Background/Purpose: Advances in the understanding of autoimmune diseases pathogenesis have led to the development of peptide-based therapies that aim to potentially reinstate tolerance to self without the need for immunosuppression. P140 peptide is a 21-mer linear peptide (sequence 131-151) that is issued from the small nuclear ribonucleoprotein U1-70K and that is phosphorylated at the Ser¹⁴⁰ position. Following a promising open phase IIa clinical trial in patients with SLE, two Phase IIb clinical trials were undertaken to evaluate the effect of peptide P140 administrated either in mannitol (Lupuzor) or in trehalose (Forigerimod) as excipient. Data obtained independently with Benlysta are used for comparison (Furie et al. 2011 Arthritis Rheum. 63, 3918-30).

Methods: Two multicenter, randomized, placebo-controlled phase IIb studies were run separately with similar “standard” protocols: 200µg P140/individual/month in addition to standard of care, inclusion of patients with clinical SLEDAI-2K scores >6 and no Bilag A score. The demographic characteristics of the study populations were similar in all three studies as well as in each treatment group. Drop-out rates were recorded irrespective of their reason and considered as treatment failure. Efficacy was evaluated using the SRI score.

Results: Clinical studies results: 

	P140	P140	Benlysta
	mannitol	trehalose	(BLISS-76)
Duration of treatment	3 months	6 months	12 months
Number of patients x arms	50 x 3	92 x 2	273 x 3
SAE active/placebo	6%/6%	10%/14%	19%/20%
Drop-out rate active	5%	22%	23%
Drop-out rate placebo	16%	23%	25%
Responder rate active	62%	34%	43%
Responder rate placebo	37%	40%	33%

Conclusion:  Lupuzor (P140 in mannitol) is safe and met its primary efficacy end point in lupus patients. Data suggest that P140 may restore tolerance by acting as an altered peptide ligand of the T cell receptor. P140 also reduces autophagic process, which has been shown recently to be abnormally enhanced in T lymphocytes from lupus mice and patients. The potential reduction by Lupuzor of the enhanced autophagy process (as seen in mouse models) led to a very short onset of action, which is supported by the efficacy data. Trehalose is a known inducer of autophagy and as anticipated, it interferes with the beneficial effect of P140. Its use together with P140 peptide is therefore inappropriate in the treatment of lupus patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/randomized-double-blind-placebo-controlled-studies-of-p140-peptide-in-mannitol-lupuzor-and-trehalose-forigerimod-in-patients-with-sle/