Background Systemic Sclerosis(SSc) is a rare autoimmune disease with fibrosis, changes in the skin, vasculature, joints and internal organs. Diffuse disease involves lung, heart and kidney and 10-year mortality is >35%.^[1] Raynaud’s attacks occur in ~95% of SSc patients. Severe Raynaud’s (RP) affects patients’ health status more than depression, obesity, and heart disease.^[2] No treatment for Raynaud’s is approved, but calcium channel blockers (CCBs) are first-line treatment. Cilnidipine, a 4th generation CCB approved for hypertension in Asia, has been shown to be safer than other CCBs in treating hypertension, and has beneficial effects on the kidney and heart. Cilnidipine is more selective for N-type Ca channels, and improves analgesia, sympathetic, autonomic and endothelial function.^[3] Cilnidipine might be repurposed for SSc-RP patients.

Objectives We studied safety and preliminary efficacy of cilnidipine use in SSc-RP, dose response and co-administration of a low dose PDE-V inhibitor. Results are compared to a 2017 meta-analysis of CCB use in SSc-RP.

Methods RECONNOITER-1 is a two-part, planned 76 patient trial. In Part 1, we evaluated safety, dose, efficacy and co-administration of tadalafil. Dose groups were cilnidipine 10mg and 20mg, alone and with tadalafil 5mg, tadalafil alone and placebo. The 1° endpoint was reduction in weekly frequency of RP. 2° endpoints included Raynaud’s Condition Score (RCS), pain, severity, duration, and a validated PRO (SHAQ). The DSMB reviewed data on the first 27 patients in 8/2022.

Results The ITT population was 27 patients, the mITT 24. Results are reported for the mITT population. Cilnidipine-only treated patients(n=7) had a reduction in weekly attacks of 42.2% versus 18.9% in placebo(n=4) Dose response was seen in weekly attack frequency and severity. Response was greater in the higher cilnidipine dose group on attack duration and RCS. Tadalafil increased treatment effect with 10 mg but not with 20 mg. Cilnidipine at either dose was well tolerated and only Grade 1 mild AEs were reported with cilnidipine (17.6%), with no treatment discontinuations due to AEs. The DSMB halted Part 1 early based on meeting study goals.

Conclusion In this preliminary study, cilnidipine was well-tolerated and efficacy trends were seen. A published metanalysis of CCB use for RP finds AE’s >46% and treatment discontinuation in >30% of patients.^[4] Cilnidipine appears superior in safety to commonly used CCBs (P= 0.0247). Our results replicate the improved safety in hypertension treatment. PRO results (SHAQ) also favor the 20 mg dose of cilinidipine over placebo with significance over placebo, depsite the small numbers (p=0.0115). Increased N-type channel blockade may increase safety and efficacy with the drug. Part 2 will compare Cilnidipine 20mg daily to placebo in a crossover trial in 38 patients.

References [1]Volkmann, E., J Scler Relat Disord. 2021 Feb; 6(1): 11–20.

[2]Frantz, C., Sem Arth Rheum. 2016, 46: 115-123.

[3]Chakraborty, R.N.; Cureus. 2021 Nov; 13(11).

[4]Rirash, F.; Cochrane Syst Rev. 2017 Dec 13;12(12)

Acknowledgements: NIL.

Disclosure of Interests Andrew Sternlicht Shareholder of: I own shares of Aisa Pharma, Inc., the company that supported this study. I am not paid by Aisa Pharma. I did discover and develop the use of the drug discussed in this abstract., Michael Shanahan Grant/research support from: This research was supported by a grant from Aisa Pharma., Erin Morton: None declared, Elizabeth Briggs: None declared, Ivana Hunt: None declared, Zoey Reed: None declared, Amanda Weragoda: None declared, Lashika Weerakoon: None declared, Meredith Todd Consultant of: Aisa Pharma Australia, Pty Ltd, Employee of: Aisa Pharma Australia, Pty Ltd.