By Catherine Shaffer
Staff Writer

Wowed by stunning Phase IIa results for nephrology candidate KAI-4169, Thousand Oaks, Calif.-based Amgen Inc. tendered an offer of $315 million in cash to buy KAI Pharmaceuticals Inc., of San Francisco.

KAI is developing KAI-4169 for treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease.

SHPT is part of chronic kidney disease (CKD) mineral and bone disorder, which affects about 1.6 million patients worldwide. In that disorder, the kidneys fail to maintain the proper levels of calcium and phosphorous in the blood, which causes abnormal bone hormone levels, eventually leading to thin bones, fractures and pain. CKD mineral and bone disorder is a major source of morbidity and mortality in patients with CKD.

Reshma Kewalramani, head of global development for nephrology at Amgen, told BioWorld Today, "There is a large unmet medical need in dialysis patients. They have a large number of co-morbidities. . . . If we are able to bring forward a medicine, safely and effectively treat SHPT that doesn't involve a pill burden, that is a real benefit for patients. This drug holds that potential."

The deal will give Amgen worldwide rights to the drug, except for Japan, in exchange for the cash payment plus a loan for Phase III planning prior to closing of the acquisition.

In November 2011, at the American Society of Nephrology's Kidney Week Meeting in Philadelphia, KAI reported that KAI-4169 produced significant reductions in parathyroid hormone in CKD patients. For a group receiving a 5-mg dose, the reduction was 33 percent, and in the 10-mg dose group, there was a 49 percent reduction.

In the 10-mg group, as well, 76 percent of subjects achieved a reduction of parathyroid hormone greater than or equal to 30 percent, and 67 percent reduced their parathyroid hormone levels to 300 pg/mL or less by the end of the treatment period.

In January, KAI began enrollment in a second Phase II trial of the drug in CKD mineral and bone disorder in hemodialysis patients with secondary hyperparathyroidism. That single-arm study will test the effect of three-times-weekly bolus administration of KAI-4169 over a 12-week treatment period, as measured by the percent change in parathyroid hormone from baseline.

The new trial also will evaluate secondary endpoints, including proportion of subjects with more than a 30 percent reduction in parathyroid hormone from baseline, proportion of subjects achieving parathyroid hormones of 300 pg/mL or less and mean change from baseline in serum calcium and phosphorous.

KAI-4169 is the only compound in KAI's active development pipeline. In the past, the firm has used its rational peptide design platform to develop peptide drugs for other targets, and it has carried out clinical trials for those compounds.

For example, in 2008, KAI partnered with Bristol-Myers Squibb Co. in a $227 million deal to develop KAI-9803 for cardiac indications, and at that time also had KAI-1678, for pain, in Phase I and II trials. (See BioWorld Today, May 14, 2008.)

"We've narrowed focus to this compound," KAI CEO Steven P. James told BioWorld Today. "It's shown the best clinical profile and the most promise. This is the 100 percent focus of the company."

KAI-4169 is a peptide agonist of human cell surface calcium-sensing receptor, a G protein-coupled receptor. James said KAI-4169 "was discovered within the four walls of KAI."

Although it potentially could have applications in other indications, Amgen's Kewalramani said it is uniquely suited to treatment of patients in dialysis.

"Patients come to the dialysis clinic three times a week," Kewalramani said. Those patients already have I.V. access because of the dialysis procedure. In other diseases and other patient populations, the need to report to the clinic for infusion three times a week would be a disadvantage.

KAI-4169 has the same mechanism as Amgen's oral caclimimetic, Sensipar (cinacalcet), but with patent protection extending into the late 2020s. Its efficacy is comparable to Sensipar, as well. The 49 percent reduction in parathyroid levels compares well with Sensipar's 50 percent reduction, but KAI-4169 does not have the adverse gastrointestinal events seen in 20 percent to 30 percent of patients taking Sensipar.

As such, KAI-4169 seems a logical addition to Amgen's pipeline to replace Sensipar when it loses patent protection in 2018. However, there is still generic Sensipar to contend with. "It is difficult to envision KAI-4169 displacing a generic Sensipar beyond 2018 within a cost-constrained bundled payment system," wrote BMO Capital Markets analyst Jim Birchenough. He added that "with CV outcomes data for Sensipar still pending from EVOLVE, we believe that a large CV outcomes study will be required for KAI-4169 whether EVOLVE is positive or negative, and we remain skeptical regarding prospects for EVOLVE success."

Generic Sensipar isn't the only challenger for SHPT market share. Abbott's intravenous Zemplar (pericalcitol) beat Sensipar plus low-dose vitamin D in a Phase IV trial in patients with secondary hyperparathyroidism on kidney dialysis. In that trial, 57.7 percent of patients in the I.V. Zemplar group achieved the primary endpoint of a mean intact parathyroid hormone level of 150 pg/mL to 300 pg/mL during weeks 21 and 28, vs. 32.7 percent in the Sensipar group.

Amgen's acquisition of KAI has been approved by KAI stockholders and by each company's board. The transaction will complete when customary closing conditions are met, including regulatory approvals.

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