phase III studies of greater than 1-year duration enrolled 2,030 postmenopausal women and 437 men.

Drugs approved to treat osteoporosis must be shown to preserve or increase bone density and maintain bone quality. The effects of teriparatide on bone mineral density and fractures were studied in 1,637 postmenopausal women with osteoporosis treated for a median time of 19-months, and 437 men with primary or hypogonadal osteoporosis treated for 10 months. Patients treated with 20 µg/day of teriparatide (approved dosage), along with calcium and vitamin D supplements, had statistically significant increases in bone mineral density (BMD) at the spine and hip, compared to patients taking placebo plus supplements. Forteo reduced the relative risk of spinal fractures by 65%, and lowered the relative risk of nonspinal fractures overall by 53%. Forteo also significantly increased spine BMD in postmenopausal women with osteoporosis beginning at 3 months of treatment, with 96% increasing from baseline, 72% achieving at least a 5% increase in spine BMD, and 44% gaining 10% or more, compared with placebo. The effects of teriparatide on fracture risk have not been studied in men. Most side effects with teriparatide were mild and included nausea, dizziness, and leg cramps. Early discontinuation due to adverse events occurred in 5.6% of patients assigned to placebo and 7.1% of patients taking teriparatide. The primary pivotal Phase III clinical trial was reported in the New England Journal of Medicine (May 10, 2001).

In Aug. 2005, results from a double-blind, head-to-head study comparing Forteo to Fosamax (alendronate from Merck) in 203 post-menopausal women were published in the Archives of Internal Medicine. Both therapies increased bone mineral density (BMD), but by different mechanisms, with Forteo increasing BMD by increasing the rate of new bone formation, and Fosamax preventing bone loss. Once-daily 20 g Forteo injection increased volumetric spine BMD by 19%, while 10 mg/day Fosamax increased volumetric spine BMD by 3.8%. At 18 months, areal spine BMD, areal BMD at the femoral neck and femoral neck trabecular BMD also increased better in Forteo patients compared to Fosamax patients. How ever, cortical bone density at the femoral neck increased 7.7% in patients receiving Fosamax compared to only 1.2% in patients taking Forteo. These findings will expand the market for Forteo, particularly if confirmed by other studies and clinical experience.

Clinical trials supporting the EU approval for glucocorticoid-induced osteoporosis (GIOP) were published in the Nov. 14, 2007 issue of the New England Journal of Medicine. The "Teriparatide or Alendronate in Glucocorticoid-Induced Osteoporosis" head-to-head comparative study showed that in patients with glucocorticoid-induced osteoporosis, teriparatide significantly increased lumbar spine bone mineral density (BMD) from baseline (8.2%) compared to alendronate (3.9%) at 18 months of therapy. In this double-blind, active comparator-controlled trial, 428 patients with glucocorticoid-induced osteoporosis were randomized to receive once-daily subcutaneous injections of teriparatide (20 µg) plus oral placebo or daily placebo injections plus once-daily oral alendronate (10 mg). The increase in lumbar spine BMD was significantly greater in patients receiving teriparatide compared with alendronate at 6, 12, and 18 months of treatment (p < 0.001 at all time points). This trial is continuing for another 18 months.

Disease: Glucocorticoid-induced osteoporosis (GIOP) is bone loss associated with chronic use of glucocorticoid medications. These medications are often prescribed for inflammatory conditions, such as rheumatoid arthritis and obstructive pulmonary disease. Globally, an estimated 1-3% of adults over the age of 50 use glucocorticoids. Up to 50% of individuals on chronic glucocorticoid therapy will develop bone loss leading to an osteoporotic fracture. Tteriparatide provides physicians and patients with a new treatment option that builds bone.

Medical: Teriparatide, 20 µg, is administered, usually self-administered, by injection once a day into the thigh or abdomen. Forteo is approved for use in both men and postmenopausal women with osteoporosis who are at high risk for having fractures. Forteo can be used by people who have had a fracture related to osteoporosis, or who have multiple risk factors for fracture.

The issue of carcinogenicity in rats is highlighted in a black box warning on the drug’s labeling for health professionals and explained in the Medication Guide (for patients). The insert warns that “teriparatide should be prescribed only to patients for whom the potential benefits are considered to outweigh the potential risk.” The risk of bone cancer from Forteo is currently not known. At the worst, the increase in risk would presumably be low (as observed in the product’s clinical trials), and there may well be no associated detectable increase in osteosarcoma or other cancer in the elderly population treated for osteoporosis (with carcinogen exposure typically requiring well over a decade to result in human cancer). Because people with growing bones (i.e., children and adolescents) and people with Paget’s disease of the bone have a higher risk for developing osteosarcoma, they should not be treated with teriparatide. Because the effects of long-term treatment with teriparatide are not known at this time, therapy for more than two years is not recommended.

Market: Total worldwide sales were $949.8 million in 2011; $830.1 million in 201; $816.7 million in 2009; $779 million in 2008; $664 million in 2007; $594.3 million in 2006; $389.3 million in 2005, $238.6 million in 2004, and $65.3 million in 2003.

The 2007 Average Wholesale Price (AWP) is $766.99 per 250 µg/mL, 3 mL vial (Red Book, 2007). The AWP was $629.17 in 2005, and $599.20 in 2004. Presuming one can get 12, 20 µg doses from each vial, each dose costs about $64.

Treatment with Forteo has been reported to typically cost about $6,700/year.

Blockbuster (>$1 billion/year) sales have been projected by some analysts, despite Forteo being used only by those with severe disease and requiring daily injection by the user. In Feb. 2003, a Decision Resources, Inc. study projected Forteo will command premium pricing; sales could reach $2 billion in 2011; and that Forteo will play a major role in driving growth in the osteoporosis market. The prevalent osteoporosis population was projected to grow from $46 million in 2001 to ~$57 million in 2011 as the post-WWII generation (baby boomers) expand the pool of elderly. More conservatively, in Sept. 2005, Bear Stearns projected sales would reach $750 million or more, presuming Lilly secures broader labeling/indications:.

Emisphere Technologies, which is developing oral PTH(1-34) in collaboration with Lilly (see below), estimates the market potential for PTH to be over $1.7 billion. Nastech, which is developing intranasal PTH in collaboration with Proctor & Gamble (see below), has projected Forteo sales will reach $800 million by 2008.

In July 2006, a study in the Archives of Internal Medicine evaluated the cost-benefits of Forteo and concluded that Forteo was “not a rational choice” for treatment of osteoporosis. The study, based on a computer simulation of over 200,000 women with post-menopausal osteoporosis, was funded by the Agency for Healthcare Research & Quality, Department of Veterans Affair. Forteo would be considered cost-effective, if it were 60% cheaper and used second-line after treatment with Fosamax (alendronate) from Merck. Cost-effectiveness for sequential Forteo/Fosamax would be “less than $50,000 per [quality-adjusted life-year] if the price of teriparatide decreased 60%,” Fosamax, at an average wholesale price of about $900 per year, compared favorably to other osteoporosis interventions, including Forteo, with an AWP of around $6,700 annually. The study recommended against use of Forteo for first-line treatment of osteoporosis.

Competition: Fortéo competes with Preos [parathyroid hormone (1-84); see related entry], calcitonin products (e.g., Fortical; see related entry) and oral bisphosphonates pills, including Merck & Co.’s Fosamax (aldronate) and Procter & Gamble Co.’s Actonel. Fortéo may be used in combinations with Fosamax and other bisphosphonates, a significant advantage over Preos (not yet approved; see entry below). With few, if any, anabolic hormones, other than Preos, in later stages of development for osteoporosis, Fortéo is expected to have little direct competition, other than Preos, in this class for at least several years.

Many analysts expect pressure to reduce the price of Forteo, particularly after Fosamax loses patent protection in 2009 (with generic versions of Fosamax)

In Sept. 2007, Ranbaxy Laboratories launched Bonista, a biogeneric brand of teriparatide, in India. Bonista was developed by Virchow Biotech Pvt Ltd with the aid of the Department of Science and Technology, India.

Ongoing: Eli Lilly & Co. had been collaborating with Emisphere Technologies, Inc. for the development of orally administered PTH(1-34) using Emisphere’s eligen synthetic carrier technology. However, in Jan. 2006, a federal court ruled that Emisphere could terminate this arrangement due to breach of contract. Lilly was ruled to have breached its contract by using Emisphere’s eligen technology outside of PTH; refusing to assign to Emisphere rights to inventions using its technology; and disclosing confidential information to Lilly personnel not involved in the PTH deal. The collaborators had tested a product in Phase I trial(s). In March 2006, Novartis AG exercised an option to license Eligen delivery technology from Emisphere Technologies Inc. for oral parathyroid hormone and assumed development of the PTH therapeutic. In Sept. 2007, Lilly and Emisphere settled their dispute, with Lilly paying Emisphere $18 million.

In Jan. 2006, having lost its collaboration with Emisphere, Lilly formed a collaboration with Alkermes, Inc. for develop and commercialization of inhaled formulations of PTH(1-34) using Alkermes’ AIR pulmonary drug delivery system. Alkermes receives funding for product and process development activities, as well as upfront and milestone payments. Lilly has exclusive worldwide rights and will pay Alkermes royalties based on product sales.

Lilly has also been reported to be considering also developing oral PTH(1-34) using another delivery technology (not Emisphere’s eligen).

R&D: Unigene Labs. has been developing oral recombinant E. coli-expressed parathyroid hormone. Worldwide development and marketing rights were granted to GlaxoSmithKline (GSK) in April 2002, and GSK is continuing its active development. This includes paying Unigene $150 million in upfront and milestone payments during the course of development, with GSK paying all development costs, including manufacture of bulk PTH by Unigene (which uses its own E. coli expression technology), plus royalties on eventual sales of the marketed product. Promising results from a Phase I trial were reported in Oct. 2004.

Theratechnologies Inc. is collaborating ALZA Corp. for development of ThPTH, a transdermal formulation of recombinant PTH. In May 2003, positive results were reported from a Phase I clinical trial. ThPTH uses ALZA’s Macroflux technology, involving a thin titanium screen with precision microprojections that creates superficial pathways through the skin’s outer layer.

In Jan. 2005, Manhattan Pharmaceuticals Inc. acquired Tarpan Therapeutics Inc., which had recently completed a Phase I trial with PTH 1-34 (or a peptide analog) for treatment of psoriasis. Manhattan began a began a double-blind, placebo-controlled U.S. Phase IIa trial in 40 patients in Dec. 2005.

In Feb. 2006, Procter & Gamble Pharmaceuticals Inc. linked with Nastech Pharmaceutical Co. to develop Nastech’s PTH(1-34) nasal spray for osteoporosis, then in Phase III trials. P&G was responsible for further development and marketing. Nastech received $10 million up front and is eligible for up to $567 million in development, regulatory and sales milestones plus royalties over 10%. P&G currently markets Actonel for osteoporosis with $1.7 billion/year in sales. P&G had exclusive worldwide rights. In Sept. 2005, an open-label, crossover, active-control Phase I trial in12 healthy volunteers showed that intranasal PTH(1-34) was well tolerated and had a pharmacokinetic profile similar to Forteo. In June 2006, P&G and Nastech concluded an agreement for Nastech to manufacture the product. In Nov. 2007, BMS withdrew from its development agreement, with Nastech purchasing all rights held by BMS.