Once-daily oral dosing: a future boon for patients with DMO, GA, kidney disease

A once-daily oral drug targets inflammatory processes and thus far has been found to be well tolerated in a Phase 2 safety trial.

Reviewed by Dr David S. Boyer.

A once-daily orally administered drug, Xiflam (InflammX Therapeutics), targets inflammatory processes and thus far has been found to be well tolerated in a Phase 2 safety trial.

This drug, which is being considered to treat diabetic retinopathy (DR), renal disease, and age-related macular degeneration, is intended to be an alternative therapy to monthly chronically administered intravitreal injections of anti-vascular endothelial growth factor drugs.

Xiflam works by modifying the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome-mediated microvascular autoinflammation, according to Dr David Boyer, adjunct clinical professor ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles.

In a disease state, he explained, the Connexin43 channels open prematurely, which releases adenosine triphosphate into the extracellular space and signals NLRP3 assembly, thus activating the inflammasome and setting off an inflammatory cascade and a resultant vicious cycle of inflammation.

Proof-of-concept trials of Xiflam

This drug has a valuable history. Two decades ago, GlaxoSmithKline first tested Xiflam’s 25-, 40-, and 80-mg concentrations to treat migraine in more than 1,000 individuals in Phase 2 clinical trials, but the formulation ultimately was shelved. The study participants were dosed for up to 3 months, and the three concentrations were found to be well tolerated. However, InflammX more recently determined that Xiflam had two unique properties, i.e., inhibition of the pathologically open Connexin43 channels and crossing of the blood brain/retinal barrier.

When the formulation was tested in a rat model of DR, the aneurysms resolved and visual function improved significantly by electroretinography compared with rats treated with placebo.1 In the same study, the researchers tested Xiflam in a rat model of geographic atrophy (GA) and found that the retinal structure was preserved 3 months after treatment with Xiflam compared with placebo.

Regarding retinal and kidney microvascular disease in patients with diabetes, recent clinical studies have shown that the two diseases are correlated. The first2 reported that progression of retinopathy appears to be associated with progression of chronic kidney disease, and the second3 that renal function may predict treatment response in certain patients with diabetic macular oedema (DMO); in this study, the investigators found that renal function was significantly worse in patients with a poor response to bevacizumab (Avastin, Genentech Inc.) and dexamethasone.

Phase 2 clinical trials

A Phase 2 randomized, double-masked, placebo-controlled clinical trial is planned by the Diabetic Retinopathy Clinical Research (DRCR) Network and InflammX to evaluate the drug’s effect on DMO. The study will enrol 130 patients randomized 1:1 to Xiflam and placebo.

The patients will be followed monthly for 3 months with interim analysis at that time point by the Data Safety Monitoring Committee; the DRCR will conduct the final analysis at 6 months.

The main efficacy outcome is the mean change in the central macular thickness at 6 months. The exploratory outcomes are the changes in the kidney function from baseline; measurement of cystatin C, a protein marker of kidney function; the change in the haemoglobin A1C from baseline; and the change in C-reactive protein, an inflammatory marker, from baseline.

A Phase 2 study of the effect of Xiflam on GA in patients with moderate-to-severe GA also is planned. The clinical end point is the significant reduction of disease progression as seen on imaging. As in the study of the drug’s effect on DMO, this study also will include 130 patients who will be evaluated at the same time points. This study then will extend out to 9 and 12 months, with the final analysis planned for 12 months.

Manufacturing of the drug has started, which will allow the clinical trials to begin. The first patient dose is planned to be administered during the second quarter of 2022.

“An oral medication that reduces inflammation and allow bilateral treatment of GA and DMO along with treatment of kidney disease is a true game changer for patients and their caregivers,” Dr Boyer commented.

David S. Boyer, MD
E: vitdoc@aol.com
This article is adapted from Dr Boyer’s presentation at the virtual Angiogenesis, Exudation and Degeneration 2022 Conference, 11 February, 2022. Dr Boyer is an InflammX board member.
References
1. Mat Nor MN, Rupenthal ID, Green CR, Acosta ML. Connexin hemichannel block using orally delivered tonabersat improves outcomes in animal models of retinal disease. Neurotherapeutics 2020;17:371–387.
2. Grunwald JE, Pistilli M,Ying G-S, et al. Association between progression of retinopathy and concurrent progression of kidney disease findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. JAMA Ophthalmology 2019; 137(7):767-774. doi: 10.1001/jamaophthalmol.2019.1052
3. Hwang H, Lee H, Kim, Jin Y, et al. Systemic factors and early treatment response to intravitreal injection for diabetic macular edema. The role of renal function. Retina 2021;41:1275-1282.