Mallinckrodt : Acthar Gel Phase 4 Keratitis ARVO Poster

Results From a Multicenter, Open-label, Phase 4 Study of Repository Corticotropin Injection in Patients With

Treatment-resistant Severe Noninfectious Keratitis

Joseph Grieco, PhD1; Eugene McLaurin, MD2; George Ousler3; Jingyu Liu1; R. Oktay Kacmaz, MD, MPH1; David Wirta, MD4

1Mallinckrodt Pharmaceuticals, Hampton, New Jersey; 2Total Eye Care, P.A., Memphis, Tennessee; 3Ora, Andover, Massachusetts; 4Eye Research Foundation, Newport Beach, California

Introduction

Background

• Keratitis is a painful inflammation of the cornea and is a significant cause of ocular morbidity1,2
• • If untreated, keratitis can lead to permanent corneal damage3
• Noninfectious keratitis is commonly treated with lubricants, corticosteroids, and immunosuppressants
• However, few treatment options are available for advanced noninfectious keratitis that has not improved after treatment with standard-of-care therapies

Repository Corticotropin Injection (RCI)

• RCI is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides4
• RCI engages all 5 melanocortin receptors on immune cells and tissues throughout the body and has demonstrated direct immunomodulatory and indirect anti-inflammatory effects5
• RCI is approved by the US Food and Drug Administration for the treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, including keratitis4

Objective

• This multicenter, open-label, phase 4 study evaluated the efficacy and safety of RCI for the treatment of refractory severe noninfectious keratitis that did not improve after treatment with first-line therapies (ClinicalTrials.gov NCT04169061)

Methods

Study Design and Data Collection

• Adults with severe noninfectious keratitis that did not improve after treatment with topical cyclosporin, lifitegrast, or any immunosuppressant were enrolled in the study
• Patients or their caregivers administered 80 U of RCI twice weekly for 12 weeks followed by a tapering period of 4 weeks (Figure 1)
• The following efficacy assessments were conducted at baseline and throughout the study (Figure 1):
• • Impact of Dry Eye on Everyday Life (IDEEL) questionnaire
  • Visual Analog Scale (VAS) for Eye Dryness
  • Ora Calibra™ Corneal and Conjunctival Staining Scales using fluorescein and lissamine green
• Safety was assessed via treatment-emergent adverse events (TEAEs) and serious TEAEs collected throughout the study (Figure 1)

Figure 1. Study Design and Data Collection

Abbreviations: BIW, twice weekly; IDEEL, Impact of Dry Eye on Everyday Life; RCI, repository corticotropin injection; SC, subcutaneously; TEAE, treatment-emergent adverse event; VAS, Visual Analog Scale.

Outcomes

• The primary efficacy endpoint was the proportion of patients with ≥12-point improvement in the IDEEL symptom bother score at week 12
• Other efficacy endpoints included proportions of patients with ≥20%, ≥30%, and ≥50% improvement in the IDEEL symptom bother score at week 12 and change from baseline to week 12 in VAS and sums of the Corneal and Conjunctival Staining Scales
• Safety endpoints were the percentage of patients who experienced any TEAE or serious TEAE throughout the study period

Statistical Analyses

• Efficacy endpoints were analyzed in the modified intent-to-treat (mITT) population (all patients who received ≥1 dose of RCI and contributed any postbaseline efficacy data)
• Safety endpoints were analyzed in the safety population (all patients who received ≥1 dose of
  RCI)
• 95% confidence intervals (CIs) were calculated based on normal approximation

Results

Demographics

• The mean (standard deviation [SD]) age of the mITT population (N=36) was 63.3 (10.2) years
• Most patients were female (71.4%), White (80.0%), and not of Hispanic or Latino ethnicity (94.3%)
• All patients had keratitis in both eyes; the mean (SD) and median durations of keratitis for all patients were 4.4 (5.4) and 2.6 years, respectively

IDEEL Symptom Bother Module

• At baseline, the mean (SD) IDEEL symptom bother score in the mITT population was 65.4 (15.5)
• • At week 12 after RCI initiation, 50.0% (95% CI
    [33.2%, 66.8%]) of patients had a ≥12-point improvement
  • 52.9% (95% CI [36.2%, 69.7%]) had a ≥12-point improvement as early as week 2

• The proportions of patients who experienced ≥20%, ≥30%, or ≥50% improvement in the symptom bother score at week 12 after starting RCI therapy are listed in Table 1

Table 1. Proportions of Patients Who Experienced ≥20%, ≥30%, or ≥50% Improvement in the IDEEL Symptom Bother Score

				Week 12 (n=34)
			≥ 20%		≥ 30%		≥ 50%
	%		95% CI, %	%	95% CI, %	%	95% CI, %
Symptom bother	50.0		(33.2, 66.8)	44.1	(27.4, 60.8)	14.7	(2.8,	26.6)

Abbreviation: IDEEL, Impact of Dry Eye on Everyday Life.

• Mean changes from baseline in the symptom bother score exceeded the minimal clinically important difference threshold at every time point (Figure 2)

Figure 2. Mean (95% CI) Change From Baseline in the IDEEL Symptom Bother Score

		0
	elin se	-5
tn	-1 0					M C ID = 1 2
em	ab
ev or	mfro	-1 5
pIm	eg n	-2 0
	ah C
		-2 5
		-3 0
			B a se lin e	W e e k 2	W e e k 4	W e e k 6	W e e k 1 2
		R C I, n	3 4	2 9	3 2	3 0	2 9

MCID is based on the threshold proposed by Fairchild et al.6

Abbreviations: IDEEL, Impact of Dry Eye on Everyday Life; MCID, minimal clinically important difference; RCI, repository corticotropin injection.

VAS

• At 12 weeks after RCI initiation, all symptoms assessed by the VAS had improved from baseline (Table 2)
• The most pronounced improvements were observed for eye dryness and eye discomfort

Table 2. Change From Baseline for Each Item of the

VAS

	Baseline (n=29)		Week 12 (n=26)
	Mean	SD	Mean	SD	95% CI
Eye dryness	77.6	18.2	−22.2	25.6	(−32.6, −11.8)
Burning/stinging	45.3	29.1	−13.5	24.3	(−23.3, −3.7)
Itching	44.1	29.5	−10.1	27.3	(−21.1, 0.9)
Foreign body	50.9	27.8	−17.7	22.5	(−26.7, −8.6)
sensation
Eye discomfort	71.3	20.3	−23.9	25.4	(−34.2, −13.7)
Photophobia	57.0	25.7	−19.5	26.5	(−30.2, −8.8)
Pain	34.5	23.3	−15.0	20.2	(−23.1, −6.9)

Abbreviations: SD, standard deviation; VAS, Visual Analog Scale.

Corneal and Conjunctival Staining Scales

• At baseline, the mean (SD) fluorescein corneal sum in the mITT population was 5.3 (0.9)
• • Improvements from baseline were observed as early as week 4 after initiation of RCI treatment
    (−1.0 [1.5]; 95% CI [−1.5, −0.4]) and were sustained

through week 12 (−1.1 [1.4]; 95% CI [−1.6, −0.6])

• At baseline, the mean (SD) lissamine green conjunctival sum in the mITT population was 3.5 (1.3)
• • Improvements from baseline were observed as early as week 4 after initiation of RCI treatment (−0.6 [0.9]; 95% CI [−0.9, −0.2]) and were sustained through week 12 (−0.7 [1.4]; 95% CI [−1.2, −0.2])

Safety

• Of patients in the safety population (N=36), 33.3% experienced ≥1 TEAE after initiation of RCI treatment; most TEAEs were single incidences (Table 3)
• No increase in intraocular pressure was observed
• One serious TEAE of intentional overdose was reported but was not related to RCI treatment

Table 3. Safety Results

	Safety populationa (N=36)
TEAEs, No. (%)
Hypertension	2 (5.6)
Abdominal pain	1 (2.8)
Ankle fracture	1 (2.8)
Blurred vision	1 (2.8)
Double vision	1 (2.8)
Fever	1 (2.8)
Increased viscosity of upper respiratory secretions	1 (2.8)
Intentional overdose	1 (2.8)
Irritability	1 (2.8)
Polymyalgia rheumatica	1 (2.8)
Weight gain	1 (2.8)
Wrist fracture	1 (2.8)
Upper respiratory tract infection	1 (2.8)

aAll patients who received ≥1 dose of RCI.

Abbreviations: RCI, repository corticotropin injection; TEAE, treatment-emergent adverse event

Conclusions

• Results of this open-label study showed that 80 U of RCI twice weekly for 12 weeks was associated with rapid and sustained improvements in the symptoms of persistent severe noninfectious keratitis that had previously not responded to standard-of-care therapies
• No new safety signals for RCI were identified
• These results support the utility of RCI as a safe and effective treatment option for refractory severe noninfectious keratitis

References

1. Singh P, et al. StatPearls [Internet]. 2020.
2. Sharma S. Biosci Rep. 2001;21(4):419-44.
3. Dargin JM, et al. Emerg Med Clin North Am. 2008;26(1):199-216.
4. Acthar Gel. Package insert. Mallinckrodt Pharmaceuticals: 2019.
5. Huang YJ, et al. J Recept Signal Transduct Res. 2020:1-9.
6. Fairchild CJ, et al. Optom Vis Sci. 2008;85(8):699-707.

Acknowledgment and Funding

Professional writing and editorial support was provided by MedLogix Communications, LLC, Itasca, Illinois, under the direction of the authors and was funded by Mallinckrodt Pharmaceuticals.

Author Disclosures

EM has financial relationships with Aldeyra Therapeutics; Allergan; Aurinia Pharmaceuticals; Hanall Biopharma; Mitotech; Ocular Therapeutix; ReGenTree, LLC; Santen Pharmaceutical Co., Ltd.; Shire; Sun Pharma; and TopiVert Pharma Limited.

GO has a financial relationship with Mallinckrodt Pharmaceuticals. JG, ROK, and JL are employees of Mallinckrodt Pharmaceuticals.

DW has received research grant support from Mallinckrodt Pharmaceuticals.

Presented at the Association For Research in Vision and Ophthalmology Annual Meeting • Virtual Congress • May 1-7, 2021