A history of Evenity's development, and the wider implications of the FDA advisory committee's decision to recommend the approval of Evenity.
The FDA’s advisory committee recently voted to recommend the approval of Amgen/UCB/Astellas’ Evenity (romosozumab). Although not a guaranteed outcome, it now seems likely that the FDA will approve the launch of Evenity in the United States. This recommendation follows on the back of Evenity’s approval in Japan the previous week. A collective cheer will no doubt have been raised at Amgen, Astellas and UCB’s headquarters after a turbulent couple of years during which Evenity’s fate hung in the balance.
In 2016, Amgen/UCB submitted marketing applications for Evenity in the United States and Japan. These applications were based on results from the Phase III FRAME placebo-controlled fracture study in postmenopausal women with osteoporosis. The results from this study were impressive, showing unprecedented gains in bone mineral density, and significant reductions in the rate of vertebral fractures. Evenity’s future looked bright. In 2017, the results from a second study, the Phase III ARCH study were published. This study compared Evenity versus alendronate (alendronate is the most-widely prescribed osteoporosis therapy) in postmenopausal women with osteoporosis at high risk for fracture. Although Evenity treatment significantly lowered the risk of fracture, the number of severe cardiovascular events were significantly higher in the Evenity arm than the alendronate arm (2.5% vs. 1.9%). Following these results, the FDA issued a complete response letter (CRL) in July 2017, requiring any resubmission to include the results from the FRAME, ARCH, and BRIDGE (a Phase III placebo-controlled trial in men with osteoporosis). Suddenly, Evenity’s future began to look much darker.
History repeating itself?
In 2016, Merck dropped development of odanacatib, a promising osteoporosis treatment, because of an imbalance in adjudicated stroke events. There was speculation that Evenity could meet the same fate. However, undeterred, UCB and Amgen submitted a Marketing Authorization Application to the European Medicines Agency (EMA) in January 2018, and resubmitted to the FDA in July 2018. In January of this year, Evenity’s developers received their first piece of major good news, with the granting of marketing authorization in Japan. The following week, the good news continued with a recommendation for approval by the FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee.
Many osteoporosis patients will be celebrating the news of Evenity’s approval. Currently there are only two approved anabolic osteoporosis therapies, which build bones – Eli Lilly’s Forteo and Radius Health’s Tymlos. Both therapies are parathyroid hormone (PTH) analogues and, prior to the arrival of Evenity, they are the most efficacious osteoporosis drugs available. However, they do have their drawbacks; PTH analogue treatment increases the risk of osteosarcoma, so they are restricted to two-years lifetime use, and can’t be prescribed to patients who have received radiation therapy (e.g., some cancer patients). Additionally, the cost of Forteo and Tymlos is substantially more than other osteoporosis drugs, therefore, reimbursement restrictions/out-of-pocket costs have restricted their use. The launch of Evenity will give patients a much-needed additional treatment option, and will add a third, but non-PTH, anabolic agent to the market.
All good news?
A fly in the ointment is the likely requirement for a boxed warning label on Evenity. To satisfy concerns the FDA had, Amgen/UCB proposed a boxed warning for cardiovascular risk. Although this will likely constrain sales – osteoporosis patients are generally older, with a subsequent higher rate of cardiovascular disease – it was likely the only way of gaining regulatory approval. The advisory committee also agreed that Amgen/UCB should carry out a postmarking observational study. Although, a randomized controlled would have been superior – the patient population in an observational trial will have a lower risk because of the label restrictions – the FDA advisory committee ultimately decided to recommend approval of an observational study. However, if Amgen/UCB are hoping to get the warning-label removed once Evenity has launched, history is not on their side. Very few medicines have successfully had their boxed warnings removed – Avandial, Chantix, ICS/LABAs, Letairis, Vivtrol, and Zyban are among the few examples of drugs to have achieved this distinction. Forteo’s boxed warning label hasn’t stopped it achieving sales of over $1 billion a year. However, this label is for a clearly defined set of patients. If the FDA opt to give Evenity a broad cardiovascular warning label, this would cover a much wider range of patients than that of Tymlos/Forteo’s label. A more clearly defined label (e.g., patients who have suffered a stroke/MI within the last year), would certainly be less damaging to Evenity’s sales.
Future osteoporosis development
The successful launch of Evenity could also have broader implications. Development of novel osteoporosis is currently somewhat limited. The osteoporosis market is highly genericized – step therapy is commonplace, with most patients initiated on generic alendronate. Additionally, the halting of Merck’s costly odanacatib’s development program sent shockwaves through the field. Thought leaders interviewed last year were fearful that a negative opinion for Evenity would reinforce the opinion that developing drugs for the osteoporosis field was too high risk, with low potential reward. This is reflected in the relatively sparse current osteoporosis pipeline. However, the approval of Evenity, and the success of Amgen’s Prolia, Eli Lilly’s Forteo, and Radius Health’s Tymlos point towards a market with real opportunities.
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