Introduction

Currently available intravenous iron formulations have an excellent safety profile, but preliminary data suggests that ferric derisomaltose (FDI) may be associated with an increased risk of mild-moderate infusion reactions compared to ferric carboxymaltose (FCM). FDI may be administered following dilution of doses of up to 1.5g in between 100 to 500ml normal saline, but whether dilution affects risk of infusion related adverse reactions via altering stability of the iron compound is uncertain. This study aimed to evaluate infusion related adverse events in patients who received FCM and two dilutions of FDI in a single tertiary centre.

Aims & Methods

A retrospective study of all patients who received intravenous FDI and FCM from January 2022 to April 2023 in a tertiary healthcare service outpatient infusion centre. Patients who received FDI were age and sex matched with patients who received FCM. Infusion reactions were classified independently by a gastroenterologist and a haematologist as either a Fishbane reaction or a hypersensitivity reaction. Fishbane reactions were defined by arthralgias, flushing and chest tightness without angioedema or hypotension. Hypersensitivity reactions were then further categorised using the Ring and Messmer classification. If discrepancies occurred, the cases were discussed individually. When consensus could not be reached, the reactions were categorised as unclassified. Rates of reactions were compared using a Fishers’ Exact test.

Results

234 patients (185 [79%] female, median age 45 [IQR 37-60] years) who received FDI were age and sex matched with 234 (185 [79%] female, median age 45 [IQR 37-60] years) patients who received FCM. There were no differences in baseline haemoglobin (mean 113 [SD 21] vs 115 [SD 19] g/L) or ferritin (mean 24 [SD 103] vs 24 [SD 19] μg/L) between patients receiving FDI and FCM, respectively. The most common cause of iron deficiency in the FDI group was blood loss [112/234]. Infusion reactions occurred in 23/234 [10%] patients receiving FDI, compared with 5/234 [2%] receiving FCM (p=0.006).
Of the patients who received FDI, 69 [29%] were diluted in 100mL normal saline and 165 [71%] were diluted in 250mL normal saline. There was no difference in the rate of infusion reactions among patients who received FDI diluted in 100mL (7/69 [10%]: 5 Fishbane and 2 hypersensitivity) or those who received FDI diluted in 250 ml (16/165 [10%]: 12 Fishbane, 2 hypersensitivity and 2 unclassified) (p=1.0). Two patients with reactions to FDI were administered adrenaline (both reactions classified as Fishbane) with one requiring hospitalisation. No other patients required hospitalisation.
In the FDI cohort, 31 [13%] received a dose of 1000mg, 202 [86%] received 1500mg and 1 [<1%] received 500mg. There was no significant difference in the rate of infusion reactions between patients who received 1000mg compared with 1500mg (5/31 [16%] vs 18/202 [9%], p=0.204). There was no infusion reaction in the patient who received 500mg.

Conclusion

In this retrospective medical record review, infusion-related reactions were more common in patients who received FDI compared with FCM. Fishbane reactions were the most common reaction type overall, and all but 1 patient were able to be discharged on the same day. Neither the dilution volume of FDI nor the dose of FDI was associated with risk of infusion reactions. Future large prospective studies are needed to confirm these findings and elucidate underlying factors that may be contributing to differing rates of infusion reactions between FDI and FCM.

Disclosure

A/Prof Mayur Garg has served on the advisory board of Pfizer and Pharmacosmos and has received speaker fees, research or travel grants from Abbvie, Celltrion, Dr Falk, Janssen, Pfizer, Pharmacosmos, Takeda. The other authors have no disclosures.

Introduction

Iron malabsorption (FeM) may lead to iron deficiency anaemia (IDA). Its most common causes are celiac disease (CD) due to atrophy of the small intestine mucosa, corpus atrophic gastritis (CAG), and gastric surgery (GS): reduced hydrochloric acid secretion derived from corpus oxyntic mucosa atrophy or surgical resection causes a decreased conversion of Fe(III)ion to Fe(II)ion, the latter being the more easily absorbable form. IDA affects more than two billion people over the world and it can cause troublesome symptoms as asthenia and fatigability. Iron oral supplementation is considered the standard therapy but frequently it leads to side effects reducing long-term compliance. Ferric carboxymaltose (FCM) is an intravenous (iv) preparation shown to be safe and effective in improving the iron status (FeS), but its efficacy in patients with FeM and IDA has not been investigated so far.

Aims & Methods

To evaluate the safety, efficacy and quality of life impact of iv FCM in treating pts with IDA due to FeM. A prospective observational single centre study was conducted on 37 pts with IDA caused by CAG (n=19/51.4%), CD (n=9/24.3%), and GS (n=9/24.3%). Pts with other causes of IDA as GI bleeding were excluded. At baseline (T0), pts were clinically and biochemically evaluated (symptoms, SF12, CBC and FeS: ferritin, iron, transferrin, transferrin saturation (TS)). FCM dosage was calculated according to Ganzoni formula considering Hb values and body weight. If the dosage needed was up to 1000mg, iv infusion was scheduled in a single session, otherwise a 2 nd infusion after 1 wk was planned. After treatment, CBC and FeS were assessed at 4 (T4) and 12 (T12) wks. SF12 was revaluated after 12 wks (cut-off physical component summary (PCS)<44, mental component summary (MCS)<46). IDA was defined as Hb<13 and <12 g/dl for men and women, ferritin<45 ng/dl or TS<15%. Moderate and severe anemia were defined as Hb 8-10 and Hb<8 g/dl. Student’s t-test was used to compare CBC and FeS parameters at baseline (T0), 4 weeks (T4) and 12 weeks (T12).

Results

All 37 patients completed 12-wks-follow-up. At T0 Hb was mean±SEM 10.9±0,2g/dl, 18.9% had moderate and 2.7% severe anaemia. In pts treated in a single-session-infusion (64.9%), dosage of FCM was mean±SEM 975±12mg; in pts treated in two sessions (35.1%), FCM dosage was mean±SEM 1400±77mg. One patient reported mild side effects (pruritus, cutaneous erythema) not requiring FCM interruption and reversing after H₂ antagonist treatment within 15 minutes. At T4 and T12, 70.4% and 78.4% of pts recovered from IDA. At T4 mean Hb significantly increased compared to T0 (12.7±0.2 vs 10.8±0.2 g/dl, p<0.0001). At T12 a further increase was observed (13.1±0.2 g/dl, p<0.05). Also, TS increased from 6% at T0 to 20% at T12, p<0.0001. At T4 ferritin levels (ng/dl) significantly increased compared to T0, but slightly decreased at T12 (T0 28.5±11.2 vs T4 188.2±25.7, p<0.0001; T12 124.9±25.7, p=0.10). RDW (%) significantly increased at T4 and significantly decreased at T12(T0 15.4±0.5 vs T4 18.6±0.7, p=0.0003; T12 14.8±0.4, p<0.0001). The proportion of patients with SF12 MCS>46 and PCS>44 scores significantly increased at T12 compared to T0 indicating improved mental and physical health perception after FCM treatment.

Conclusion

In pts with IDA due to FeM, ivFCM is an effective and safe treatment, leading to recovery of IDA in nearly 80% of cases at 12 weeks after treatment and concomitantly to an improved mental and physical health perception. These data show that ivFCM treatment could be considered as a first line treatment for IDA patients with FeM.

References

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Introduction

Chemotherapy-induced diarrhea (CID), a dose-limiting toxicity impairing treatment adherence and anticancer efficacy, lacks targeted prophylaxis. While short-acting glucagon-like peptide-2 (GLP-2) analog was approved for short bowel syndrome (SBS), the mucosal regenerative properties of GLP-2 suggest therapeutic potential for CID prevention. GLP-2 can also enhance the intestinal mucosal barrier and may provide a new treatment option for inflammatory bowel disease (IBD). In this study, we developed FT1, a long-acting GLP-2 analog engineered for sustained exposure, and reported first-in-human phase I trial data of FT1 in Chinese healthy adults.

Aims & Methods

This randomized, double-blind, placebo-controlled, single-center phase I study (NCT06610487) evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of FT1 to establish dosing rationale for the future CID trials. Single ascending dose (SAD: 0.05-0.4 mg/kg) and multiple ascending dose (MAD: 0.1-0.2 mg/kg, once weekly for 3 weeks) were administered subcutaneously. Participants were randomized 3:1 (SAD; except for 0.05 mg/kg: 2:1) or 4:1 (MAD) to receive FT1 or placebo. Plasma citrulline, a validated biomarker of enterocyte mass, served as the primary PD endpoint. Safety, PK, PD, and immunogenicity were assessed up to 28 days post-dose.

Results

Currently available analyzed data (n=50) revealed:
1. PK: FT1 exhibited dose-proportional exposure (C_max/ AUC_0-inf) across SAD doses (0.05-0.4 mg/kg). Median T_max was 24 h with prolonged t_1/2 = 67.6-69.1 h. MAD regimens showed moderate accumulation (1.42- 1.73-fold post-3rd dose).
2. PD: Citrulline elevation was dose- and regimen-dependent. SAD 0.4 mg/kg achieved maximal change in plasma citrulline (ΔE_max) = 3,340 ng/mL (baseline: 5,125 ng/mL) at 8.5 days post-dose. After weekly administration of FT1, the citrulline level was further enhanced. MAD 0.2 mg/kg induced 33% greater ΔE_max vs MAD 0.1 mg/kg (4,512 vs 3,390 ng/mL; both post-3rd dose), exceeding SAD 0.4 mg/kg response.
3. Safety: All adverse events were Grade 1-2 (CTCAE v5.0) with no dose-limiting toxicities or immunogenicity signals.

Conclusion

FT1 demonstrated favorable safety and linear PK up to 0.4 mg/kg (SAD) and 0.2 mg/kg weekly×3 (MAD) in healthy participants. The 0.2 mg/kg MAD regimen achieved superior enterotrophic effects (citrulline ΔE_max) versus lower doses while maintaining tolerability, supporting it as a priority candidate for further clinical evaluation in patients with once-weekly dosing.

References

1. McQuade RM, et al. Chemotherapy-induced constipation and diarrhea: pathophysiology, current and emerging treatments. Front. Pharmacol. 2016, 7:414.
2. Barzał J, et al. Plasma citrulline level as a biomarker for cancer therapy-induced small bowel mucosal damage. Acta Biochim Pol. 2014; 61(4):615-31

Disclosure

Chengyong Tang, Mingxue Zhu, and Lei Wan have no conflicts of interest that are directly relevant to the content of this article. Kai Fan, Qing Chen, and Yanmin Bai are Chongqing Peg-Bio Biopharm Co., Ltd employees.