Renal Safety of Broad Spectrum Antiviral CMX001 in the Prevention of CMV Infection Post- Allogeneic Hematopoietic Cell Transplantation (HCT)

Background: CMX001 is an orally bioavailable, broad spectrum, lipid acyclic nucleoside phosphonate converted intracellularly into the active antiviral, cidofovir diphosphate. Unlike cidofovir, CMX001 is not a substrate for the anion organic transporter and therefore is not concentrated in the kidney.

Methods: Study CMX001-201 was a 9-11 week randomized, placebo-controlled, double-blind, dose-escalation study (evaluating 40 mg weekly [QW], 100 mg QW, 200 mg QW, 200 mg twice-weekly [BIW] and 100 mg BIW) of CMX001 for the prevention of CMV infection post-HCT (ClinicalTrials.gov ID: NCT00942305). Treatment was initiated at the time of engraftment and continued until Week 13 post-HCT. Results presented elsewhere have shown that CMX001, at various doses, was active and well tolerated in the prevention of CMV infection or disease. Renal safety was assessed throughout the duration of therapy using serum creatinine, urinalysis and estimated glomerular filtration rate (GFR, MDRD4 formula).

Results: 230 subjects were enrolled in the study; 59 received placebo and 171 received CMX001 at various doses. 24 subjects (41%) on placebo and 77 subjects on CMX001 (45%) had BK viruria prior to dosing.  One subject discontinued CMX001 40 mg QW due to acute renal failure; no other subject discontinued from the study due to renal adverse events. Results of calculated GFR by Study Cohort and over time are presented in Table 1 below. Overall, renal function tended to decline in placebo recipients while renal function appeared to improve in subjects who received CMX001 at 200 mg per week (either QW or divided into 2 BIW doses). The renal function decline in placebo recipients appeared to be associated by the presence of BK virus (BKV) in the urine at the time of treatment commencement, while the proportion of subjects with renal dysfunction was similar between BKV positive and negative subjects among CMX001 recipients. There was also a decreased incidence of microscopic hematuria in BKV infected subjects treated with CMX001 as compared to placebo recipients (6% vs. 25%).

Conclusions: CMX001 when administered at doses of 200 mg per week is not associated with signs of nephrotoxicity and may mitigate the effect of BKV infection post-HCT. Further studies are warranted to assess the effect of CMX001 on BKV infection and its association with improved renal function.

Table 1: Study 201: Mean (N) Change from Baseline in GFR (mL/min/1.73m²) by Visit and Dose

Visit	Placebo	CMX001 40 mg QW	CMX001 100 mg QW	CMX001 200 mg QW	CMX001 100 mg BIW
Week 2	-6.5 (56)	-7.7 (23)	-11.6 (26)	-9.5 (37)	-4.5 (49)
Week 4	-8.7 (46)	-9.4 (19)	-8.6 (25)	-12.4 (31)	-3.3 (44)
Week 6	-10.1 (35)	-7.0 (13)	-12.0 (22)	-1.9 (24)	1.3 (33)
Week 8	-18.5 (36)	-2.2 (12)	-11.3 (19)	5.8 (18)	12.2 (31)*
Week 10	-15.4 (21)	-7.3 (5)	-15.6 (13)	5.7 (14)	6.1 (21)*
Post-Week 1	-13.3 (57)	-5.8 (19)	-2.8 (25)	8.8 (35)	7.7 (49)*

*P< 0.05 t-test versus placebo