Lixivaptan

Lixivaptan
Clinical data
ATC code
  • none
Identifiers
  • N-[3-chloro-4-(6,11-dihydropyrrolo[2,1-c] [1,4]benzodiazepine-5-carbonyl)phenyl]-5-fluoro-2-methylbenzamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.126.016 Edit this at Wikidata
Chemical and physical data
FormulaC27H21ClFN3O2
Molar mass473.93 g·mol−1
3D model (JSmol)
  • C1c2cccn2Cc3ccccc3N1C(=O)c4ccc(cc4Cl)NC(=O)c5cc(F)ccc5C
  • InChI=1S/C27H21ClFN3O2/c1-17-8-9-19(29)13-23(17)26(33)30-20-10-11-22(24(28)14-20)27(34)32-16-21-6-4-12-31(21)15-18-5-2-3-7-25(18)32/h2-14H,15-16H2,1H3,(H,30,33) ☒N
  • Key:PPHTXRNHTVLQED-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Lixivaptan (VPA-985) is an orally-active, non-peptide, selective vasopressin 2 receptor antagonist being developed as an investigational drug by Palladio Biosciences, Inc. (Palladio), a subsidiary of Centessa Pharmaceuticals plc. As of December 2021, lixivaptan is in Phase III clinical development for the treatment of Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to lixivaptan for the treatment of ADPKD.

Mechanism of action

Lixivaptan is a potent, non-peptide, selective vasopressin receptor antagonist. It is a member of the vaptan class of drugs.

Hyponatremia

V2 receptor antagonists inhibit the binding of arginine vasopressin to vasopressin receptor 2 (V2R) in kidney tubular epithelial cells, thereby having a net effect of aquaresis, or electrolyte free water excretion.[1] This property of vaptans explains their use as therapies to treat euvolemic and hypervolemic hyponatremia.[2]

ADPKD

V2 receptor antagonists may have utility as therapies for ADPKD. Genetic mutations associated with ADPKD cause an increase in intracellular levels of cyclic adenosine monophosphate (cAMP), which results in increased cellular proliferation and cyst formation and expansion in the kidney.[3] Cyst growth displaces and destroys normal kidney tissue, leading to a decreased number and function of nephrons. Because intracellular cAMP is a secondary messenger for vasopressin acting at V2R (vasopressin receptor 2), V2 receptor antagonists can restore normal levels of intracellular cAMP, thereby delaying cyst growth. Treatment with specific V2 receptor antagonists have shown a reduction in kidney size and cyst volume in animal models of PKD.[4][5] In particular, lixivaptan has demonstrated beneficial effects on cystic disease progression in rat and mouse models of ADPKD. [6][7]

Research

V2 Receptor Antagonists in ADPKD

Proof of efficacy for V2 receptor antagonists to treat ADPKD has been demonstrated by clinical trials with tolvaptan, a vasopressin antagonist in the same drug class as lixivaptan.[8] In clinical studies, tolvaptan showed a significant decrease in the rate of disease progression in patients with ADPKD, which led to regulatory approvals for tolvaptan as a treatment of ADPKD in many countries, including the U.S., the EU, Japan, Canada, Australia, and Korea, among others.[9] However, tolvaptan therapy is associated with potentially life-threatening liver toxicity in patients with ADPKD.[10] Because of the risk of liver toxicity, in the US, tolvaptan is only available for ADPKD under a restricted distribution program (a Risk Evaluation and Mitigation Strategies (REMS program). The FDA-approved prescribing information for tolvaptan for ADPKD includes a boxed warning for the risk of serious liver toxicity.[11]

Clinical studies

Hyponatremia

Lixivaptan was previously administered to more than 1600 subjects across 36 clinical studies as part of a prior clinical development program for the treatment of hyponatremia sponsored by Cardiokine, Inc.[1] Across these studies, lixivaptan showed prolonged inhibition of the vasopressin V2 receptor, as measured by changes in pharmacodynamic markers such as urine osmolality, plasma copeptin, and estimated glomerular filtration rate (eGFR).[12] Development of lixivaptan for hyponatremia indications is no longer ongoing.

ADPKD

Palladio conducted the ELiSA Phase II study with lixivaptan in 31 ADPKD patients. In this study, the proportion of study subjects who showed a urine osmolality response consistent with full vasopressin V2 receptor inhibition was qualitatively and quantitatively similar to the published effect seen in clinical studies conducted with tolvaptan.[13]

A Phase III study by Palladio to investigate whether it is safe and effective for the treatment of ADPKD was commenced in October 2021.[14] The Phase III program with lixivaptan consists of two ongoing clinical trials: the ACTION and ALERT studies.

The ACTION study

The ACTION study[14] is a pivotal registration-enabling Phase III clinical trial of lixivaptan in patients with ADPKD. It is projected to enroll 1350 patients in more than 20 countries worldwide. If the ACTION study is successful, it will provide the main clinical evidence supporting the potential safety and efficacy of lixivaptan for the treatment of ADPKD.

The ACTION trial consists of two main parts.[14] In Part 1 of the study, after completing the screening, run-in and titration periods, study subjects will enter a two-arm, double-blind, placebo-controlled, randomized period during which they will receive lixivaptan or placebo for 12 months. This part of the trial will compare the change in estimated glomerular filtration rate (eGFR) measurements between the two groups to investigate the efficacy of lixivaptan in slowing the decline in kidney function. This is followed by Part 2 of the study, during which all study participants who complete Part 1 will receive lixivaptan in a single-arm, open-label phase for an additional 12 months. Part 2 will investigate whether lixivaptan's effect on kidney function continues to accrue over time. Altogether, including the titration periods, participants in the ACTION study will be taking study drug for more than two years, including lixivaptan for at least one year. It is expected that Part 1 will be completed for all participants by February 2025; Part 2 is projected to run until April 2026.[14]

The ALERT study

The second Phase III study with lixivaptan is the ALERT study.[15] The goal of this study is to investigate whether lixivaptan can be safely used in patients with ADPKD who were previously treated with tolvaptan, but who had to permanently discontinue tolvaptan therapy due to liver toxicity. In the study, following titration to an optimal dose, up to 50 patients with ADPKD will be enrolled and treated with lixivaptan for 52 weeks. They will be monitored frequently for signs of liver toxicity for as long as they are taking lixivaptan. At the completion of the 52 weeks maintenance period, patients will be eligible to continue to receive lixivaptan in an open label extension study.

DILIsym simulations

Tolvaptan was studied in DILIsym®, a state of the art, multiscale computational model that uses non-clinical and clinical drug data to predict whether a drug could cause idiosyncratic liver toxicity.[16] DILIsym® replicated accurately the liver toxicity observed with tolvaptan in clinical studies.[17] Conversely, results from the DILIsym® study with lixivaptan suggest that lixivaptan may be less likely to cause idiosyncratic liver toxicity within this modeling system.[18] Whether this result reliably predicts a lower risk of liver injury for lixivaptan will require more clinical safety data, which will be collected as part of the two ongoing Phase III clinical studies.

References

  1. ^ a b Bowman BT, Rosner MH (2013). "Lixivaptan - an evidence-based review of its clinical potential in the treatment of hyponatremia". Core Evidence. 8: 47–56. doi:10.2147/CE.S36744. PMC 3712664. PMID 23874242.
  2. ^ Verbalis JG, Grossman A, Höybye C, Runkle I (July 2014). "Review and analysis of differing regulatory indications and expert panel guidelines for the treatment of hyponatremia". Current Medical Research and Opinion. 30 (7): 1201–1207. doi:10.1185/03007995.2014.920314. PMID 24809970. S2CID 21539659.
  3. ^ Chebib FT, Sussman CR, Wang X, Harris PC, Torres VE (August 2015). "Vasopressin and disruption of calcium signalling in polycystic kidney disease". Nature Reviews. Nephrology. 11 (8): 451–464. doi:10.1038/nrneph.2015.39. PMC 4539141. PMID 25870007.
  4. ^ Gattone VH, Wang X, Harris PC, Torres VE (October 2003). "Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist". Nature Medicine. 9 (10): 1323–1326. doi:10.1038/nm935. PMID 14502283. S2CID 30926917.
  5. ^ Wang X, Gattone V, Harris PC, Torres VE (April 2005). "Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat". Journal of the American Society of Nephrology. 16 (4): 846–851. doi:10.1681/ASN.2004121090. PMID 15728778.
  6. ^ Wang X, Constans MM, Chebib FT, Torres VE, Pellegrini L (2019). "Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model". American Journal of Nephrology. 49 (6): 487–493. doi:10.1159/000500667. PMC 6647848. PMID 31117065.
  7. ^ Di Mise A, Wang X, Ye H, Pellegrini L, Torres VE, Valenti G (October 2021). "Pre-clinical evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for autosomal dominant polycystic kidney disease". FASEB Journal. 35 (10): e21874. doi:10.1096/fj.202100774R. PMC 9290345. PMID 34486176.
  8. ^ Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, et al. (November 2017). "Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease". The New England Journal of Medicine. 377 (20): 1930–1942. doi:10.1056/NEJMoa1710030. PMID 29105594. S2CID 41483400.
  9. ^ "Otsuka's JYNARQUE™ (tolvaptan) Approved by U.S. FDA as the First Treatment to Slow Kidney Function Decline in Adults at Risk of Rapidly Progressing Autosomal Dominant Polycystic Kidney Disease (ADPKD)". Otsuka press release. Retrieved November 12, 2021.
  10. ^ Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, et al. (November 2015). "Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database". Drug Safety. 38 (11): 1103–1113. doi:10.1007/s40264-015-0327-3. PMC 4608984. PMID 26188764.
  11. ^ "Jynarque- tolvaptan kit Jynarque- tolvaptan tablet". DailyMed. March 31, 2020. Retrieved November 12, 2021
  12. ^ Ku E, Nobakht N, Campese VM (May 2009). "Lixivaptan: a novel vasopressin receptor antagonist". Expert Opinion on Investigational Drugs. 18 (5): 657–662. doi:10.1517/13543780902889760. PMID 19379124. S2CID 72325634.
  13. ^ Shusterman NH, Hogan LC, Pellegrini L (2019). Results of ELiSA, a Phase 2 Clinical Study with Lixivaptan in Patients with Autosomal Dominant Polycystic Kidney Disease. ASN Kidney Week 2019 Abstract supplement. Journal of the American Society of Nephrology. Vol. 30. p. 339. Poster PO844.
  14. ^ a b c d Clinical trial number NCT04064346 for "Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (ACTION)" at ClinicalTrials.gov
  15. ^ Clinical trial number NCT04152837 for "Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease (ALERT)" at ClinicalTrials.gov
  16. ^ Woodhead JL, Brock WJ, Roth SE, Shoaf SE, Brouwer KL, Church R, et al. (January 2017). "Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors". Toxicological Sciences. 155 (1): 61–74. doi:10.1093/toxsci/kfw193. PMC 5216653. PMID 27655350.
  17. ^ Watkins PB (March 2019). "The DILI-sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation". Clinical and Translational Science. 12 (2): 122–129. doi:10.1111/cts.12629. PMC 6440570. PMID 30762301.
  18. ^ Woodhead JL, Pellegrini L, Shoda LK, Howell BA (January 2020). "Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling". Pharmaceutical Research. 37 (2): 24. doi:10.1007/s11095-019-2726-0. PMC 6944674. PMID 31909447.

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