The 505(b)(2) registration pathway for new drug products allows the applicant of the new drug product to reference the literature and the FDA’s findings of safety and/or effectiveness (e.g., as listed on the Listed Drug product’s label) to fulfill various registration requirements. From a nonclinical perspective, these sources of nonclinical safety data can greatly reduce or even eliminate the amount of nonclinical testing required to support clinical trials and/or full registration of the new drug product.

One such example of when the 505(b)(2) pathway is applicable is when the salt of the Listed Drug is changed, such as a change from a sodium salt to a potassium salt of the same active moiety.^[i]

On the surface, this appears to be a very promising pathway since changes in a salt may have little impact on the safety of the drug substance. Assuming the nonclinical package for the Listed Drug meets current standards and the indications, dosages, and route of exposure for the new drug product match the Listed Drug label, it is reasonable to assume that no new nonclinical data would be required for the change in the salt.

Safety Concerns

Unfortunately, changes in a salt may raise safety concerns, especially if the salt is not commonly used in other drug substances. This may necessitate the conduct of specific nonclinical studies to assess the safety of the salt in relation to the Listed Drug’s salt.

One such example that will be reviewed to demonstrate the potential pitfalls of using uncommon salts is the registration of esomeprazole strontium via the 505(b)(2) pathway.

The applicant for esomeprazole strontium used Nexium (esomeprazole magnesium) as the Listed Drug. A large database of strontium safety data (i.e., animal and human studies) exist that supported the safety of the low dose of strontium that would result from taking esomeprazole strontium clinically.

Despite the supportive literature regarding the safety of strontium, the FDA had concerns about the safety of strontium, particularly for young, actively growing patients, which are the most sensitive subpopulation for strontium adverse effects on developing bone. To address the safety concerns, the FDA required the applicant to conduct a very detailed and targeted battery of developmental and juvenile toxicity studies with toxicokinetic analysis of the active moiety (esomeprazole) and extensive toxicokinetic and distribution analysis of both strontium and calcium.

Esomeprazole Strontium

Nexium (esomeprazole magnesium) and esomeprazole strontium are proton pump inhibitors and are both indicated in adults for the treatment of gastroesophageal reflux disease (GERD), including healing of erosive esophagitis, maintenance of healing of erosive esophagitis and symptomatic gastroesophageal reflux disease; risk reduction of NSAID-associated gastric ulcer; Helicobacter pylori (H. pylori) eradication to reduce the risk of duodenal ulcer recurrence (in combination with amoxicillin and clarithromycin as triple therapy); and pathological hypersecretory conditions, including Zollinger-Ellison syndrome.^[ii],[iii]

Nexium is also indicated for use in pediatric patients; whereas, the drug label for esomeprazole strontium only lists adults, most likely because clinical trials in pediatric patients were not required for initial registration and are probably ongoing to meet post-registration Pediatric Research Equity Act (PREA) requirements. Even though esomeprazole strontium does not currently include pediatric patients on the drug label, based on the FDA’s Summary Basis of Approval, the FDA had serious concerns about the use of esomeprazole strontium in pregnant and lactating women and pediatric patients due to the potential for adverse effects of strontium on bone growth and development.^[iv] Due to this concern, the FDA issued the applicant a complete response (CR) for the submitted New Drug Application (NDA) due to lack of adequate nonclinical safety data to support the use of esomeprazole strontium in pregnant and lactating women and in children under the age of 2.

Strontium is an interesting element since at low to moderate doses it can increase bone strength; whereas, at very high doses in animals (≥500 mg/kg/day), it can induce adverse bone effects similar to Rickets. As an example of the beneficial effects of strontium on bone strength, strontium ranelate (Protelos) is approved in the European Union for the treatment of severe osteoporosis.^[v] Juveniles, especially those with poor nutrition, are most vulnerable to strontium since strontium, as an imperfect surrogate for calcium, interferes with bone mineralization in the developing skeleton. Other contributing factors include deficiencies in vitamin D, protein, and calcium.

Several regulatory bodies have developed acceptable daily intakes for strontium. The US Agency for Toxic Substances and Disease Registry (ATSDR) derived a Minimal Risk Level (MRL) of 2.0 mg/kg/day and the US Environmental Protection Agency (EPA) derived a Reference Dose (RfD) of 0.6 mg/kg/day, with both levels reflecting exposures to strontium that are unlikely to cause adverse effects, even in the most sensitive juvenile population.^[vi],[vii]

Patient strontium exposure from the maximum dose of esomeprazole strontium (49.3 mg esomeprazole strontium/day) is estimated to be 0.17 mg Sr/kg/day (for a 30 kg pediatric patient), which is well below the MRL and RfD even in this most sensitive subpopulation. Adding normal environmental strontium exposure (0.046 mg Sr/kg/day) to the clinical exposure (0.17 mg Sr/kg/day) is still well below the MRL (2.0 mg/kg/day) and RfD (0.6 mg/kg/day).

Despite the extensive literature and risk analysis demonstrating the safety of the clinical strontium exposure, the FDA still required additional nonclinical studies to address the safety of esomeprazole strontium in pregnant and lactating women and juvenile patients.

FDA Deficiencies Addressed

In order to address the deficiencies identified in the CR letter, the applicant conducted reproductive and developmental toxicology studies in rats, comparing esomeprazole strontium (ES) to esomeprazole magnesium (EM), at equimolar concentrations of esomeprazole. Bone effects of treatment with ES and EM were assessed in all developmental toxicology studies. The applicant conducted a rat segment II embryo-fetal development study, a rat segment III pre- and post-natal developmental toxicity study with an emphasis on bone development, a rat segment III pre- and post-natal developmental toxicity study in animals receiving a calcium and vitamin D deficient diet, and a rat juvenile toxicity study. All studies included TK analysis of esomeprazole and TK and distribution data for strontium and calcium.

Since bone is the most sensitive target organ for strontium, bone morphometry and detailed histopathological analyses were included in the segment III and juvenile toxicity studies. These were very complicated studies due to 1) the inclusion of EM and ES comparator groups, 2) the strontium and calcium TK and distribution analyses, and 3) the detailed bone histopathology and morphometry assessments.

Overall, the studies revealed that ES and EM shared a similar toxicity profile in rats when administered during pregnancy and lactation and had similar effects on growth and development in young animals (after in utero, lactational, or direct exposure to ES or EM). Neither salt of esomeprazole was teratogenic.

Femur length, weight, cortical thickness and tibial growth plate thickness were affected in a similar manner in offspring of dams treated with ES and EM during pregnancy and lactation. Physeal dysplasia in the femur was identified as an adverse effect with the potential for growth abnormalities in pups born to dams treated with ES and EM.

Results

These studies clearly showed that any adverse effects noted in the various studies were due to the active moiety, esomeprazole, and not due to the associated salts, strontium or magnesium. Based on this, the FDA approved esomeprazole strontium under the 505(b)(2) process.

This example demonstrates that changing the salt of the active moiety can lead to unique and highly complex nonclinical issues. Premier Consulting can evaluate such 505(b)(2) salt changes and other changes made to an active moiety. Contact us to learn more.

Author:

William Salminen, PhD, DABT, PMP
Director of Scientific and Regulatory Affairs

References:

[i] US FDA.  Draft Guidance for Industry: Application covered by section 505(b)(2). October 1999.

[ii] AstraZeneca Pharmaceuticals. Drug Label: Nexium (esomeprazole magnesium) delayed-release capsules for oral use. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022101s014021957s017021153s050lbl.pdf.  December 2014.

[iii] Amneal Pharmaceuticals. Drug Label: Esomeprazole strontium delayed-release capsules for oral use. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202342s002lbl.pdf. December 2014.

[iv] US FDA CDER. Pharmacology/Toxicology NDA/BLA review and evaluation for esomeprazole strontium (NDA 20-2342). April 2013.

[v] European Medicines Agency (EMA). European Public Assessment Report: Protelos (strontium ranelate). April 2014.

[vi] US Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. Toxicological profile for strontium. April 2004.

[vii] US Environmental Protection Agency. Integrated Risk Information System (IRIS) Chemical Assessment Summary for Strontium. October 1992.