TOP: Trial of the Effect of Recombinant Human Parathyroid Hormone (ALX1-11) on Fracture Incidence in Women With Postmenopausal Osteoporosis

This is an 18-month, double-blind, placebo-controlled, Phase III trial with a 12-month interim analysis of the effect of ALX1-11, recombinant human parathyroid hormone (1-84) (rhPTH [1-84]), on fracture incidence in women with postmenopausal osteoporosis, the TOP study.

Parathyroid hormone (PTH), a polypeptide consisting of 84 amino acids that is synthesized and secreted by the parathyroid glands, is a principal regulator of calcium homeostasis through concerted action on kidney, intestine and bone. Parathyroid hormone exerts its action on bone to release calcium into the extracellular fluid as a process of bone remodeling and also to maintain the serum calcium concentration, but the exact mechanisms are not fully understood. In some circumstances, PTH may exert an anabolic action on bone and can stimulate osteoblast proliferation and mature osteoblast function. The net effect of exogenous PTH administration on bone turnover depends on the pattern of delivery. A continuous long-term infusion gives a net decrease in trabecular bone volume, whereas daily single injections result in a net increase.

NPS Allelix Corp. is developing ALX1-11, recombinant human parathyroid hormone (1-84), for the treatment of osteoporosis. ALX1-11 is identical to the endogenous intact 84 amino acid human hormone and will be self-administered on a daily basis by subcutaneous (sc) injection.

Currently, there is no approved therapy for osteoporosis capable of stimulating the formation of new bone of normal composition and structure. Most therapies in development are anti-catabolic and only prevent further bone loss (e.g., estrogen replacement, bisphosphonates, and calcitonins). ALX1-11 has the potential to stimulate new bone formation in osteoporotic patients, thereby increasing bone mass and preventing fractures. Patients with moderately or severely reduced bone density and a fracture would be expected to benefit from treatment, thereby improving functional status and alleviating symptoms.

Inclusion Criteria:

• Women who are postmenopausal with at least one year since the last menstruation. If a patient's menopausal status at screening is in question, by history or due to the patient having a hysterectomy without oophorectomy, a follicle-stimulating hormone (FSH) level can be obtained after discussion with the Project Medical Officer (PMO). Patients with an FSH > 40 mIU/mL will satisfy the definition of postmenopausal status.

• Women who are 45-54 years of age with the following bone mineral density (BMD) and/or vertebral fracture:

  • BMD 3.0 standard deviations (SDs) or more below peak bone mass of young females at the lumbar spine, femoral neck, or total hip; or
  • BMD 2.5 SDs or more below peak bone mass of young females at the lumbar spine, femoral neck or total hip with the presence of a vertebral fracture verified by the central imaging organization before the patient is enrolled into the study.

• Women 55 or more years of age with the following BMD and/or vertebral fracture:

  • BMD 2.5 SDs or more below peak bone mass of young females at the lumbar spine, femoral neck or total hip; or
  • BMD 2.0 SDs or more below peak bone mass of young females at the lumbar spine, femoral neck or total hip with the presence of a vertebral fracture verified by the central imaging organization before the patient is enrolled into the study.

• The following types of vertebral fractures should not be considered for patient enrollment into this trial:

  • Pathological fractures due to malignant disease or infection
  • Fractures due to excessive trauma sufficient to cause a fracture in young individuals with normal bone mass
• Women with the ability to self-administer a daily injection or have a designee who will give the injections
• Women who are capable of understanding and giving written, voluntary informed consent before the clinical trial screening visit

Exclusion Criteria:

A. Vertebral Deformity:

• Patient has 5 or more vertebral (thoracic and lumbar) deformities
• Patient has 2 or more lumbar vertebral deformities (L1 to L4)
• Severe lumbar scoliosis (>15 degrees) which precludes a reliable evaluation of the dual x-ray absorptiometry (DXA)

B. DXA Imaging:

• Inability to have a DXA scan performed, e.g.:

  • A history of a lumbar laminectomy which interferes with the DXA measurement of the lumbar vertebrae
  • The presence of pedicle screws
  • The patient cannot lay flat on her back for the required time to provide accurate imaging
  • Patient is not able to have an A/P lumbar vertebral DXA performed
  • Patient has a history of vertebroplasty
  • Any other excessive degenerative disease which interferes with the DXA measurement of the lumbar vertebrae or hip.

C. History or Concurrent Illness:

• Disorders of immunity:

  • HIV
  • Significant immunological disorders
  • Possible allergies to the product (ALX 1-11) or its constituents

• Endocrine system:

  • Any history of hyper- or hypoparathyroidism
  • Cushing's disease
  • Hyperthyroidism (within 12 months prior to the screening visit)
  • Significant endocrine disorders

• Gastrointestinal system:

  * Significant gastrointestinal disorders

• Kidney and collecting system:

  • Clinically important history of nephrolithiasis or urolithiasis
  • Current impaired renal function and/or verified kidney calcification
  • Significant renal disorders

• Liver, biliary tract and pancreatic systems:

  • Active hepatitis or pancreatitis
  • Significant hepatic or pancreatic disorders

• Musculoskeletal system:

  * Any history of other metabolic bone diseases within the past 5 years, e.g., Paget´s disease, osteogenesis imperfecta, osteomalacia

• Neoplasia:

  • Any history of bone cancer

  • Any cancer within the previous 5 years, with the exception of squamous or basal cell carcinoma. Patients who have had either squamous or basal cell carcinoma of the skin may enter the screening visits for this study if:

    1. the lesion(s) were fully resected with clear margins described in a written report by a pathologist; and
    2. the patient has had no recurrence of lesions for at least one year from the time of the original resection.

• Nervous system:

  * Significant neurological or psychiatric disease

• Vascular, respiratory and cardiac system:

  * Significant unstable cardiac or pulmonary disease

• Significant diseases or disorders are determined by history, physical exam or laboratory screens and judged by the Principal Investigator to be significant.

D. Concurrent Medication:

Any patient who does not require medication washout (discontinuation) as specified below may start study drug dosing after 2 weeks of stabilization treatment with calcium and vitamin D3 supplements. All exceptions will be documented in the case report form (CRF).

• Patients cannot be enrolled into this clinical trial if they have received any of the following therapies at any time:

  • Any PTH or PTH analogs [e.g., rhPTH(1-84), PTH(1-34), PTHrP and analogs]
  • Fluoride
  • Strontium

• Patients must have been off the following agents for the specified times before entering the screening phase of this clinical trial:

  • Any investigational drug (30 days)
  • Anabolic steroids or androgens (6 consecutive months)
  • Active vitamin D3 metabolites and analogs, e.g., calcitriol (90 days)
  • Systemic corticosteroids, more than 5 mg/day prednisone or a systemic corticosteroid formulation equivalent to 5 mg/day prednisone (12 consecutive months). Steroid use in excess of 5mg/day requires PMO approval and may require consultation with the CAB.

  • A patient who has been enrolled in the study and needs to receive an acute bolus of steroids (oral or injectable) for a self-limited illness may continue treatment in the study if the following requirements are met:

    1. Exposure to steroids is limited to no more than 30 consecutive days
    2. The maximal dose of steroid (prednisone equivalent) is limited to no more than 225 mg (7.5 mg each day for 30 days)
    3. The illness is acute in nature and is not expected to recur during the remaining treatment period of the study
  • Daily inhaled corticosteroids unless dose is below 1200 mg/day of beclomethasone.
  • Bisphosphonates, including investigational bisphosphonates. If the patient has received bisphosphonates for more than 90 days during the 12-month period prior to start of study drug, the patient is excluded from this study. The patient may be enrolled if she: has taken bisphosphonates for greater than or equal to 30 days but less than or equal to 90 days, and completes a washout (i.e., bisphosphonate is discontinued) for an amount of time equivalent to the amount of time that bisphosphonate therapy was received prior to having any screening visit and evaluations performed. No washout is necessary if the patient has taken bisphosphonates for less than 30 days. If the patient has ever received more than 12 months of bisphosphonate therapy, the patient is excluded from this study.
  • Intravenous (IV) pamidronate. Patient must be receiving pamidronate specifically to treat osteoporosis. Patient can have received only ONE IV dose of pamidronate in the 12 months immediately preceding the screening visit. Patient should not have received this one dose within the three months immediately prior to the screening visit. Patient must not have received more than TWO IV doses of pamidronate as treatment at any time.
  • Cyclical etidronate. Exposure to cyclical etidronate must be less than or equal to 6 months on a standard dose (e.g. 400 mg/day). Patient should not have exposure to cyclical etidronate for 9 months prior to the screening visit.
  • Phenytoin for seizure control. If the patient has received phenytoin within five years of the screening visit, the patient is excluded from this study. The patient may continue in the screening process if 15 years have passed since the last dose of phenytoin at the time of the screening visit. If the phenytoin use was between 5-15 years before the screening visit and the patient received phenytoin for less than 2 months.

• Patients may be enrolled if they have been stabilized on the following therapy for the specified amount of time:

  • Thyroid hormone (<0.1 mg/day thyroxine) therapy for at least 6 months. If taking > 0.1 mg/day but < 0.2 mg/day, must have serum thyroid stimulating hormone (TSH) level > 0.1 mU/L. Patients will be excluded if they are taking doses of > 0.2 mg/day. If a patient has had a minimal change in L-thyroxine dose of less than or equal to 0.025 mg/day within 6 months of the screening visit, and has been on this new dose for at least 2 months, she may continue in the screening process for this clinical study. The patient's history with L-thyroxine must be clearly documented in the source documents. If a patient requires an increase in her thyroid replacement dose, after she has been enrolled in this clinical study, each increment should be less than or equal to 0.025mg/day, and increments should not occur more frequently than once per month, as recommended by a physician who is caring for the patient. The patient must have a TSH and T4 level within 3 months of the dose change to ensure that the patient does not become hyperthyroid.
  • Stable dosage of thiazide for at least 3 consecutive months.

• All patients must stop the following therapies at least 4 weeks prior to the screening visit and remain off these therapies for the remainder of the clinical trial. Screening laboratories must be performed after the washout is complete. However, imaging studies (BMD, X-rays) may be performed prior to starting the calcitonin, estrogen, and selective estrogen receptor modulation (SERM) washout.

  • Calcitonin
  • Estrogen replacement therapy by oral, transdermal or intramuscular administration
  • SERM drugs, e.g., tamoxifen, raloxifene, Evista
  • Vaginal application of estrogen-containing creams unless the dose is conjugated estrogen or estradiol: maximum of 0.5 g twice each week (total of 1.0 g weekly); or Estrace (Ogen): maximum of 1.0 g twice each week (total of 2.0 g weekly).
  • Cytostatics, e.g., azathioprine, recombinant human tumor necrosis fusion (Fc) protein, monoclonal antibody against tumor necrosis factor (e.g., remicade [infliximab])
  • The drug class tetracyclines
  • Medication known to affect the metabolism of bone (the Principal Investigator should discuss this with the Project Medical Officer before the patient is excluded from enrollment)

E. Miscellaneous Concurrent Medications:

• Methotrexate - The antimetabolite, methotrexate, which interferes with DNA synthesis, repair and cellular replication should not be used by patients participating in this Phase III study. In general, immunomodulatory agents with antiproliferative activity are not permitted as a concomitant medication in this Phase III study.
• Intra-articular injections - Patients with chronic, active joint disease should be excluded from this Phase III study. Patients may receive a maximum of one intra-articular injection (ONE JOINT ONLY) every 6 months while participating in this Phase III study. The dose of corticosteroid injected should not exceed the anti-inflammatory equivalent dose of prednisone 40 mg suspension. The dose and volume should be adjusted downward as appropriate to the size of the joint.
• Provera is an acceptable concomitant medication when used according to the label instructions.

F. Laboratory Values and Physical Examination Findings:

• Serum calcium greater than 10.7 mg/dL (2.66 mmol/L). At screening, if the serum calcium is abnormal, the patient may have the additional evaluation described below ONCE:

  1. Discontinue all oral calcium and vitamin D3 supplements.
  2. Repeat a fasting serum calcium level two weeks later.
  3. If the fasting serum calcium level is still abnormal, the patient is discontinued from the study.
  4. If the repeat fasting serum calcium is normal, the patient should have supplemental calcium and vitamin D3 restarted at the time of study drug dosing, without going through a two-week stabilization period.
• Serum creatinine > 1.5 mg/dL (132.6 mmol/L)

• Urinary calcium to creatinine ratio is greater than or equal to 1. At screening, if a patient's urinary calcium to creatinine ratio is abnormal, the patient may have the additional evaluation described below ONCE:

  1. Discontinue all oral calcium and vitamin D3 supplements.
  2. Repeat a fasting urine calcium to creatinine ratio two weeks later.
  3. If the fasting urinary calcium to creatinine ratio is still abnormal, the patient is discontinued from the study.
  4. If the repeat fasting urinary calcium to creatinine ratio is normal, the patient should have supplemental calcium and vitamin D3 restarted at the time of study drug dosing, without going through a two-week stabilization period.
• Total serum alkaline phosphatase >130 U/L except as noted - Argentina (311 U/L); Brazil (278 U/L); Mexico (159 U/L).
• Any other clinically significant abnormal value as judged by the investigator
• Body weight below 40 kg

G. Substance Abuse:

• Alcohol and/or drug abuse

H. Psychiatric Disease:

• Current or history of psychiatric disease that would interfere with the ability to comply with the clinical trial protocol

I. Compliance:

• Suspected or confirmed poor compliance in completing clinical trial evaluations and/or clinical trial required questionnaires