Cell lines

Primary human renal proximal tubule epithelial cells

Preparation Method

About 24 h after seeding 150 μl of the medium was replaced with fresh medium with or without purified BKV-Dunlop in the presence or absence of CMX001 (final concentration of 0.31 μM). The cells were grown for 96 h, and impedance was measured every 15 min for the first 6 h and then every 30 min.

Reaction Conditions

0.31 μM; 24h

Applications

CMX001 reduced the extracellular BKV load in a concentration-dependent manner.The CMX001 concentration of 0.31 μM consistently provided this level of inhibition.

Animal models

8 week (3-4 lb) old New Zealand White rabbits

Dosage form

20 mg/kg per dose; i.v.

Preparation Method

Animals were given a total of one, two or three doses of CMX001 (20 mg/kg per dose) spaced every other day beginning on the day secondary lesions were detected in the ears of the animals.

Applications

As with the intradermal infection model, one, two, or three doses of CMX001 appeared to significantly reduce disease symptoms and have a survival benefit.

CMX001 is a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV) used for treatment of smallpox.^[1]

In vitro experiment it shown that 0.079 μM CMX001 inhibited JCV replication in COS-7 cells. And treatment with 0.038 μM or 0.6 μM CMX001 in PDA cells resulted in a obviously decreased the number of infectious JCV progeny in a concentration-dependent manner. Treatment with 0.079 to 10 μM CMX001 in COS-7 cells reduced the metabolic activity to 52% and BrdU incorporation to 10% at the highest concentration.^[2]CMX001 was active with EC90 of 0.31 μM at about 400-times-lower concentrations than the EC90 for CDV in the same test system.^[3]In vitro efficacy test it exhibited that treatment with 0.01 μM to 0.1 μM resulted in minimal cytotoxic effects in human fetal brain SVG cells.^[4]In vitro, CMX001 has against five variola virus strains with EC50 of averaged 0.11 μM.^[5]

In vivo clinical study it shown that treatment with oral CMX001 at a dose of 100 mg twice weekly obviously reduced the incidence of CMV events in recipients of hematopoietic-cell transplants.^[6]In ECTV-infected A/NCR mice, a 2.5 mg/kg dose of CMX001 given once daily for five days starting 4 h post-infection provides complete protection against a lethal intranasal challenge. Mice were treated with 10 mg/kg CMX001 when the fifth day, then followed by a 2.5 mg/kg dose every other day for 14 days can be completely protected from mortality. However, treatment with 20 mg/kg CMX001 orally as late as four days post-infection provided 100% protection against lethal ECTV infection.^[7]

References:

[1].Rice AD, et al. Efficacy of CMX001 as a post exposure antiviral in New Zealand White rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans. Viruses. 2011 Jan;3(1):47-62.

[2].Gosert R, et al. CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes. Antimicrob Agents Chemother. 2011 May;55(5):2129-36.

[3].Rinaldo CH, et al. 1-O-hexadecyloxypropyl cidofovir (CMX001) effectively inhibits polyomavirus BK replication in primary human renal tubular epithelial cells. Antimicrob Agents Chemother. 2010 Nov;54(11):4714-22.

[4].Jiang ZG, et al. Hexadecyloxypropyl-cidofovir (CMX001) suppresses JC virus replication in human fetal brain SVG cell cultures. Antimicrob Agents Chemother. 2010 Nov;54(11):4723-32.

[5].Olson VA, et al. In vitro efficacy of brincidofovir against variola virus. Antimicrob Agents Chemother. 2014 Sep;58(9):5570-1.

[6].Marty FM, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013 Sep 26;369(13):1227-36.

[7].Lanier R, et al. Development of CMX001 for the Treatment of Poxvirus Infections. Viruses. 2010 Dec;2(12):2740-2762.