Does tenapanor hydrochloride (Ibsrela) produce a clinically meaningful effect on serum phosphorus for patients with chronic kidney disease (CKD) on dialysis?
That question will be front and center for independent advisors to the FDA on Wednesday, as the will weigh data from three phase III trials to determine whether the drug's potential benefits, when given alone or in combination with other agents, outweigh its risks for this patient population.
The meeting comes as the result of an appeals process after the agency last year sponsor Ardelyx's sodium/hydrogen exchanger 3 (NHE3) inhibitor for the proposed indication. (Tenapanor is approved for irritable bowel syndrome with constipation.)
In its complete response letter, FDA reviewers stated that "although we agree that the submitted data provide substantial evidence that tenapanor is effective in reducing serum phosphorus in CKD patients on dialysis, the magnitude of the treatment effect is small and of unclear clinical significance." The agency subsequently recommended an additional trial, according to FDA's released ahead of the meeting.
FDA considers a reduction in serum phosphorus levels as a surrogate endpoint for the efficacy of treatments for hyperphosphatemia in patients with CKD on dialysis, but notes that data from randomized controlled trials demonstrating that treatments that lower serum phosphorus improve patient outcomes are lacking.
Effective, safe, and well-tolerated treatments for hyperphosphatemia is an unmet need, according to the FDA. While four classes of agents have already been approved for this use -- calcium-based binders, sevelamer-based products, lanthanum carbonate, and iron-based binding agents -- these therapies are difficult to implement, and the pill burden for patients can be particularly high.
By contrast, tenapanor is administered twice daily. In the three phase III studies of the drug, which involved more than 1,000 patients and met their primary endpoints, tenapanor's largest treatment effect appeared to be a reduction of 1.4 mg/dL at 12 weeks in an enriched patient population that initially responded to the NHE3 inhibitor during a run-in phase. In that trial, , a "more modest" reduction was observed in the broader intention-to-treat population, noted FDA reviewers.
"The magnitude of the treatment effect in this broader subset (0.7 mg/dL) appears to be less than that observed with approved agents (~1.5 to 2.2 mg/dL)," the FDA reviewers wrote in the briefing documents. "When used in combination with phosphate binders, the magnitude of the treatment effect was similar to that seen when used as monotherapy."
A reduction in serum phosphorus levels has been accepted by the FDA as a basis for traditional approval in patients with CKD on dialysis "when the effect on serum phosphorus was sufficiently large to be considered clinically meaningful with benefit that outweighed the risks," the briefing documents noted. "It is important to note, however, that even for accepted surrogate endpoints, a drug effect may be so small that it does not provide any meaningful clinical benefit or alters the benefit/risk assessment. It is challenging to define a minimum drug effect on serum phosphorus given that the relationship between phosphorus lowering and clinical benefit has not been established."
NHE3 is an antiporter expressed in the small intestine and colon. Unlike the currently approved agents for controlling serum phosphorus, which bind phosphate in the gastrointestinal tract to decrease its absorption, tenapanor reduces sodium absorption and decreases phosphate absorption by reducing phosphate permeability through the paracellular pathway.
Another consideration for the committee is the risk of diarrhea, which may limit the ability of patients taking tenapanor to adhere to long-term treatment. For example, more than half (54%) of patients treated with tenapanor in PHREEDOM reported diarrhea during the initial 26 weeks of treatment, compared with 8% of those treated with sevelamer as an active control. About 40% in the tenapanor arm reported at least one moderate or severe diarrhea event, compared with only 3% in the sevelamer arm. In the tenapanor arm, discontinuations or dose reductions due to diarrhea occurred in 16% and 32%, respectively.
"Although the incidence of serious adverse events of diarrhea was low (0.5%) in the tenapanor arm, the risks of severe diarrhea and its potential sequelae (e.g., dehydration, hypotension, falls, ischemia) must be considered where there is a reasonable expectation of wider use in the real-world setting, i.e., a more diverse patient population that is not as closely monitored as in a clinical trial setting," FDA staff wrote.
In contrast to the monotherapy studies, treatment discontinuation due to diarrhea was uncommon when tenapanor was used in combination with existing phosphate-binding treatment.