Switch of psoriasis therapy from a fumaric acid ester mixture to dimethyl fumarate monotherapy: Results of a prospective study.

BACKGROUND: Fumaric acid esters (FAEs) are used for systemic therapy of moderate to severe psoriasis. Until recently, only a mixture of dimethyl fumarate (DMF) and three salts of ethyl hydrogen fumarate was available. However, a drug containing DMF as the sole ingredient was registered for the same indication in 2017. This prospective study aimed to investigate the switch from the currently used FAE mixture to DMF alone. PATIENTS AND METHODS: Forty patients were consecutively recruited, for whom the FAE mixture was switched to DMF alone on the basis of the last DMF-equivalent dose without interrupting treatment. At the first check-up after switching, the efficacy and tolerability of the DMF drug was compared with that of the previous treatment.
RESULTS: The data show that the efficacy remained unchanged in the majority of patients. Tolerability (e.g. gastrointestinal complaints and flushing) of the DMF drug was rated equal or better in most patients than with the previous treatment.
CONCLUSIONS: The results show that it is possible to switch psoriasis patients under stable therapy with the FAE mixture to the DMF drug directly and without interruption.

Introduction

Fumaric acid esters (FAEs) are widely used for systemic therapy of moderate‐to‐severe psoriasis in Germany, with a prescription rate of more than 50 %. Fumaric acid esters are also used frequently in the Netherlands, United Kingdom, and Ireland for first‐line treatment 1, 2. Until recently, a mixture of four different fumaric acid esters including the main active compound dimethyl fumarate (DMF, Fumaderm®) was only authorized in Germany. Since 2017, a product containing DMF alone (Skilarence®) has been authorized in Europe and is now available outside Germany as well.

The advantages of the DMF product are that the only active substance it contains is DMF, flexible dosing is possible using the 30 mg and 120 mg tablets, and the DMF product is cheaper than the FAE mixture in Germany. The only requirement for safety monitoring is ensuring that laboratory parameters are within the normal range every three months. Switching from the FAE mixture to the DMF product therefore seems reasonable.

There are no data yet as to whether a direct switch from the FAE mixture to the DMF product can be performed without a washout period. A prospective study was performed to address this issue. Patients who were stable under treatment with the FAE mixture were asked to switch to the DMF product. Patients were asked about tolerability and other treatment‐related parameters at the first follow‐up visit after switching.

Methods

This prospective observational trial was approved by the Ethics Committee of the University of Kiel (AZ: D553/17). Patients who were treated with the FAE mixture and presented at the outpatient service of the Kiel Psoriasis Center for routine safety monitoring were asked to participate, and written informed consent was obtained before they entered the study. Patients whose psoriasis had improved and who could tolerate treatment with the FAE mixture were recruited.

Treatment with the FAE mixture was switched to the DMF product without any interruption on the basis of the current DMF dose in the FAE mixture. Patients were then scheduled for the next regular check‐up three months later.

To assess psoriasis severity, we used the PASI (psoriasis area and severity index). When presenting for their first check‐up after switching, patients were handed a questionnaire to investigate their views about tolerability and efficacy and to provide a global judgment of the switch.

Results

A total of 40 patients (24 male, 16 female) were prospectively and consecutively recruited to the study and underwent a check‐up after switching treatments.

The age of adult patients ranged from 18 to 74 years with a mean age of 46 years. One patient was 13 years old and received treatment off‐label. Table 1 shows the demographics of the patients and the DMF dose at the time of switching from the FAE mixture to the DMF product. Most patients were treated with a daily DMF dose between 120 mg and 480 mg, and had previously been treated with the FAE mixture for one to five years (Figure 1).

Table 1

Demographic characteristics of patients before switching from the FAE mixture to the DMF product, including the daily dose of DMF at the time of switching. One patient received a dose of DMF of 120 mg every third day; the calculated daily dose was 40 mg

Pat. No.	m/f	*FDPso	Age	**DMF	Start DMF	Duration of FAE‐mixture therapy (months)	Comorbidity	Comedication	Smoking	Alcohol	***Previous therapies
1	m	1984	44	120	01/2017	11	Rosacea	None	Yes	Yes	CS, CS+D3
2	m	Unknown	33	720	02/2017	9	None	None	Unknown	No	CS, (UVB)
3	m	1984	57	240	2009	108	None	None	Unknown	No	CS, D3
4	m	1995	67	120	2009	84	Hypertension, muscle pain, coronary artery disease, disc prolapse	Ramipril, aspirin, ­nitroglycerine, ibuprofen	Yes	No	CS, CS+D3, dithranol
5	m	2001	35	240	12/2015	27	Upper airway syndrome, sleep apnea	None	No	Yes	CS, (UVB)
6	m	1989	56	600	1996	84	None	None	Yes	No	CS, MTX, PUVA
7	m	1995	53	480	03/2012	68	None	None	Yes	Yes	None
8	f	2011	61	360	03/2017	8	None	None	Yes	Yes	CS, CS+D3
9	m	2013	49	120	01/2014	45	Recurrent tonsillitis, asthma	Pantoprazole, inhaled ­steroids	Yes	Yes	CS
10	m	2000	57	480	12/2014	37	Hypercholesterolemia, hypertension,	Simvastatin, diltiazem	No	Yes	CS, D3
11	f	1995	49	480	07/2015	30	None	L‐thyroxine	Unknown	No	CS, CS+D3, UVB
12	f	1997	52	240	01/2017	11	None	None	Yes	Yes	PUVA
13	f	1988	62	720	07/2008	115	Reflux esophagitis	Pantoprazole	Yes	No	Dithranol
14	f	2009	42	120	07/2013	51	None	Pantoprazole	Yes	No	PUVA
15	m	2007	43	360	06/2016	17	None	None	Yes	No	CS, UVB
16	f	1987	44	60	11/2015	23	None	None	Unknown	No	PUVA, CS
17	f	2010	13	30	07/2013	54	None	None	No	No	None
18	m	1999	38	240	12/2014	36	None	None	Unknown	Yes	CS, D3, UVB
19	m	1992	47	240	09/2014	40	Hypothyroidism	L‐thyroxine	Yes	Yes	D3, CS+D3
20	m	1997	74	240	07/2017	7	Prostate cancer, COPD, hypothyroidism, ­osteoporosis, ventricular cardiac arrhythmia	Alendronic acid, levothyroxine, omeprazole, aspirin, flecainide, atorvastatin, sotalol, budesonide, tiotropium, ipratropium, salbutamol, n‐butylscopolamine, ­oxaceprol	Yes	Yes	UVB
21	f	2004	26	480	01/2016	23	Hypothyroidism, hypersomnia	L‐thyroxine, bupropion	No	No	PUVA
22	m	2012	63	360	11/2016	13	Tremor	Propranolol	Yes	Yes	PUVA
23	f	1984	61	60	07/2015	28	Lung emphysema	None	Yes	No	CS+D3, UVB
24	m	1996	34	360	01/2014	47	None	None	Yes	Yes	CS, D3, CS+D3, PUVA
25	m	2000	37	240	10/2014	39	None	None	Unknown	Yes	None
26	f	2002	26	240	10/2016	14	Migraine‐like headache	Metamizole	Yes	No	None
27	m	1995	46	240	07/2015	28	Dilated cardiomyopathy, complete left atrial block, single coronary occlusion, hypertension, adiposity, hyperlipoproteinemia	Aspirin, metoprolol, ­ramipril, torsemide, eplerenone, ­simvastatin	Yes	No	CS, CS+D3, MTX, golimumab, PUVA
28	m	2000	47	120	03/2016	19	None	None	Yes	Yes	CS, D3
29	m	1970	54	480	03/2017	8	Hypertension, depressive mood disorder	Amlodipine, St. John's wort	Yes	Yes	CS, UVB
30	f	2009	25	30	11/2011	72	None	None	Unknown	No	CS
31	m	2011	30	480	03/2012	68	None	None	Yes	Yes	None
32	f	1958	69	360	1997	48	None	Candesartan	Unknown	No	CS
33	m	1973	54	240	09/2011	74	Hypertension, ­hypercholesterolemia	Atorvastatin, minoxidil, spironolactone, nebivolol, candesartan, doxazosin	No	No	D3, PUVA
34	f	1965	59	720	2009	60	Radicular pain ­syndrome	None	Yes	No	None
35	f	2006	70	360	02/2017	9	Type 2 diabetes, ­hyperlipidemia, ­coronary artery disease, disc prolapse	Insulin, aspirin, atorvastatin, diclofenac, nitroglycerine	No	No	CS, CS+D3
36	f	2012	27	40	04/2014	42	None	None	No	No	Systemic ­steroid
37	m	2008	30	Unknown	08/2017	3	Asthma, ­adiposity, alopecia areata ­universalis,	None	No	Yes	MTX, ­systemic ­steroid, CS
38	m	2003	39	720	04/2017	6	Kyphosis, scoliosis	None	No	Yes	CS, D3
39	m	2012	18	720	05/2017	5	None	None	Unknown	No	CS
40	f	2005	24	360	11/2016	12	Vitiligo	None	No	No	UVB

*FDPso: Time point of first psoriasis diagnosis.

**DMF: Corresponding dose of DMF in the FAE mixture at the time of switching.

***Previous psoriasis treatments. CS: topical steroids, CS+D3: fixed topical combination of steroid and vitamin D3 analog; D3: topical vitamin D3 analogs; MTX: ­methotrexate; UVB: broad or narrow‐band UVB; PUVA: psoralen + UVA.

Figure 1

Number of patients related to the duration of continuous FAE therapy that they received before switching from the FAE mixture to the DMF product (n = 40).

In general, the patients regarded the outcome of the switch to the DMF product as neutral or positive (18 positive, 18 neutral, 4 negative). Efficacy as assessed with the PASI was equal or better in 34/37 patients, while 3/37 had a higher PASI severity after switching (Figure 2). A PASI estimate was not available at one of the visits in 3/40 patients.

Figure 2

Clinical course of PASI in patients treated with the FAE mixture before (t1) and after (t2) switching to the DMF product. The mean time between the two visits was 91.8 days (minimum 42 days, maximum 133 days; n = 37).

According to regulatory requirements, both drug products have a similar formulation. Therefore, adverse drug effects such as gastrointestinal (GI) complaints should not differ in symptoms or intensity. The majority of patients (27/40) did not experience any difference in GI complaints after switching from the FAE mixture to the DMF product. Gastrointestinal tolerability was judged as better for the DMF product by 7/40 patients and worse by 2/40 patients. No GI complaints were reported with either drug product by 4/40 patients. Flushing was unchanged in 24/40 patients, 8/40 reported less flushing and 6/40 reported more flushing. Flushing did not occur with either drug product in 2/40 patients.

Regarding the question of overall tolerability, 28/40 patients reported similar tolerability, 8/40 reported better tolerability with the DMF product and 4/40 said that tolerability was worse after switching. In answer to the question about skin status in general, 27/40 patients reported that it was unchanged after switching from the FAE mixture to the DMF product, patients, 7/40 reported that it was better and 6/40 said it was worse.

Discussion

Therapy of systemic psoriasis with FAE has a long tradition in Germany and also in the Netherlands. In Germany, a mixture of DMF and three salts of ethyl hydrogen fumarate (Fumaderm®) has been authorized since 1994; the FAE mixture has been made up in compounding pharmacies in the Netherlands. Scientific evidence has shown that DMF is the active ingredient in the FAE mixture, and acts as a prodrug for the main DMF metabolite (monomethyl fumarate; MMF) after oral administration 3. In fact, the first DMF product was registered earlier for the treatment of relapsing‐remitting multiple sclerosis (Tecfidera®). Since fall 2017, another DMF product has been approved for oral first‐line therapy of moderate‐to‐severe plaque psoriasis (Skilarence®) 4.

The extent of gastrointestinal symptoms and flushing depends on the formulation of the DMF‐containing drugs. Due to regulatory requirements, the FAE mixture and the DMF product have similar formulations. Consistent with this, the results of our observational study showed that the majority of our patients did not observe any difference after switching from the FAE mixture to the same dose of DMF. This was also shown for flushing, although there is little evidence that flushing depends on the details of the formulation.

Omitting the three salts of ethyl hydrogen fumarate from the FAE mixture did not result in any change in the tolerability or efficacy of the DMF product. As stated in a recent review, there is no scientific evidence that ethyl hydrogen fumarate salts have a pharmacological effect in psoriasis 5.

Most of the patients in our study had already been treated with the FAE mixture for one to five years, and 22.5 % were long‐term users, having taken the drug for 5 to 10 years. The patients investigated in the study were clinical responders to FAE and were able to tolerate potential adverse effect such as GI complaints and flushing. The unexpectedly high proportion of patients who regarded the switch from the FAE mixture to the DMF product as positive may be due in part to the fact that recommended intervals between check‐ups are three months with the DMF product instead of one month with the FAE mixture.

In conclusion, the results of this study show that psoriasis patients can switch from the traditional FAE mixture to the same dose of DMF with similar clinical relief but without any washout period.

Conflicts of interest

Ulrich Mrowietz was advisor, study coordinator or participant and has received funding from all companies who market or develop fumaric acid ester compounds for psoriasis (Almirall, Biogen, Forward Pharma, Dr. Reddy's and Xenoport). Sandra Falkvoll and Sascha Gerdes have no conflicts of interest to disclose.