Boniva I.V. Once-Quarterly Safety Concerns Few, But Renal Tests Advised

Roche/GlaxoSmithKline's once-quarterly osteoporosis therapy Boniva injection does not present serious safety concerns compared with oral bisphosphonates, labeling for the I.V. formulation of the drug suggests.

The injectable ibandronate carries warnings similar to the oral forms of Boniva, with the exception of an enhanced precaution on renal impairment and hypocalcemia. The product also lacks the gastrointestinal precautions of oral bisphosphonates.

While oral ibandronate only cautions against treating patients who have severe renal impairment, labeling for the new product states that "patients who receive Boniva injection should have serum creatinine measured prior to each dosage administration."

Physicians should also pay attention to patients with diseases that adversely affect the kidneys or who are taking concomitant drugs with renal side effects.

"Treatment with intravenous bisphosphonates has been associated with renal toxicity manifested as deterioration of renal function and in rare cases, acute renal failure," labeling states. However, "no cases of acute renal failure were observed in controlled clinical trials" of Boniva injection.

Boniva injection was approved Jan. 6 as the first I.V. treatment for postmenopausal osteoporosis.

Injectable ibandronate requires one 15-30 second intravenous administration by a healthcare professional every three months. Boniva is also approved in once-monthly and once-daily tablet forms.

Dosing convenience has been an issue for bisphosphonates. Once-daily Boniva tablets were approved in 2003, but Roche and GSK postponed the launch until they could offer a less-frequent dosing regimen. Once-monthly Boniva was approved in March.

Because of the time interval between dosing with once-monthly Boniva tablets, Roche and GSK established a reminder program, in which patients are notified by phone, email or mail that it is time to take the next dose (¹ (Also see "Roche/GSK Boniva Launch Plan Includes Reminders For Once-Monthly Dose" - Pink Sheet, 4 Apr, 2005.), p. 4).

The firms have not yet said whether they will establish a similar program for Boniva injection. However, they noted that because Boniva injection is administered by a healthcare professional, "clinicians will have a greater awareness of patient compliance with therapy."

Roche noted that a survey presented at the American Society for Bone & Mineral Research in December found that two out of three women said they preferred the once-monthly oral Boniva to once-weekly competitors, Merck's Fosamax (alendronate) and Procter & Gamble/Sanofi-Aventis' Actonel (risedronate).

Since its April 2005 launch, Boniva has taken a roughly 10% share of the bisphosphonate market, Roche said Jan. 12.

Novartis is developing a once-yearly injectable dosage form of zoledronic acid ( Zometa for bone metastases) that will be marketed as Aclasta for osteoporosis and Paget's disease. An NDA filing for osteoporosis is planned for 2007; the compound was deemed "approvable" for Paget's disease in July 2005 (² (Also see "Novartis Sticks With Heart Of Pipeline: Growth Is In Cardio-Metabolic Sector" - Pink Sheet, 26 Sep, 2005.), p. 22).

Amgen is developing twice-yearly bone resorption inhibitor AMG 162 for osteoporosis. In July, Amgen announced that submission of an NDA for the product would be postponed to 2008 in order to acquire three years of pivotal data as required by FDA.

Boniva injection enjoys fewer contraindications than oral bisphosphonates: it is contraindicated only for patients with known hypersensitivity to Boniva or uncorrected hypocalcemia, while the tablets are also contraindicated for patients who are unable to stand or sit upright for at least 60 minutes.

The therapy "will provide an alternative for patients who have difficulty with oral bisphosphonate dosing requirements," the firms said.

Boniva injection does not carry the warnings of the tablet formulations regarding upper gastrointestinal adverse events such as dysphagia, esophagitis and esophageal and gastric ulcer.

The new product does carry a warning on hypocalcemia. Boniva, "like other bisphosphonates administered intravenously, may cause a transient decrease in serum calcium values." The section adds that Boniva injection must be administered intravenously. Boniva injection's precaution on mineral metabolism is otherwise similar to oral products.

Another concern with injectable bisphosphonates is the risk of jaw osteonecrosis. However, Boniva injection carries a similar precaution as that added to all bisphosphonate products at the request of FDA (³ (Also see "Boniva Labeling Reflects Class Osteonecrosis, Musculoskeletal Pain Risk" - Pink Sheet, 4 Apr, 2005.), p. 6).

As with oral bisphosphonates, Boniva injection labeling states "most reported cases have been in patients treated with bisphosphonates intravenously, but some have been in patients treated orally."

In the one-year, 1,358-patient Dosing IntraVenous Administration (DIVA) study of women with postmenopausal osteoporosis, which randomized patients to Boniva injection or once-daily tablets, "the overall safety and tolerability profiles of the two dosing regimens were similar," labeling states.

However, 8.5% of Boniva injection patients withdrew from treatment due to adverse events compared to 6.7% of once-daily ibandronate patients.

Boniva injection will also benefit from a slight efficacy superiority to oral once-daily ibandronate.

In the DIVA study, the average increase in lumbar spine bone mineral density observed in the Boniva injection cohort was significantly superior to that of the once-daily Boniva cohort (4.5% vs. 3.5%). Boniva injection also showed increases compared to once-daily tablets in total hip BMD at one year (2.1% vs. 1.5%) and femoral neck and trochanter BMD.

Roche and GSK have undertaken active direct-to-consumer advertising campaigns for the once-monthly Boniva tablets.

P&G and Sanofi-Aventis recently filed suit against Roche and GSK in New York federal court alleging that an ad for Boniva tablets wrongly claims that the drug has been proven to reduce risk of nonspinal (nonvertebral) fractures and that it is more convenient than other oral bisphosphonates. Actonel and Fosamax are approved for nonvertebral fractures; Boniva is not.

[Editor's note: Coverage of the suit against Roche and GSK appeared in ⁴ "The Pink Sheet" DAILY Jan. 4, 2006. To read the article and sign up for a free trial, visit our website, ⁵ www.ThePinkSheetDAILY.com .]