ESCP Models - Hepatitis C Medications (Part 1)
By: Josef Bossart, PhD, Managing Director, The Pharmanumbers Group
Introduction
In a series of four articles earlier this year1,2,3,4 the principles of the ESCP Analysis process were outlined with a few simple to understand examples. To better explain the application of the process, I have summarized the evolution of Hepatitis C (HCV) treatment5 from naked Interferon alpha treatment through to the latest combination polymerase and protease inhibitors. This is a top-level analysis as might be done for any new product concept, but with the benefit of hindsight. The figures relating to Efficacy and Safety presented in this analysis are sourced from public documents, generally the product labels. Treatment costs are rough estimates using current US 2021 prices as sourced from GoodRx6, which generally reflect the real-world prices paid by patients who are not eligible for some sort of formulary or governmental program. These prices should be consistent on a relative, if not absolute basis, allowing for reasonably accurate pricing comparison.
(Pre-1997) In the Beginning – Interferon Alpha (Intron A, Schering-Plough)7
The first pharmaceutical to have a significant treatment benefit for HCV patients was Schering-Plough’s Intron A. With an overall efficacy of a bit less than 10%, treatment consisted of 24 weeks of treatment that involved subcutaneous injection three times weekly. Safety and tolerability were an issue with more than 20%, in some cases more than 50%, of patients reporting Fever, Headache, Fatigue, Asthenia, and/or Flu-like Symptoms. The cost of therapy was about $6,600 using current prices. [For the purpose of comparing prices between various treatment protocols, this $6,600 price is defined as 1 PU (Pricing Unit)]. On the seesaw, Intron A has the winning position despite having limited efficacy, significant safety and tolerability issues, and poor convenience. When you are the only product on a seesaw you win by default.
Advantage: Intron A
(1999) Interferon Alpha (Intron A) and Ribavirin (Rebetol8, ICN)
The next evolution of treatment for HCV involved the addition of Rebetol (ribavirin) to the standard protocol for Intron A. This combination treatment improved general efficacy to about 33%. The use of ribavirin required the same 24 weeks of three-a-week injections plus twice-daily oral dosing. As well as the safety and tolerability issues seen with Intron A, ribavirin safety and tolerability issues included Anorexia, Myalgia, Arthralgia, Insomnia, and Depression, in >20% of patients. The cost of therapy jumped to about 4 PU based on the additional cost of Rebetol. (Note: Rebetol is no longer available. Copegus, Roche’s branded version of ribavirin was used for pricing.)
Advantage: Intron A and Rebetol Combination
Approvals soon followed for PEGylated versions of interferon alpha, Schering-Plough’s PegIntron and Roche’s Pegasys. PegIntron was approved as a combination with Rebetol while Pegasys was initially approved as a single active treatment.
(2001) PegIntron9 (Schering-Plough) and Rebetol
The combination of PegIntron and Rebetol increased efficacy to 40%-50% for Genotype-1 patients with treatment times increased to 48 weeks. The co-administration of Rebetol (ribavirin) more than doubled the response seen with PegIntron alone. The combination treatment involved twice-daily Rebetol and once-weekly subcutaneous injections of PegIntron. In the case of Genotype 2 and 3 patients, efficacy increased to 70%-80% with only a 24-week treatment program. Tolerability was similar in many respects to the Intron A and Rebetol treatment with the addition of Anxiety and Alopecia. Relative pricing jumped to about 14 PU on the basis of the premium price for PegIntron and the extended 48-week treatment period.
Advantage: PEG-IFN and Rebetol Combination
(2002) Pegasys10 (PEG-Interferon, Roche)
Because Roche did not have license rights to ICN’s Rebetol, it was filed for approval based on Pegasys as a single active treatment for HCV. Efficacy rates varied depending on genotype. Efficacy for Genotype 1 patients was 23%, all other genotypes, largely undefined, saw an overall efficacy rate of 48%. Tolerability issues included Neutropenia, Fatigue, Pyrexia, Nausea, Myalgia, and Depression, all in >20% of patients. Dosing involved weekly injections for 48 weeks. Relative pricing was about 8 PU, around $50,000, for a full 48-week course of treatment at current list prices.
Advantage: PEG-IFN and Rebetol Combination (even at a premium cost)
(2004) Pegasys (PEG-Interferon, Roche) and Copegus11 (Ribavirin, Roche)
Approval of a Pegasys and ribavirin combination significantly improved overall efficacy on the order of that provided by the PegIntron and ribavirin combination. There were suggestions that the Pegasys combination by virtue of pharmacokinetic properties was somewhat more efficacious although this was not definitively validated. Relative pricing was increased to about 14 PU with the added cost of Copegus.
Advantage: PEG-IFN and Rebetol Combination
(2013) Sovaldi12 (sofosbuvir, Gilead) and Peg-IFN and Ribavirin
The next step in the evolution of treatments involved the introduction of Gilead’s Sovaldi, an oral polymerase inhibitor. This three-product combination significantly improved efficacy to 90% for Genotypes 1 and 4. Tolerability was somewhat improved relative to the Peg-IFN and ribavirin combinations. This may have been accounted for by the dosing period being reduced to 12 weeks. Sovaldi was dosed orally once a day, PEG-IFN once weekly, and ribavirin twice daily. Relative pricing was about 17 PU using Copegus pricing. This may be a little high and would be closer to 15 PU if generic ribavirin, available at the time, was used.
Advantage: Sovaldi, PEG-IFN and Ribavirin Combination
Sovaldi (sofosbuvir, Gilead) and Ribavirin
Sovaldi was also approved for use with only ribavirin for the treatment of HCV Genotypes 2 and 3. The efficacy for these two genotypes was 95% and 56%, respectively. The protocol is similar to the three-agent combination, 12 weeks for Genotype 2 and 24 weeks for Genotype 3, but without the PEGylated interferon. Safety and tolerability is somewhat improved with only Fatigue, Nausea, and Headache being experienced by more than 20% of patients. Relative pricing for the Sovaldi and Copegus combination for Genotype 3 is about 15 PU, or 13 PU with generic ribavirin.
Advantage (large): Sovaldi and Ribavirin Combination
(2014) Harvoni13 (sofosbuvir & lepidasvir, Gilead)
The next generation of treatments saw the introduction of Harvoni, a single tablet combination of an HCV virus inhibitor and the previously approved polymerase inhibitor Sovaldi (sofosbuvir). This eliminated the need for interferon and ribavirin. Efficacy for Genotype 1 increased to 98%-100%. Dosing was oral once a day for 12 weeks. Tolerability was excellent, relatively speaking, with no side effects exceeding 20%. Relative pricing remained high at about 15 PU. The value was also high with the elimination of injections and the improvement in safety and tolerability compared with PEG-IFN and ribavirin. The higher price of Harvoni was offset by the elimination of the costs for PEG-IFN and ribavirin.
Advantage: Harvoni
(2016) Epclusa14 (sofosbuvir & velpatasvir, Gilead)
Epclusa saw the swapping out of Harvoni’s lepidasvir for velpatasvir while retaining sofosbuvir. Efficacy increased to 95%-100% for all HCV Genotypes 1 to 6. Dosing was one tablet daily for 12 weeks. Tolerability was also much improved with Headache at 22% being the only major issue. Relative pricing dropped to about 11 PU.
Advantage: Epclusa
(2017) Vosevi15 (sofosbuvir, velpatasvir, voxilaprevir, Gilead)
The latest generation of HCV medications from Gilead is a three active single tablet combination. Efficacy is similar to Epclusa as is safety and tolerability. Dosing is one tablet daily for 12 weeks. Pricing is the same as Epclusa at 12 PU. While there doubtless are improvements provided by Vosevi these not as significant as the benefits offered by earlier generations of Hepatitis C treatments.
Advantage: Neither
Other HCV Medications
The text and illustrations reflect a simple summary of the evolution of Hepatitis C treatments using the ESCP analysis methodology. Attention has been paid primarily to the offerings from Schering-Plough (Merck), Roche, and Gilead Sciences. Several other companies active in the HCV sector introduced their own HCV products. These products will be reviewed and analyzed in Part 2 of this series.
There was an obvious step wise progression of therapeutic improvements in the treatment of Hepatitis C starting with Efficacy eventually reaching 100%, Safety and tolerability issues were largely eliminated, and Convenience progressed from injections and multiple daily oral dosing for almost a year, to one oral tablet daily for 12 weeks.
At this point ,the relentless improvements have shaken out many of the earlier products. Only a couple of products currently enjoy significant sales in the US, presumably at lower negotiated prices. What was at one point a $20-billion annual market in the US has been reduced by about three quarters to $5 billion as the patient pool is slowly reduced with the introduction of what is essentially a cure, and competitive contract pricing.
The last horizon it seems is Pricing. Any significant reduction in the cost of these therapies probably awaits the expiration of patents and the introduction of generic equivalents of approved products.
References
- Drug Development & Delivery March 2021 Vol 21 No 2, p. 69. https://drug-dev.com/product-development-strategy-escp-estimating-product-performance-part-1-playground-physics/.
- Drug Development & Delivery April 2021 Vol 21 No 3, p. 44. https://drug-dev.com/product-development-strategy-escp-estimating-product-performance-part-1-playground-physics/.
- Drug Development & Delivery May 2021 Vol 21 No 4, p. 39. https://drug-dev.com/prodyct-development-strategy-escp-estimating-product-performance-part-3-mind-the-axle.
- Drug Development & Delivery June 2021 Vol 21 No 5, 40. https://drug-dev.com/product-development-strategy-escp-estimating-product-performance-part-4-building-playgrounds-fences/.
- Wikipedia HCV – https://en.wikipedia.org/wiki/Hepatitis_C
- GoodRx – https://www.goodrx.com/
- Intron A – https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103132Orig1s5199lbl.pdf
- Rebetol – https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020903s056,021546s012lbl.pdf
- PegIntron – https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103949s5313lbl.pdf
- Pegasys – https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103964s5275lbl.pdf
- Copegus – https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021511s029lbl.pdf
- Sovaldi – https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204671s017,212480s002lbl.pdf
- Harvoni – https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205834s032,212477s003lbl.pdf
- Epclusa – https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208341s017lbl.pdf
- Vosevi – https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209195s003lbl.pdf
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