Generic treatments for HIV, HBV, HCV, TB could be mass produced for <$90 per patient Dr Dzintars Gotham MBBS BSc(Hons) on behalf of Andrew Hill1, Melissa Barber2, Dzintars Gotham3, Joseph Fortunak4, Sanjay Nath3, Anton Pozniak5 1 Department of Pharmacology and Therapeutics, University of Liverpool, UK. 2 Centre for Development Studies, Cambridge University, Cambridge, UK. 3 Faculty of Medicine, Imperial College London, London, UK. 4 Department of Chemistry and Pharmaceutical Sciences, Howard University, Washington DC, USA. 5 St Stephen’s AIDS Centre, Chelsea & Westminster Hospital, London, UK.

Disclosures Nothing to disclose.

Background There is little general understanding of costs of drug production HIV/AIDS in 2001: Yusuf Hamied’s announcement of a “dollar a day” price ushered dramatic price reductions – 19.5 million on treatment today 2014: Estimated cost of $68-136 USD for 12-weeks of sofosbuvir, based on similarities in chemical structure and synthesis processes to generic ARVs 2015–2017: Cost based on price of active pharmaceutical ingredient and available analyses of other components of manufacture We have now costed: hepatitis C, hepatitis B, MDR-TB, all solid oral medicines in WHO essential medicines list, plus other cancer medicines

HCV (703,800) Deaths per year HBV (686,000)

Methodology Cost of the raw drug (active pharmaceutical ingredient, API) using data on exports from India Cost of making this into tablets (“conversion cost”) Taxes, profit margin Comparison of estimated prices to current lowest prices from Médecins Sans Frotières (MSF), Global Drug Facility, WHO reports

TDF = $159 per kilogram. 1kg is enough to treat 9 people for 1 year.

1kg is enough to treat 30 people. Cost/kg of sofosbuvir API exports Jan 2015 to Jul 2016, weighted by size of shipment SOF= $1050 per kilogram. 1kg is enough to treat 30 people.

Cost-based generic price of sofosbuvir (12 weeks) API needed per person = 34g (400mg x 84 days) Cost of API = $1,050/kg API per 12 weeks = $35 Formulated drug = $36 Packaged drug = $37 Final generic price = $42 Formulation = $0.01/tablet Packaging = $0.35/month Profit margin and tax = 13%

Assumed cost per tablet of converting active pharmaceutical ingredient to a finished product chosen cost assumption = $0.01/tablet

Comparing estimated generic prices to current lowest available prices Bubble area scaled to kg exported from India in 2Q2016. TB – per 6 month course. HCV – per 12 week course. HIV & HBV – per patient per year.

Lowest prices of SOF/DCV in selected countries

Calculated target prices, current prices, and years of patent expiry DRUG USA PRICE GLOBAL LOWEST PRICE ESTIMATED PRICE PATENT EXPIRY (US) ABC $1,938 $72 $149 2018 ATV $16,093 $170 $126 2017-2019 DRV $15,980 $438 $364 2016-2027 TDF/FTC/EFV $28,204 $100 $78 2017-2029 TDF/3TC/EFV $107 $82 Generic TDF/FTC $17,258 $67 $54 2017-2032 LPV/r $10,818 $231 $262 2016-2028 Entecavir $5,915 $409 SOF $81,925 $45 $42 2028-2030 SOF+LDV $91,207 $307 $79 2028-2032 SOF+DCV $142,710 $108 $47 2028-2031 TB: RHZE $945 $27 $38 HCV – per 12-week course, TB – per 6 month course, HIV and HBV – per year. Patent expiries from US FDA Orange Book, for solid oral dosage forms only.

Limitations Not included: But: Transport Bioequivalence trials and registration Prequalification costs But: Good predictive ability anyway After-tax profit margin of 10% may offset this Data only on exported API cost – in house manufacture or domestic procurement presumably significantly cheaper

MDR-TB medicines – estimated prices for 6 months of treatment* DRUG USA PRICE GLOBAL LOWEST PRICE TARGET PATENT EXPIRY (US) RHZE $945 $27 $38 Generic Bedaquiline* $27,192 $816 $47–103 2026-2029 Delamanid* No data $1,698 $29–94 2023-2031† Linezolid* $1,728 $102 $26–56 Moxifloxacin* $1,182 $42 $21–47 Regimens (full course) STREAM arm C (40 weeks) $1799 $231–359 STREAM arm D (28 weeks) $1325 $168-262 PaMZ $140 $53–114 BPaZ $967 $84-181 BPaL $2749 $120-276 Patent expiries from US FDA Orange Book, for solid oral dosage forms only. †patent expiry from MedsPaL *Gotham et al. J Antimicrob Chemother. 2017 Apr 1;72(4):1243-1252. doi: 10.1093/jac/dkw522.

Estimated cost of medicines for ”average TB case” if 95% of patients have DS-TB with drugs costing $27 per full course (GDF price) and 5% have MDR-TB with drugs costing $359 per full course (highest estimated total regimen cost) average cost = $44 per patient for full treatment course

Treatment for HIV, HCV, HBV, TB should cost <$90 TDF/FTC/EFV: $78 per year TDF/3TC/EFV: $82 per year SOF/DCV: $47 per 12 weeks Entecavir: $82 per year “average TB patient”: $44 per course

Implications $90 per person could now become a ceiling price for treating HIV, TB, HCV, HBV, which kill over 4 million people a year TDF, 3TC, and EFV are generic worldwide – this combination should be available in all countries for <$90 Estimation of cost-plus prices is feasible, and valuable for improving transparency in negotiations Precedents for governments using cost of production estimates in price control mechanisms: India1, South Africa2, China3, Bangladesh3, Iran3, Pakistan3 Kotwani A, Levison L. Price components and access to medicines in Delhi, India. 2007. Republic of South Africa National Department of Health. Special Requirements and Conditions of Contract. HP09–2016SD/01. The supply and delivery of solid dosage forms to the Department of Health for the period up to 31 July 2018. 2017 World Health Organization. WHO guidelines on country pharmaceutical pricing policies. 2015.