Extended Dosing Intervals (EDI), a new option for long-term drug therapy in patients with large limbs!

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Pharmacotherapy is an important treatment option for acromegaly ("extremity"), and most patients with large extremities who receive medical treatment require long-term ^treatment1, however, higher frequency oral or injection modalities may place a serious medication burden on many patients with large extremities and may reduce treatment ^adherence2
.
Therefore, it is important to optimize the long-term medication regimen of patients with large limbs to improve the acceptability and adherence of long-term ^treatment1
.

Expert introduction

Professor Wang Xiaoli

Chief physician, professor and master tutor of the Department of Endocrinology, First Affiliated Hospital of China Medical University

·Graduated from China Medical University in 2005 with a seven-year clinical medical major

In 2011, he obtained a doctorate degree in endocrine metabolism from Japan Autonomous Medical University

In 2016, he was a member of the eighth batch of Liaoning Medical Team for Xinjiang Aid by the Organization Department of the CPC Central Committee

He is a member of the Rare Disease Group of the 11th Committee of the Endocrine Society of the Chinese Medical Association

·Vice Chairman of the Youth Committee of the Third Committee of the Osteoporosis and Bone Salt Metabolism Disease Branch of Liaoning Medical Association

Youth Committee Member of Liaoning Diabetes Branch

Member of Liaoning Provincial Immunology and Endocrine Immunology Branch

Member of the 1st Diabetes Prevention and Control Professional Committee of Liaoning Preventive Medicine Association

Member of the First Professional Committee of Osteoporosis Prevention and Control in the Elderly of Liaoning Preventive Medicine Association

Member of the Professional Committee of Parathyroid and Bone Metabolism Diseases of the Chinese Research Hospital Association

EDI, an important solution to reduce the drug burden in patients with large limbs

Limb enlargement, as an endocrine metabolic disease with insidious onset, is characterized by over-secretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) in ^circulation3
.
Long-term excess secretion of GH and IGF-1 in patients with large limbs can cause complications of multiple organs/systems such as respiratory, cardiovascular, digestive, and glycolipid metabolism, and lead to increased ^mortality1
。 Pharmacotherapy is one of the main methods of treating acromegaly, often recommended for surgical removal of adenomas, the disease is still in a state of continuous activity or not suitable for surgery in patients, drug treatment options include long-acting somatostatin receptor ligands (SRLs, lanmireotide, octreotide and parreotide), dopamine receptor agonists (bromocriptine, cabergoline) and GH receptor antagonists (pevisomen), among others, SRLs can not only achieve high biochemical remission rates but also significantly reduce tumor volume (Table 1), Often recommended as the treatment of ^choice3
.

Table 1.
Comparison of treatment methods for large extremities

Given that limb size is a chronic, progressive disease, most patients receiving medication require long-term treatment, pevisomon requires daily injections, bromocriptine requires daily oral administration, cabergoline requires oral administration twice a week, traditional somatostatin analogues (SSA) require monthly injections by healthcare professionals, frequent visits to the clinic for injections can be a serious burden on some patients and can negatively affect the patient's quality of life (QoL), treatment adherence, and treatment satisfaction, EDI can not only reduce the frequency of medication, reduce the cost of treatment, convenient treatment, but also reduce the risk of treatment-related side ^effects2, providing an important solution
for long-term drug treatment of patients with large limbs.
So how to choose the most appropriate long-term EDI treatment plan for patients with large limbs?

Lanreotide, an EDI protocol that combines good efficacy, safety and improves quality of life

The recent European Congress of Endocrinology (ECE) published a systematic literature review evaluating the clinical efficacy/efficacy, safety and tolerability, health-related quality of life (HRQoL), treatment preference and economic outcomes of long-acting somatostatin receptor ligands (SRLs), GH receptor antagonists, and dopamine agonists EDI regimens in patients with large limbs, including Lanreotide acetate sustained-release injection (pre-filled) (Lanreotide ATG), Octreotide and parmiotide (both used less than once every four weeks), oral Octreotide (less than 2 times a day), pevisomene (no more than 1 time per day) and cabergoline (less than 2 times a week), a total of 35 articles reported 27 studies (14 in pevisomen, 9 in lanmiotide ATG, 4 in octreotide [monotherapy/combination therapy]), the results showed ⁴:

In terms of biochemical control, IGF-1 levels were generally reduced across all EDI protocols from baseline to the end of the study; GH levels decreased in patients receiving SRL EDI and were not associated with baseline biochemical control levels; Patients with normal baseline IGF-1 levels (previously treated with standard regimens) received Lanreotide ATG, Octreotide, and Pevisomon EDI regimens and maintained IGF-1 levels at the end of the study (Table 2);

Table 2.
IGF-1 and GH results after EDI treatment

In terms of tumor size, only Lanreotide ATG (n=1/1; 8-9 patients per treatment group) and pevisopemone combined with SRL (n=4/4; 32-104 patients) EDI protocol has been reported to achieve tumor reduction;

In terms of adherence, the compliance of the Lanreotide ATG standard administration interval regimen is higher than that of the Pevisomon EDI regimen;

In terms of safety, the proportion of adverse events (AEs) in EDI regimens or standard dosing intervals did not vary much (n=4 studies; Lanreotide ATG, Pevisopong combined with SRL; All interventional studies), AEs are generally mild to moderate;

In terms of HRQoL, the HRQoL of the EDI protocol of Pevisomon and Pevisomon did not deteriorate, the HRQoL of the octreotide EDI protocol was maintained, and the Lanreotide ATG EDI protocol improved HRQoL (Figure 1);

In terms of economic benefits, patients are more inclined to the lanreotide ATG EDI protocol than octreotide, with higher satisfaction and reduced economic costs (Figure 1
).

It can be seen that Lanreotide ATG is the preferred EDI protocol
that combines good efficacy, safety and can improve quality of life, improve treatment adherence and reduce economic costs.

Figure 1.
Efficacy, safety, HRQoL and economic benefits of multiple EDI regimens (LAN: Lanreotide; OCT: octreotide; PEG: Pevisomon)

Lanreotide EDI protocol to meet the long-term treatment needs of patients with different limb sizes

Previous studies have confirmed that the Lanreotide ATG EDI protocol is effective, safe, and improves quality of life in patients with different limb sizes:

Patients with initial treatment of SSA: An open-label, non-comparative, stage III, multicenter clinical study showed that the efficacy and safety of Lanreotide ATG 120 mg injected every 4-8 weeks were evaluated, and the results showed that after 48 weeks of treatment with 6-week and 8-week EDI regimens, the control rate of GH reached 100% and 73%, respectively, and the proportion of patients with normal IGF-I levels reached 65% and 33%, respectively (Figure 2); With the exception of pelvic and shoulder pain, most clinical symptoms (especially the five common clinical symptoms) were significantly improved and there was no difference between different groups of administration ^intervals5
.

Figure 2.
Biochemical control of lanmireptine ATG 120 mg 8/6 weeks after 48 weeks of treatment

Patients treated with long-acting octreotide: In a multicenter, open-ended, uncontrolled, 48-week, two-stage study showing that adult limb adults with normal biochemical parameters after long-acting octreotide 10 mg or 20 mg/4 weeks switched to Lanreotide ATG 120 mg for 6 or 8 weeks of EDI for 48 weeks, 94.
4% of patients had GH≤2.
5 ng/ml and remained stable, in addition, most patients preferred the Lanreotide ATG EDI regimen, Lanrepetide ATG 8-week EDI preference rate up to 92.
3% (Figure 3)¹; A phase III, multicenter, open study showed that patients with limb size who had previously been treated with long-acting octreotide (10-30 mg)/4 weeks of EDI with Lanreotide ATG 120 mg 4-8 weeks of EDI maintained a comparable level of biochemical control, had good safety, and patients were more satisfied with Lanreotide ATG for 6-8 weeks EDI (Figure 4)⁶;

Figure 3.
Proportion of patients selected for different regimens

Figure 4.
Patient satisfaction after long-acting octreotide (OCT LAR) is converted to lanreotide ATG EDI protocol

Patients who have achieved clinical and biochemical control (normal IGF-1 levels) through other treatment regimens: a cross-sectional, multicenter, observational, real-world study included 109 patients who had achieved clinical and biochemical control (73 Lanreotide ATG 120 mg, 7 Lanreotide other dosage forms, 28 octreotide, 1 pevisomen, 81 previous surgical and/or radiotherapy therapy), Lanreotide ATG 120 mg > 4 weeks EDI treatment after 6 months of results, IGF-1 levels were effectively controlled in more than 90% of patients with good patient satisfaction and adherence, with 94.
5% patient treatment adherence and no significant effect on adherence at 5-6 weeks and EDI regimens at 7-8 weeks (Figure 5)²
.

Figure 5.
Patient compliance after different lanreotide ATG EDI regimens

brief summary

In summary, most of the limb patients receiving drug treatment need long-term treatment, EDI can not only reduce the frequency of medication, reduce the cost of treatment, convenient treatment, and can reduce the risk of treatment-related side effects, is an important program to optimize long-term drug therapy in patients with large limbs, wherein, Lanreotide ATG EDI program is both good efficacy, safety and can improve quality of life, improve treatment compliance and reduce economic costs of the preferred program, can meet the initial treatment of SSA, long-acting octreotide therapy, Through other treatment options, the treatment needs
of patients with various extremities such as clinical and biochemical control have been met.

Expert reviews

For patients with large limbs, long-term maintenance of biochemical remission is of great significance for improving survival and quality of life, and for patients with large limbs who need to receive drug therapy for a long time, the convenience and compliance of medication is one of the key factors in maintaining the efficacy of long-term treatment, and EDI is of great significance
in reducing medical burden, improving patient treatment convenience, improving compliance, and reducing treatment burden 。 At present, the domestic use of injection SSA is mostly administered at 4-week intervals, and Lanreotide ATG is the only treatment drug approved internationally for EDI in patients with large limbs, and the injection interval can be extended to 8 weeks, and Lanreotide ATG has been included in the national medical insurance drug list, I believe that the future can benefit more patients with large limbs!

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References:

1.
Neggers S, et al.
Eur J Endocrinol.
2015 Sep; 173(3):313-323.

2.
Bernabéu I, et al.
Endocrine.
2020 Dec; 70(3):575-583.

3.
Endocrinology Branch of Chinese Medical Association.
Chinese expert consensus on the diagnosis and treatment of acromegaly (2020 edition) [J] .
Chinese Journal of Endocrinology and Metabolism,2020,36(09): 751-760.

4.
Maria Fleseriu, et al.
Presented at 2022 ECE.
P432

5.
Lombardi G, et al.
J Endocrinol Invest.
2009 Mar; 32(3):202-9.

6.
Schopohl J, et al.
Experimental and Clinical Endocrinology & Diabetes.
2011; 119(03):156-162.

Approval number: SOM-CN-001410

Validity: September 26, 2023