Discovery
Pegylated interferon alfa-2a, typically shortened to peginterferon alfa-2a, is an antiviral prescription medication taken to treat chronic hepatitis B (HBV) and hepatitis C (HCV) infections. It is administered through a subcutaneous injection, once weekly for a course of 48 weeks.1 Peginterferon alfa-2a is a type of interferon; interferons, a type of cytokines, are proteins in the body which interfere with a virus ability to proliferate, thus treating HBV and HCV.2
In 1957, A. Isaacs and J. Lindeman discovered interferons in the chorioallantoic membranes of chick embryos after the membranes were stimulated with the influenza virus.3 Later, interferons were found in humans after human leukocytes were stimulated with viruses, and from this some clinical trials were started. However, the preparation being used in these clinical studies only consisted of 1% interferons, with the other 99% being a mix of different proteins. Clinical trials for interferon as an antiviral were halted until 1978, when interferon was purified to homogeneity. This was achieved through the incubation of human leukocytes from donors with New-castle disease virus or Sendai virus. Rather than using human or bovine serum for the culture medium, milk casein was used. Because a singular protein was used, extraction of interferons was much easier.4 There are three commonly expressed types of interferons (alfa, beta, and gamma), but the alfa-2a interferon was found to be the most effective for treating HBV and HCV. The current version of peginterferon alfa-2a, approved for treatment of HBV and HCV in 1991, is produced using recombinant DNA technology. The human leukocyte gene is inserted into Escherichia coli, where it is expressed to produce interferon alfa-2a. The brand name for peginterferon alfa-2a is Pegasys, and is produced by Genentech.5
In order to increase biological activity, a single branched bis-monomethoxy polyethylene glycol (PEG) is attached to the interferon at a single site via a stable amine bond to lysine.5 This process, referred to as pegylation, makes the molecule larger; this improved the pharmacodynamics and pharmacokinetics of the drug, as well as increasing half-life, increasing drug stability, slowing absorption, and decreasing the rate of clearance from plasma when compared to native interferons.6,7 In addition to pegylation, treatment of HBV and HCV with peginterferon alfa-2a was improved by using ribavirin in combination with the drug. With peginterferon alfa-2a monotherapy, treatment success rates were around 10-20%; with the ribavirin and peginterferon alfa-2a combination, treatment success rates were around 54-56%.6
Interferons work by binding to specific receptors on the cell surface, initiating intracellular signaling through a cascade of protein to protein interactions, which leads to the rapid activation of gene transcription. Genes stimulated by the interferons modify many biological effects, including the inhibition of viral replication in infected cells, inhibition of cell proliferation, and immunomodulation.5 Specifically, peginterferon alfa-2a stimulates the production of effector proteins with antiviral effects, such as protein kinase, 2’,5’ oligoadenylate synthetase, adenosine deaminase, and protein GTPase.6
One of the major reasons that peginterferon alfa-2a is no longer the most widely used treatment for HBV and HCV are the many adverse reactions to the medication. The most frequent adverse effects are flu-like symptoms, as well as the following: fatigue, pyrexia, rigors, nausea/vomiting, neutropenia, anorexia, myalgia, arthralgia, headache, irritability, insomnia, depression, alopecia, and pruritus.5 These, along with the frequency and duration of treatment, relatively low treatment success rates, and form of dosage (injection) of peginterferon alfa-2a, are the main reasons that Harvoni (Ledipasvir / Sofosbuvir) is now the most widely used drug for treating HBV and HCV.
Commercialization
Commercial Aspects
Peginterferon alfa-2a is manufactured as PEGASYS by Genentech, a member of the Roche group, a company also known as Hoffmann- La Roche or Roche Holding AG. Roche is a Swiss multinational healthcare company that focuses on pharmaceuticals and diagnostics. As well as manufacturing PEGASYS, Genentech also sells the product. The current share price of Genentech is $85 a share on the New York Stock Exchange and there are 20 million shares offered.8 Because Roche is an international company, it is traded in the US as US dollar-denominated American Depositary Receipt (ADR) on OTCQX International Premier Market. ADRs represent ownership of equity in a non-US company. Additionally, Roche also sells shares on the SIX Swiss Exchange.9
The original owners of Genentech, Herbert Boyer and Robert Swanson, could not fully fund the company themselves, so they turned to a venture capitalist. The co-owner of Kleiner-Perkins, Tim Perkins, was who the two turned to for venture funding. In 1985, Genentech formed a Canadian market joint venture with Boehringer Ingelheim Ltd. to market and sell the product in Canada.12 Later, in 2009, Genentech was acquired by the Roche group for $47 billion.10
In the pharmaceutical division of Roche, Pegasys is the 7th highest selling product. PEGASYS sales in 2006 were approximately $1460 million, and the total pharmaceutical EBITDA for the Roche group was $12,000 million. In looking at the overall Roche group sales, PEGASYS sales represented 4% of total sales.11
A market analysis study was done by PharmaPoint to analyze the future of PEGASYS from 2012 to 2022. In 2012, the total global sales were $1052 million, with $499.6 million in the US, $273.6 million in five EU countries, $80.9 million in Japan, $102.5 million in Brazil, and $95.4 million in China. The projected sales for 2022 for PEGASYS are as follows: $625.6 million in global sales, $119.1 million in the US, $271.7 million in five EU countries, $34.9 million in Japan, $1.1 million in Brazil, and $198.8 million in China. The five EU countries considered are France, Germany, Italy, Spain, and the UK. The major driving force of PEGASYS is the patients in cost-conscious markets, as is seen in the projected market in China. This is because the price of next-generation HBV and HCV therapies is very high. One of the major barriers to the PEGASYS market is interferon-free therapies, such as Gilead’s Harvoni, AbbVie’s combination therapy, and BI’s faldaprevir. Other barriers are new interferon derivatives, such as Bristol-Myers Squibb’s peginterferon lambda therapies which may have less adverse effects and biosimilar products that cost less to the consumer.13
Intellectual Property
Hoffmann- La Roche has 36 total patents for PEGASYS, with one in the US and 35 others in various international countries. Roche used to have a patent for PEGASYS in India, but in 2012, the Indian Patent office renounced the patent.14 The patent is/was set to expire in 2018.15 PEGASYS is a registered trademark of Hoffmann- La Roche.16
The composition of matter of PEGASYS is 180µL of peginterferon alfa-2a in 0.5 mL of solution and 135µL of peginterferon alfa-2a in 0.5 mL of solution. The method of delivery is a pre-filled syringe.17
Regulatory Information
Genentech employs current Good Manufacturing Practices (cGMP). A Biological License Application was approved for Hoffmann- La Roche for PEGASYS on October 12, 2002. The BLA number is 103964. There have been 19 supplemental materials submitted to the FDA for the BLA since, with the earliest on December 3, 2002 and the latest on October 13, 2007.18 PEGASYS is most likely manufactured at Genentech’s Vacaville, California location, based on descriptions from their website. The Vacaville website says that the plant specializes in “large scale production of pharmaceutical proteins from mammalian cells,” which is a category into which peginterferon alfa-2a fits.19
For the preclinical toxicity of PEGASYS, the studies were limited due to species specificity of interferons; natural interferons from the cynomolgus monkeys that were being used in the studies are different from the natural human interferons from which peginterferon alfa-2a was derived. When ribavirin was used in combination with peginterferon alfa-2a, there were no effects that had not been previously observed in either substance independently. The major effect of treatment was mild-to-moderate, reversible anemia.20 According to the European Medicines Agency, “The safety pharmacology studies did not reveal any particular effects of peginterferon on body temperature, central nervous system, gastro-intestinal and respiratory functions in rats and mice at doses up to 600 µg/kg.” However, decreases in urine output were observed in rats, and no cardiovascular effects were observed in monkeys.21
There are 381 completed clinical studies that involve peginterferon alfa-2a on Clinicaltrials.gov. The following clinical trials are just a few of the several hundred.
The ACCELERATE trial was a phase 4 study that looked at PEGASYS (peginterferon alfa-2a) in combination with COPEGUS (ribavirin) in interferon-naïve patients with Chronic Hepatitis C (CHC) infection. The sponsor and responsible party were both Hoffmann-La Roche. There were 1469 participants, and the requirement for participants was to be 18 years old or older, have CHC infection, no HIV infection, and not pregnant of breastfeeding. The study occurred in the following locations: USA, Australia, Canada, France, Germany, Italy, New Zealand, Puerto Rico, and Spain.22
One phase 3 trial studied the efficacy and safety of Pegasys in the treatment of Chronic HBV. The sponsor and responsible party were both Hoffmann-La Roche. There were 820 participants. The study occurred in the following locations: USA, Australia, Brazil, Canada, China, France, Germany, Israel, Korea, New Zealand, Poland, Puerto Rico, Singapore, Spain, Switzerland, Taiwan, Thailand, and the UK.23
One phase 1 trial studied the administration of peginterferon alfa-2a by auto injector versus pre-filled syringes in patients with CHC. The sponsor and responsible party were both Hoffmann-La Roche. There were 60 participants, and the requirement for participants was to be 18 years old or older and have CHC infection. The study occurred in the following location: USA.24
Another phase 1 trial studied pharmacokinetics and pharmacodynamics of Intravenously Administered Pegasys in patients with CHC and previous non-responders to peginterferon and ribavirin combination therapy. The sponsor and responsible party were both Hoffmann-La Roche. There were 31 participants, and the requirement for participants was to be 18-70 years old, have CHC Genotype I infection, and be non-responders to previous anti-HCV therapy with peginterferon alfa and ribavirin. The study occurred in the following location: Germany.25
One phase 2 trial studied peginterferon alfa-2a with and without ribavirin in participants with Chronic Hepatitis D (CHD) infection. The sponsor and responsible party were both Hoffmann-La Roche. There were 12 participants, and the requirement for participants was to be 18 years old or older and have CHD infection. The study occurred in the following location: Italy.26
References
1. “Pegasys® (Peginterferon Alfa-2a) - Information for Patients.” Genentech, 1 Nov. 2018, www.gene.com/patients/medicines/pegasys.
2. Britannica, The Editors of Encyclopaedia. “Interferon.” Encyclopædia Britannica, Encyclopædia Britannica, Inc., 7 Aug. 2009, www.britannica.com/science/interferon.
3. “Virus Interference. I. The Interferon.” Journal of Interferon Research, vol. 7, no. 5, 1987, pp. 429–438.
4. Pestka, Sidney. “The Interferons: 50 Years after Their Discovery, There Is Much More to Learn.” Journal of Biological Chemistry, vol. 282, no. 28, 2007, pp. 20047–20051.
5. “PEGASYS(Peginterferon Alfa-2a), Roche, Supplement.” Accessdata.fda.gov, 26 Sept. 2003, www.accessdata.fda.gov/drugsatfda_docs/label/2002/pegihof120302LB.htm#dose.
6. Noureddin, and Ghany. “Pharmacokinetics and Pharmacodynamics of Peginterferon and Ribavirin: Implications for Clinical Efficacy in the Treatment of Chronic Hepatitis C.” Gastroenterology Clinics of North America, vol. 39, no. 3, 2010, pp. 649–658.
7. Baker, DE. “Pegylated Interferon plus Ribavirin for the Treatment of Chronic Hepatitis C.” Rev Gastroenterol Disord, vol. 3, no. 2, 2003, pp. 93–109.
8. "GENENTECH INC (DNA) IPO". Nasdaq, 2018, https://www.nasdaq.com/markets/ipos/company/genentech-inc-3902-4388. Accessed 5 Nov 2018.
9. "Genentech: How To Invest". Gene, 2018, https://www.gene.com/about-us/investors/how-to-invest. Accessed 5 Nov 2018.
10. Hardymon, Felda, and Tom Nicholas. "Kleiner-Perkins and Genentech: When Venture Capital Met Science." Harvard Business School Case 813-102, October 2012.
11. "Roche Annual Report 2006 Part 2 Finance Report". Roche, 2006, https://www.roche.com/dam/jcr:137cb8e0-caae-434a-805d-ec7d72078b85/en/fb06e.pdf. Accessed 5 Nov 2018.
12. "Genentech: Press Releases". Gene, 1985, https://www.gene.com/media/press-releases/4228/1985-03-21/genentech-forms-canadian-marketing-joint. Accessed 5 Nov 2018.
13. "Pegasys (Hepatitis C Virus) Forecast And Market Analysis To 2022". Marketresearch.Com, 2013, https://www.marketresearch.com/product/sample-7692189.pdf. Accessed 5 Nov 2018.
14. "November 2018 - When Will The Patents On PEGASYS Expire, And When Will Biosimilar PEGASYS Enter The Market?." Deep knowledge on small-molecule drugs and the global patents covering them. N. p., 2018. Web. 5 Nov. 2018.
15. Hunziker, Erich. "Roche: Navigating Through A Volatile Environment". Roche, 2010, https://www.roche.com/dam/jcr:e1eb6d3d-ebbd-4c27-b790-8e2bce45c44f/en/irp100111.pdf. Accessed 5 Nov 2018.
16. "Genentech: Pegasys® (Peginterferon Alfa-2A) - Information For Healthcare Providers". Gene, 2016, https://www.gene.com/medical-professionals/medicines/pegasys. Accessed 5 Nov 2018.
17. "Data Sheet Pegasys". Medsafe, 2016, http://www.medsafe.govt.nz/profs/Datasheet/p/Pegasysinj.pdf. Accessed 5 Nov 2018.
18. "Drugs@FDA: FDA Approved Drug Products". FDA, 2018, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103964. Accessed 5 Nov 2018.
19. "Genentech: Vacaville." Gene.com. N. p., 2018. Web. 5 Nov. 2018.
20. "Data Sheet Pegasys RBV". Medsafe, 2016, http://www.medsafe.govt.nz/profs/datasheet/p/PegasysRBVinjtab.pdf. Accessed 5 Nov 2018.
21. EMA, 2005, https://www.ema.europa.eu/documents/scientific-discussion/pegasys-epar-scientific-discussion_en.pdf. Accessed 5 Nov 2018.
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