Daclatasvir

In this analysis, the molecular structures of HCV DAAs were compared with their closest analogues in the treatment of HIV. We evaluated the likely routes of manufacturing as published by the originator companies and assumed a volume demand based on 1–5 million patients per year to arrive at approximate costs of DAA APIs. We then added on a 40% margin for finished production manufacturing (formulation) to arrive at a projected cost of therapy.
The purpose of this analysis is to logically speculate whether DAAs can be provided for millions of people at a reasonable cost. The analysis is not meant to be exact or to arrive at a “most likely optimized cost” for any individual or combination DAA therapy. Very little information is presently available to estimate actual commercial formulation costs for DAAs. These DAAs are all delivered orally using conventional technologies. Projected API costs for these DAAs range from US$1400–to US$21 000 per kilogram; as such, the very high relative costs of API would justify a 40% increment as a reasonable add-on for estimating cost of the finished dosage form.
The minimum treatment costs of comparator HIV ARVs were calculated using the lowest prices reported by manufacturers to Médecins Sans Frontières in 2012 [19 ]. Minimum costs per gram of ARVs ranged from US$0.20 to US$0.90 per gram for nucleoside analogues, US$0.50 per gram for nucleotide analogues, and US$0.70–$2.10 per gram for protease inhibitors (Table 3).
Table 3.

Minimum Costs of HIV Antiretrovirals, by Increasing Cost per Gram

Agent	Chemical Formula	Molecular Weight, g/mol	Daily Dose, mg	Overall Dose Per Year, g	Cost Per Gram, US$	Cost Per Year, US$
Lamivudine	C8H11N3O3S	229	300	110	0.19	21
Zidovudine	C10H13N504	267	600	219	0.34	75
Tenofovir disoproxil fumarate	C23H34N5O14P	636	300	110	0.52	57
Indinavira	C36H47N5O4	614	1600	584	0.67	394
Abacavir	C14H18N6O	286	600	219	0.77	169
Emtricitabine	C8H10FN3O3S	247	200	73	0.79	58
Stavudine	C10H12N2O4	224	60	22	0.86	19
Lopinavir/ritonavirb	C37H48N4O5	629	800/200 = 1000	365	1.01	368
Darunavira	C27H37N3O7S	548	1200	438	1.83	803
Saquinavira	C38H50N6O5	671	2000	730	1.87	1366
Atazanavira	C38H52N6O7	705	300	110	2.11	231

^a Prices of protease inhibitors do not include the cost of the ritonavir booster drug, except for lopinavir/ritonavir.

^b Chemical formula and molecular weight for lopinavir only.

Source: MSF Drug Access Team [19 ].

Four HCV DAAs were included in this study: daclatasvir (phase 3), sofosbuvir (approved December 2013), faldaprevir (phase 3), and simeprevir (approved November 2013). Ribavirin, already available in generic form, was also included in this analysis due to its likely inclusion in future drug regimens. Using the most likely daily dosage identified from clinical trials, the total drug requirement for each DAA was calculated for a 12-week course of each HCV DAA. To estimate the manufacturing cost of each HCV DAA, current routes of synthesis and critical cost-limiting raw materials were taken from the patent literature. In an alternative comparison, each compound was matched to the closest equivalent HIV ARV based on structural similarity.
Production costs per gram of HCV DAA were assumed to be 1–10 times higher than the equivalent HIV ARV, dependent on the complexity of chemical synthesis. Complexity was assessed by identifying the most likely cost-limiting intermediates for the synthesis of each DAA. Additional considerations included ease and number of steps of manufacture and availability and cost of starting materials. Using this estimate for the production cost per gram of drug together with the total drug requirement, an estimate for the minimum cost of a 12-week course of treatment with each HCV DAA was calculated. These costs were used to provide estimates for the production costs of 2- or 3-drug combination therapy based on the combinations currently being investigated in clinical trials (Table 2).