Cytochroma Seeks To Bring Advance Over Hectorol, Zemplar To Market For CKD

Phase II candidate CTA018 is intended as safer alternative to existing hormone replacement therapies for vitamin D insufficiency.

Cytochroma is building a portfolio of drugs addressing vitamin D insufficiency in patients with chronic kidney disease with the aim of supplanting existing hormone replacement treatments with safer alternatives.

The company's strategy of gathering an experienced management team and focusing on a specialized, niche market could pay off. The U.S. market for vitamin-D based drugs may reach more than $1.4 billion annually by 2013, the firm estimates, although safety concerns about the current products' use in the delicate CKD patient population limit use. Cytochroma - and its partner, Mitsubishi Tanabe--are betting that a new, safer therapy would significantly expand the market, especially in earlier-stage chronic disease patients.

Cytochroma's size and focus on this area could be an advantage. Genzyme's Hectorol , Abbott's Zemplar and Amgen's Sensipar , make up the current therapeutic selection list. Hectorol generated under $200 million in annual sales in 2008, while Sensipar generated quite a bit more, $597 million (Abbott doesn't break out sales of Zemplar). For Cytochroma, success in vitamin-D therapy is a key to its survival.

To help support its goals, the Canadian specialty pharma has found some deep pockets. Japanese drug maker Mitsubishi Tanabe in July 2008 acquired co-development and commercialization rights for Cytochroma's lead candidate CTA018. The companies are looking to complete Phase II testing of the novel vitamin D analog by the end of the year and then push ahead as soon as possible with Phase III trials.

A dual mechanism of action is key to CTA018

Secondary hyperparathyroidism is common in CKD patients on dialysis. About 40 percent to 60 percent of patients with moderate disease and 90 percent of those with severe disease have SHPT, Cytochroma says.

Impaired kidneys are unable to produce sufficient quantities of vitamin D hormones, leading to excessive secretion of parathyroid hormone by the parathyroid gland. The prolonged elevation of PTH causes excessive calcium to be released from the bone into the blood, leading to softening of the bones and calcification of vascular tissues, which can result in heart disease.

CTA018, in development for the treatment of SHPT in CKD patients on dialysis, elicits a therapeutic response even as it reduces resistance to vitamin D hormone therapy. That's because it has a dual mechanism of action that activates the vitamin D signaling pathway while also inhibiting CYP24, which scientists believe protects cells from receiving excessive levels of vitamin D hormones.

The company's aim is to develop a drug that controls serum parathyroid hormone without having an adverse impact on serum calcium and serum phosphorus levels.

"Here's an opportunity for all of us who know the field very well to meet the treatment goals of CKD much more fully," Cytochroma's CEO Charles Bishop said in an interview.

An experienced team eyes safety enhancements

Bishop is an expert in the field of vitamin D hormone therapies. Before joining Cytochroma, he previously worked as the CEO of Bone Care International, where he developed Hectorol (doxercalciferol) and oversaw its approval by FDA for SHPT. With Hectorol its sole marketed drug, Bone Care International was bought by Genzyme in 2005 for $600 million (¹ (Also see "Hectorol Will Drive Genzyme’s Renal Business; “Share Of Voice” To Jump" - Pink Sheet, 18 Jul, 2005.), p. 30).

Just months ahead of the buyout, Abbott had launched the oral form of its vitamin D analogue Zemplar (paricalcitol) for SHPT in Stage 3 and 4 CKD patients, who are pre-dialysis. Development of Zemplar was overseen at Abbott by Joel Melnick, who has also joined Cytochroma as VP-Clinical and Regulatory Affairs.

A third drug on the market for the disorder, Amgen's Sensipar (cinacalcet), was approved in 2004 for treatment of SHPT in patients on dialysis.

All three drugs have limitations. Although Hectorol and Zemplar are both approved in capsule formulations for patients with earlier stages of kidney disease (Stages 3 and 4, which is pre-dialysis), physicians remain cautious about using the drugs in these patients due to the risks of hypercalcemia, according to Bishop. Amgen opted not to pursue a treatment indication for Sensipar in patients with earlier-stage chronic renal insufficiency in 2007 after results of a Phase III study demonstrated incidence of hypocalcemia in that population.

"These products are predominately for dialysis patients, and that is about 400,000 patients," he said. "The market potential includes Stage 4 and Stage 3 patients...and that population probably totals very close to 8 million people. It is a very under exploited market."

Cytochroma's development and regulatory strategy for CTA018 injection is to target the most severe SHPT market - patients on dialysis - initially. Then, the company will seek to move the drug's indications into the pre-dialysis population. Beyond that, however, there is an "enormous" market for patients with osteoporosis and age-related elevation of the parathyroid hormone, Bishop noted.

Cytochroma, with partner Mitsubishi Tanabe, is on track to complete Phase II testing of CTA018 by the end of the year. Under the deal announced last summer, Mitsubishi is paying Cytochroma $84.7 million (1CDN=$.80) in upfront and milestone payments and an equity investment. In exchange, the partners would jointly develop and commercialize CTA018 in the U.S.

Connected to that deal, the company closed on a $36.3 million Series C financing led by Mitsubishi last July. Cytochroma ended 2008 with $41.9 million in cash, but with an aggressive burn rate expected this year, the firm plans to close 2009 with roughly $20.2 million.

"We do have several other opportunities that are under review right now to bring additional money into the company through partnering," CFO Richard Wieland said.

Those opportunities include Cytochroma's currently unpartnered assets: European rights to CTA018 and two Phase I drugs, both of which are also in the vitamin D insufficiency arena.

CTAP101 is a potential first-in-class treatment for vitamin D insufficiency in patients with Stage 3 or 4 CKD. The oral product would be a precursor to hormone replacement therapy, a first step for treating such patients. CTAP201 is a vitamin D hormone therapy that is in development for mild to moderate SHPT.

-Jessica Merrill ([email protected])