Lumasiran is proven to be safe and effective again | patients with rare disease PH1 are expected to bid farewell to liver and kidney transplantation!

Primary hyperoxaluria (PH) is a genetic disease, usually caused by abnormal metabolism of the liver, which produces excessive oxalate and causes kidney involvement.

As an RNA interference therapy drug, Lumasiran can inhibit alcohol oxidase and reduce the production of glycyrrhizic acid.

In 2020, Lumasiran was approved by the US Food and Drug Administration for PH1 treatment.

The recently published European multinational clinical trials once again proved that Lumasiran is safe and effective in the treatment of PH1 type.

Study Design This study is a phase 1 and phase 2 clinical trial of Lumasiran in many European countries.

Phase 1 was conducted in a single center in the United Kingdom, with 32 healthy adults, while the Phase 2 trial included 20 patients with PH1 type in multiple research centers in the United Kingdom, Germany, Israel, France, and the Netherlands.
get on.

The duration of the two trials is from March 8, 2016 to January 23, 2019.

This article mainly introduces the experimental process and results of the Phase 2 trial.

01 Baseline information Phase 2 trial included a total of 20 people, who were divided into Lumasrian group and control group according to 3:1.

Participants are young in the range of 6-64 years old, the patient's 24-hour oxalic acid excretion is greater than 0.
7mmol/1.
73㎡ (the upper limit of normal is 0.
46mmol/24h/1.
73㎡) and the estimated glomerular filtration rate (eGFR)> 45ml/min/1.
73㎡.

Researchers believe that the renal function of these patients can satisfy their excretion of oxalate.

02 Trial intervention The phase 1 clinical trial was divided into 4 groups, each with 8 cases, of which three groups were injected with Lumasrian (1) 0.
3 mg/kg; (2) 1 mg/kg and (3) 3 or 6 mg/kg, the last one The group was the control group and was injected with 0.
9% saline.

 The Phase 2 clinical trial is divided into 4 groups with 5 cases in each group.

In the 3 groups, 15 patients were in the Lumasrian group.
In this group, the monthly injection dose of Lumasiran was (1) 1 mg/kg; (2) 3 mg/kg and (3) 3 mg/kg every three months.

The last group of PH1 patients was injected with 0.
9% saline as a control group.

In terms of the primary endpoint of the 03 study endpoint trial, Phase 1 and Phase 2 are the same, that is, the safety inspection, including the incidence of adverse events, and the detection of vital signs.

 The secondary endpoints of the phase 1 and phase 2 trials are different.
The phase 1 trial is to observe the plasma glycolic acid concentration; the phase 2 trial is to observe the 24-hour urine oxalate excretion and serum urine oxalate.

In terms of the main endpoint of the study results, in this trial, most adverse events were mild to moderate in severity and were considered not related to Lumasiran.

At the same time, no serious adverse events were reported in the phase 1 or phase 2 trials, and no participants died or withdrew from the study.

 In terms of secondary endpoints, among the participants in the phase 1 clinical trial, only those who used doses above 1 mg/kg had an increase in plasma glycolic acid concentration.

Therefore, researchers believe that 1mg/kg is the smallest "significant pharmacological effect" dose of Lumasiran.

 In the Phase 2 clinical trial, the oxalic acid excretion of all 20 patients in the Lumasiran group was ≤0.
69mmol/24h/1.
73㎡, which was about 1.
5 times the upper limit of normal.
At the same time, about 15 patients (75%) were within the normal range.
That is, ≤0.
46 mmol/24h/1.
73㎡.

Among the 12 patients who injected 3 mg/kg every month or every 3 months, 11 patients (92%) had 24-hour urinary oxalic acid excretion within the normal range.

 In addition, after using Lumasiran, the patient's plasma oxalate concentration decreased, with an average maximum decrease of 74% (range, 38%-94%).

Regarding PH, primary hyperoxaluria is caused by congenital abnormalities in the metabolism of oxalic acid and oxalic acid, and has recessive genetic characteristics.

PH1, 2, and 3 are essentially due to the lack of corresponding enzymes in the liver and excessive production of oxalate, which affects the kidneys.

The most common clinical manifestations of PH are recurrent urinary tract or kidney stones, and decreased renal function.

The development of PH in the later stages often causes end-stage renal disease (ESRD).

 The current treatment methods include drinking a lot of water and long-term combined use of calcium oxalate crystal inhibitors and vitamin B6, which can effectively prevent ESRD.

If a complete cure (that is, to correct enzyme deficiency) is required, combined liver and kidney transplantation is required.

  Conclusion Lumasiran is safe and effective for PH1 patients, and can reduce the patient's urinary oxalic acid excretion to near normal levels.

This is undoubtedly very good news for PH1 patients with rare diseases, and deserves the attention of physicians.

 In April this year, the results of Lumasiran's Phase 3 clinical study were published in the New England Journal of Medicine, and the results are also encouraging.

For details, please see >>>Lumarian, a new drug for the treatment of rare disease hyperoxaluria.

References: 1.
Frishberg Y, Deschênes G, Groothoff JW, et al.
Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial.
Clin J Am Soc Nephrol.
2021 May 13.
2.
Bouzidi H, Majdoub A, Daudon M, et al.
Hyperoxalurie primitive: une revue de la littérature [Primary hyperoxaluria: A review].
Nephrol Ther.
2016 Nov.