Lumasiran 94.5mg/0.5ml solution for injection vials

Introduction Primary hyperoxaluria (PH) is a devastating disease in children and adults. Recently, a substantial progress in the treatment of this deadly disease has been made that consists of the introduction of the RNA inhibitors, lumasiran and nedosiran, which deplete the substrate for oxalate synthesis. Methods Lanthanum carbonate (Lanth.Carb., La2[CO3]3) is a powerful phosphate binder having a strong affinity to oxalate. Its use as such in PH is not relevant because patients with normal renal function develop a severe phosphate depletion without a clear effect on oxalate balance. Considering that the absorption of phosphate is in the early gastrointestinal (GI) tract and mainly in the distal part of the GI tract for oxalate, we developed a targeted release capsule (trc) containing 500 mg Lant.Carb. released in the distal part of the GI tract as proven by radiological investigations of the radiopaque trcLanth.Carb. Results Four patients with PH and estimated glomerular filtration rate > 60 ml/min per 1.73 m2 were treated with trcLanth.Carb., which turned out to decrease the urinary oxalate concentrations clearly < 0.51 mmol/24 h per 1.73 m2,45 mg/24 h per 1.73 m2 (considered as upper limit of normal), after 2.5 months of treatment in 3 patients and 18 months in 1 patient. Calciuria remained normal or decreased slightly. Phosphaturia and phosphatemia remained normal and stable in all 4 cases. Conclusion trcLanth.Carb. is a promising repurposed, efficient, nontoxic, and cheap drug, lacking serious side effects in the treatment of any type of PH in whatever place in the world. A randomized controlled trial supporting this proof-of-concept is the next step.

Abstract licence: CC BY-NC-ND

Small RNA or oligonucleotide therapeutics represent a unique modality outside the traditional treatment paradigm of small molecule and protein-based drugs that have historically only targeted a small fraction of the proteome. Innovations in the structural design and chemical modification have been invaluable for recent oligonucleotide therapeutics, greatly improving their biological stability, intracellular delivery, and targeting. Widespread adoption of these strategies has further enabled the application of oligonucleotides as viable drugs and expanded the class of RNA therapeutics, with thirteen antisense oligonucleotides (ASOs) (fomiversen, mipomersen, nusinersen, inotersen, eteplirsen, golodirsen, casimersen, viltolarsen, tofersen, eplontersen, olezarsen, and donidalorsen), seven small interfering RNAs (siRNAs) (patisiran, givosiran, lumasiran, inclisiran, vutrisiran, nedosiran, and fitusiran), and two aptamers (pegaptanib and avacincaptad pegol) that have been approved by the United States Food and Drug Administration (FDA). RNA therapeutics have expanded the druggable space and provide a novel treatment strategy, they do not fit within the framework of our current methodology in evaluating risk of drug-drug interactions (DDIs) and assessing pharmacokinetic/pharmacodynamic (PK/PD) relationships. This article provides an overview of FDA-approved oligonucleotide therapies, emphasizing chemical modifications, molecular targets for mechanistic actions, and available ADME and PK/PD properties, followed by the discussion of critical needs for risk assessment strategies suited for this unique modality that focuses on possible DDIs with concomitant drugs. The latter may involve direct competition for the endogenous RNA interference machinery to alter ADME or relevant PD gene expression, rather than uncommon binding or interactions with drug-metabolizing enzymes or transporters found and recommended for small molecule drugs.

Abstract licence: CC BY