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ALLN-177, oral enzyme therapy for hyperoxaluria.

ABSTRACT: PURPOSE:To evaluate the potential of ALLN-177, an orally administered, oxalate-specific enzyme therapy to reduce urine oxalate (UOx) excretion in patients with secondary hyperoxaluria. METHODS:Sixteen male and female subjects with both hyperoxaluria and a kidney stone history were enrolled in an open-label study. Subjects continued their usual diets and therapies. During a 3-day baseline period, two 24-h (24-h) urines were collected, followed by a 4-day treatment period with ALLN-177 (7,500 units/meal, 3?×?day) when three 24-h urines were collected. The primary endpoint was the change in mean 24-h UOx from baseline. Safety assessments and 24-h dietary recalls were performed throughout. RESULTS:The study enrolled 5 subjects with enteric hyperoxaluria and 11 with idiopathic hyperoxaluria. ALLN-177 was well tolerated. Overall mean (SD) UOx decreased from 77.7 (55.9) at baseline to 63.7 (40.1) mg/24 h while on ALLN-177 therapy, with the mean reduction of 14 mg/24 h, (95% CI -?23.71, -?4.13). The calcium oxalate-relative urinary supersaturation ratio in the overall population decreased from a mean of 11.3 (5.7) to 8.8 (3.8) (-?2.8; 95% CI -?4.9, -?0.79). This difference was driven by oxalate reduction alone, but not any other urinary parameters. Mean daily dietary oxalate, calcium, and fluid intake recorded by frequent diet recall did not differ by study periods. CONCLUSION:ALLN-177 reduced 24-h UOx excretion, and was well tolerated. The results of this pilot study provided justification for further investigation of ALLN-177 in patients with secondary hyperoxaluria. TRIAL REGISTRATION:Clinicaltrials.gov NCT02289755.

SUBMITTER: Lingeman JE

PROVIDER: S-EPMC6459785 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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ALLN-177, oral enzyme therapy for hyperoxaluria.

Lingeman James E JE Pareek Gyan G Easter Linda L Pease Rita R Grujic Danica D Brettman Lee L Langman Craig B CB

International urology and nephrology 20190219 4

<h4>Purpose</h4>To evaluate the potential of ALLN-177, an orally administered, oxalate-specific enzyme therapy to reduce urine oxalate (UOx) excretion in patients with secondary hyperoxaluria.<h4>Methods</h4>Sixteen male and female subjects with both hyperoxaluria and a kidney stone history were enrolled in an open-label study. Subjects continued their usual diets and therapies. During a 3-day baseline period, two 24-h (24-h) urines were collected, followed by a 4-day treatment period with ALLN- ...[more]

PMID: 30783888

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Project description:BackgroundLutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited.Case descriptionA 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27-4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9-1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0-34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65-193 ng/dl)] and FT4 [3.9 ng/dl (1.2-2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi 177Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.SummaryWe report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland.ConclusionsThyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.

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ALLN-177, oral enzyme therapy for hyperoxaluria.

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ALLN-177, oral enzyme therapy for hyperoxaluria.

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