Amgen competitor Opko plans year-end NDA for Rayaldee
This article was originally published in Scrip
Opko Health will submit a new drug application (NDA) to the US FDA for Rayaldee (CTAP101) based on a second set of positive Phase III results in the treatment of secondary hyperparathyroidism (SHPT) in patients with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency.
The Miami, Florida-based company's Phase III results and NDA submission timeline put Rayaldee, an oral small molecule drug, at least a few months ahead of the Amgen's intravenous drug candidate AMG 416 (KAI-4169, velcalcetide), which is expected to make up for lost market share when the Thousand Oaks, California biotechnology giant loses patent protection for the blockbuster drug Sensipar/Mimpara (cinacalcet), an oral hyperparathyroidism drug (scripintelligence.com, 17 July 2014).
Opko's Rayaldee is a first-in-class oral vitamin D prohormone treatment that is being developed as a safer and potentially more effective drug than what is available today to treat SHPT. However, its efficacy relative to Amgen's Sensipar (Mimpara in the EU) and AMG 416 is unknown without more detailed Phase III results. Both Amgen drugs target the calcium-sensing receptor on the parathyroid gland.
As when Opko reported top-line results from its first Phase III Rayaldee clinical trial in August, the company did not reveal the magnitude of the drug's effect in the second Phase III trial. Opko's stock closed down 0.5% at $8.25 per share on 23 September after the second set of Phase III results was announced. The company's market cap is $3.5bn.
Opko's second Phase III clinical trial – a mirror image of the first Phase III trial – enrolled 216 adults who were randomized 2-to-1 to treatment with Rayaldee or a placebo for six months. Both Phase III studies were conducted under a special protocol assessment (SPA) negotiated with the FDA.
The primary endpoint was a responder analysis looking for a greater percentage of patients in the Rayaldee arm of the study who demonstrated an average 30% decrease in plasma parathyroid hormone (PTH) from pre-treatment baseline during the last six weeks of the treatment period. Opko said a significantly higher response rate was observed for Rayaldee in the second Phase III study.
Also, vitamin D insufficiency was corrected in 96% of patients treated with Rayaldee versus 8% in the placebo group. Safety and tolerability were described as comparable in both treatment groups.
Stuart Sprague, chief of the division of nephrology and hypertension at NorthShore University Health System, part of the University of Chicago's Pritzker School of Medicine, noted in Opko's statement regarding the second Phase III study that "these patients are treated with high doses of nutritional vitamin D, but fewer than 50% show an adequate response. Inadequate correction of vitamin D insufficiency with nutritional vitamin D allows secondary hyperparathyroidism to become established and less responsive to treatment."
Opko's renal division CEO Charles Bishop said patients enrolled in an extension study for the Phase III clinical trials are experiencing gradual, but progressive PTH lowering during the six-month treatment period with the company's vitamin D prohormone treatment, "allowing PTH levels to return to the normal range in a significant proportion of patients." The extension study enrolled 298 patients and 180 patients have completed the six-month treatment period to date.
Market size and competition
Stage 3 and 4 of CKD are considered moderate – not quite severe enough to require dialysis. There are about 8m pre-dialysis CKD patients in the US who have SHPT associated with vitamin D insufficiency. The number of individuals with SHPT rises to 20m in the US when stage 5 CKD patients, who are on dialysis, are included.
SHPT affects 40-60% of patients with moderate CKD and approximately 90% of patients with severe CKD. Left untreated, elevated PTH levels lead to elevated serum calcium and phosphorus, softening of the bones (osteomalacia) and calcification of vascular and renal tissues.
A late 2014 NDA filing for Opko's oral SHPT treatment could translate to a late 2015 FDA approval for Rayaldee. Amgen intends to report results from its second Phase III clinical trial for intravenous AMG 416 later this year and from a head-to-head study against Sensipar in 2015, so the big biotech's submission to the FDA could trail Opko's.
Without detailed results from the Phase III studies, it's hard to say if Rayaldee would be able to compete against AMG 416 or the established oral hyperparathyroidism treatment Sensipar, which loses patent protection in the US in 2018, and generic Mimpara, after the brand-name drug goes off patent in 2015 in the EU.
Sagient Research gives Rayaldee a 62% likelihood of FDA approval (LOA), which is 2% above average for Phase III drugs that treat endocrine diseases. The LOA could go higher or lower based on detailed Phase III results.
Sagient noted in an 11 August BioMedTracker report when Opko disclosed the first set of top-line Phase III Rayaldee data that numerical results from a Phase II clinical trial for Rayaldee were similar or slightly inferior to PTH reduction observed in Amgen's first Phase III trial for AMG 146.
However, patients treated with 30mcg of Rayaldee in Opko's Phase III studies could have their dose titrated up to 60mcg. Patients received either 30mcg, 60mcg or 90mcg doses in the Phase II clinical trial and the 60mcg dose was most effective in that trial.
Opko acquired Rayaldee when it bought Cytochroma in early 2013 (scripintelligence.com, 9 January 2013).