ASBMR 2014: Four bone drug updates, including Merck's odanacatib
This article was originally published in Scrip
Merck & Co reported positive Phase III efficacy for its osteoporosis drug odanacatib during the American Society for the Bone and Mineral Research (ASBMR) Annual Meeting from 12 to 15 September in Houston, Texas, but the company will not seek US FDA approval until 2015.
Merck said during a research and development update in May that it would submit a new drug application (NDA) for its cathepsin-K inhibitor during the second half of 2014, but the NDA submission has been delayed while cardiovascular safety data from the Phase III LOFT clinical trial undergo additional analyses (scripintelligence.com, 7 May 2014). However, the company will submit its NDA at least a year before Amgen seeks FDA approval for its osteoporosis candidate romosozumab, for which new Phase II results were reported at the ASBMR meeting.
A review of long-term impacts of treatment with Amgen's approved bone drug Prolia (denosumab) for postmenopausal women with osteoporosis also was presented during the conference.
Outside of the osteoporosis realm at the ASBMR meeting, long-term Phase II results for asfotase alfa from Alexion Pharmaceuticals showed the impact that the enzyme replacement therapy had on survival for children with severe hypophosphatasia.
Merck's odanacatib
Efficacy results were statistically significant in the 16,713-patient Long-term Odanacatib Fracture Trial (LOFT) with effects on fractures and bone density that were comparable to approved osteoporosis treatments, but the Phase III study's cardiovascular safety results could make or break Merck's chances of winning FDA approval for the once-weekly drug.
Sagient Research increased the likelihood of approval for odanacatib by 1% to 70% in a 15 September BioMedTracker report, because Sagient said the adverse event profile may not prevent FDA approval even with a numerically higher incidence of major adverse cardiovascular events (MACE) relative to placebo.
The difference in MACE – 215 events for odanacatib-treated patients versus 194 in the placebo group – was not statistically significant (HR=1.12; 95% CI 0.93, 1.36).
"Of note, bisphosphonates also cause atrial fibrillation at low rates. As a result, if approved, odanacatib usage may be limited to patients without major CV risk factors," according to the BioMedTracker report.
Bone resorption exceeds the rate of bone formation in osteoporosis, so odanacatib was designed to selectively inhibit cathepsin K, which is a primary enzyme in osteoclasts – the cells that resorb bone. Sagient's BioMedTracker analysis notes that femoral shaft fractures observed in the LOFT clinical trial – five for odanacatib-treated patients and none in the placebo group – are common among anti-resorptive therapies that treat osteoporosis.
Twelve of the postmenopausal women aged 65 and older who were treated with odanacatib had morphea-like skin lesions versus three women who received a placebo, but the skin-hardening condition went away when patients stopped taking the Merck drug.
The LOFT clinical trial met its primary endpoints with statistically significant reductions in hip, spine and non-vertebral fractures compared with placebo. The relative risk of new and worsening fractures was reduced by 54% for morphometric vertebral fractures, 47% for clinical hip fractures, 23% for clinical non-vertebral fractures and 72% for clinical vertebral fractures (p<0.001 for="" all="">
Sagient noted that the fracture risk reductions were similar to results seen in Phase III for Amgen's Prolia, which targets the RANK ligand, and the Novartis bisphosphonate Reclast (zolendronic acid). But odanacatib did not cause osteonecrosis of the jaw, which is a known side effect for bisphosphonates and Prolia.
"While odanacatib did not result in osteonecrosis of the jaw and had a low rate of atypical femoral shaft fractures, the numerical imbalances of cardiovascular events (afibrillation, stroke, MACE events and deaths) will be analyzed closely by the FDA and commercially could make detailing the drug to doctors more difficult," ISI Group's Mark Schoenebaum said in a 15 September note to investors.
ISI forecasts peak odanacatib sales of $300m per year.
Amgen's romosozumab
Amgen and romosozumab development partner UCB are evaluating the sclerostin inhibitor in two Phase III clinical trials enrolling 10,000 women, but data presented at the ASBMR meeting were from Phase II extension studies. Phase II results were published at the start of 2014 (scripintelligence.com, 2 January 2014). The highest dose tested – 210mg administered monthly – was the most effective dose versus placebo and Eli Lilly's Forteo (teriparatide).
Adverse events were similar across all treatments arms of the Phase II clinical trial, with the exception of injection site reactions for romosozumab. Nasopharyngitis and arthralgia were the most common side effects during the trial's 12-month treatment period. Romosozumab's adverse event profile did not change in the two years of the extension study.
Lumbar spine BMD increased 15.7% from baseline for postmenopausal women treated with 210mg of romosozumab monthly for two years and total hip BMD increased 6% in the extension period, according to data presented at ASBMR. When women were switched to Prolia or placebo in the third year of treatment, Prolia-treated patients saw continued BMD gains while placebo-treated patients declined toward pre-treatment levels.
"Assuming the [Phase III] fracture studies (data expected in 2016) are positive as expected based on the strong BMD effect, the one-year treatment duration used in current Phase III trials appears sufficient for supporting the initial launch, although the ultimate commercial potential could be enhanced if 'treatment re-cycling' (re-starting romosozumab [romo] after romo in year one and Prolia or Fosamax in year two) is shown to be an effective strategy," Leerink Swann analyst Howard Liang wrote in a 16 September research note.
In another Phase II analysis presented at ASBMR, romosozumab outperformed Forteo in an analysis of vertebral cortical mass and thickness after 12 months of treatment. The mean cortical thickness (CTh) increased 11.2% for women treated with romosozumab versus 5.6% for Forteo-treated patients (p<0.001). the="" mean="" increase="" in="" cortical="" mass="" (cmass)="" was="" 12.7%="" in="" the="" romosozumab="" group="" and="" 4.6%="" in="" the="" forteo="" group=""><>
Eight-year Prolia results
About 1,500 women from Amgen's Phase III Prolia program were treated for eight years between the pivotal stage and the extension study. Most women achieved non-osteoporotic T-scores by the end of eight years of treatment.
Mean lumbar spine and total hip T-scores were -2.83 and -1.85, respectively, at baseline. The percentage of women with lumbar and hip T-scores greater than -2.5 jumped from 11% at baseline to 82% at eight years, while the percentage jumped from 4% to 65% for T-scores above −2.2, from 2% to 53% for T-scores above -2, and from 1% to 39% for T-scores above −1.8.
In an analysis of patients in the placebo arm of the Phase III study, cortical bone density at the radius declined despite concurrent treatment with calcium and vitamin D. Women who were given Prolia for three years in the extension phase reversed the bone loss and another two years of treatment provided BMD gains that reduced wrist fractures.
Alexion's asfotase alfa
Hypophosphatasia (HPP) is an ultra-rare genetic, chronic and progressive metabolic disease characterized by defective bone mineralization that leads to bone destruction and deformity, muscle weakness, seizures, respiratory failure and premature death.
The FDA granted a breakthrough therapy designation for Alexion's asfotase alfa to treat HPP in 2013 and the company initiated a rolling biologic license application (BLA) for the enzyme replacement therapy in April (scripintelligence.com, 29 May 2013). The European Medicines Agency validated Alexion's marketing authorization application (MAA) for asfotase alfa and granted accelerated assessment for the MAA in July.
Results were presented at the ASBMR meeting from an analysis of two open-label, Phase II clinical trials with children aged 5 or younger at enrollment compared with data from a retrospective natural history study of untreated HPP patients. After up to five years of treatment with asfotase alfa (median was two years), 89% of young HPP patients at high risk of death (33 out of 37) survived versus 27% (13 out of 48) of historical control patients (p<>
"Improved survival in treated patients likely reflects better mineralization of the rib cage, which then had a positive effect on respiratory function," Dr Michael Whyte, medical-scientific director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children in St Louis, Missouri, said in Alexion's announcement of the long-term results.
Other asfotase alfa results presented at ASBMR showed growth and function gains for infants and toddlers treated in a separate Phase II clinical trial.
Also, juvenile patients in a Phase II extension study experienced significant reductions in disability and pain accompanied by improvements in strength, agility and height.