Sofosbuvir

Initial HCV treatment

Sofosbuvir is used for the treatment of chronic hepatitis C, genotypes 1, 2, 3, 4, 5, and 6, usually in combination with other medications depending on the specific genotype. For the treatment of genotypes 1, 4, 5, and 6 hepatitis C infections, sofosbuvir is used in combination with the viral NS5A inhibitor ledipasvir. For the treatment of other genotypes, sofosbuvir is used in combination with weight-based ribavirin alone in genotype 2 HCV infections, and together with peginterferon in genotype 3 HCV infections.

Compared to previous treatments, sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a two- to four-fold reduced duration of therapy. Sofosbuvir allows most people to be treated successfully without the use of peginterferon, an injectable drug with severe side effects that is a key component of older drug combinations for the treatment of hepatitis C virus.

In 2016, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America jointly published a recommendation for the management of hepatitis C. In this recommendation, sofosbuvir and ledipasvir, or sofosbuvir and ribavirin, with or without peginterferon, are part of all first-line treatments for HCV genotypes 1 to 6, and are also part of some second-line treatments.

Prior failed treatment

For people who have experienced treatment failure with some form of combination therapy for hepatitis C infection, one of the next possible steps would be retreatment with sofosbuvir and ledipasvir, with or without weight-based ribavirin. What particular combination therapy a person was on when the initial treatment failed is also taken into consideration when deciding on which combination to use next. The duration of retreatment can also range from 12 weeks to 24 weeks depending on factors such as which medications are used for the retreatment, whether the person has liver cirrhosis or not, and whether the liver damage is classified as compensated cirrhosis or decompensated cirrhosis.

Pregnancy and breastfeeding

Sofosbuvir alone has been assigned a Pregnancy Category B by the FDA (meaning that it there are no adequate and well-controlled studies in pregnant women but animal reproduction studies have not demonstrated a risk to the fetus and, or that adverse effects have been seen in animal studies, but adequate and well-controlled studies in pregnant women have not, in any trimester). However, ribavirin, a medication that is often given together with sofosbuvir to treat hepatitis C, is assigned a Pregnancy Category X (contraindicated in pregnancy) by the FDA. Pregnant women with hepatitis C who take ribavirin have shown some cases of birth defects and death in their fetus. It is recommended that sofosbuvir/ribarivin combinations be avoided in pregnant females and their male sexual partners in order to reduce harmful fetal defects caused by ribavirin. Females who could potentially become pregnant should undergo a pregnancy test 2 months prior to starting the sofosbuvir/ribavirin/peginterferon combination treatment, monthly throughout the duration of the treatment, and 6 months post-treatment to reduce the risk of fetal harm in case of accidental pregnancy.

It is unknown whether sofosbuvir and ribavirin pass into breastmilk; therefore, it is recommended that the mother does not breastfeed during treatment with sofosbuvir alone or in combination with ribavirin.

Contraindications

There are no specific contraindications for sofosbuvir when used alone. However, when used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to these agents are applied.

Side effects

Sofosbuvir used alone and in combination with other drugs such as ribavirin with or without a peginterferon has a good safety profile. Common side effects are fatigue, headache, nausea, rash, irritability, dizziness, back pain, and anemia. Most side effects are significantly more common in interferon-containing regimens as compared to interferon-free ones. For example, fatigue and headache are nearly cut in half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and neutropenia is almost absent in interferon-free treatment.

Sofosbuvir may reactivate hepatitis B in those who have been previously infected.

Interactions

Sofosbuvir (in combination with ledipasvir, daclatasvir or simeprevir) should not be used with amiodarone due to the risk of abnormally slow heartbeats.

Sofosbuvir is a substrate of P-glycoprotein, a transporter protein that pumps drugs and other substances from intestinal epithelium cells back into the gut. Therefore, inducers of intestinal P-glycoprotein, such as rifampicin and St. John's wort, could reduce the absorption of sofosbuvir.

In addition, coadministration of sofosbuvir with anticonvulsants (carbamazepine, phenytoin, phenobarbital, oxcarbazepine), antimycobacterials (rifampin, rifabutin, rifapentine), and the HIV protease inhibitor tipranavir and ritonavir is expected to decrease sofosbuvir concentration. Thus, coadministration is not recommended.

The interaction between sofosbuvir and a number of other drugs, such as ciclosporin, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil, were evaluated in clinical trials and no dose adjustment is needed for any of these drugs.

Mechanism of action

Sofosbuvir inhibits the hepatitis C NS5B protein. Sofosbuvir appears to have a high barrier to the development of resistance.

Sofosbuvir is a prodrug. It is metabolized to the active antiviral agent GS-461203 (2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate). GS-461203 serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis. Although sofosbuvir has a 3' hydroxyl group to act as a nucleophile for an incoming NTP, a similar nucleotide analogue, 2'-deoxy-2'-α-fluoro-β-C-methylcytidine, is proposed to act as a chain terminator because the 2' methyl group of the nucleotide analogue causes a steric clash with an incoming NTP. Sobosbuvir would act in a similar way.

Pharmacokinetics

Sofosbuvir is only administered orally. The peak concentration after oral administration is 0.5–2 hours post-dose, regardless of initial dose. Peak plasma concentration of the main circulating metabolite GS-331077 occurs 2–4 hours post-dose. GS-331077 is the pharmacologically inactive nucleoside.

Plasma protein binding of sofosbuvir is 61–65%, while GS-331077 has minimal binding.

Sofosbuvir is activated in the liver to the triphosphate GS-461203 by hydrolysis of the carboxylate ester by either of the enzymes cathepsin A or carboxylesterase 1, followed by cleaving of the phosphoramidate by the enzyme histidine triad nucleotide-binding protein 1 (HINT1), and subsequent repeated phosphorylation. Dephosphorylation creates the inactive metabolite GS-331077. The half life of sofosbuvir is 0.4 hours, and the half life of GS-331007 is 27 hours.

Following a single 400 mg oral dose of sofosbuvir, 80% is excreted in urine, 14% in feces, and 2.5% in expired air recovery. However, of the urine recovery 78% was the metabolite (GS-331007) and 3.5% was sofosbuvir.

Chemistry

Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been examined as antihepatitis C treatments, but these exhibited relatively low potency. This low potency arises in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of sofosbuvir, based on the ProTide approach, avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell. The NS5B protein is a RNA-dependent RNA polymerase critical for the viral reproduction cycle.

History

Sofosbuvir was discovered by Michael Sofia, a scientist at Pharmasset, in 2007 and the drug was first tested in people in 2010 and in 2011 Gilead bought Pharmasset for about $11 billion. Gilead submitted the New Drug Application for sofosbuvir in combination with ribavirin in April 2013, and in October 2013 it received the FDA's Breakthrough Therapy Designation. In December 2013, the FDA approved sofosbuvir in combination with ribavirin for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive people with HCV genotypes 1 and 4. Two months before, the FDA had approved another drug for HepC, simeprevir.

In 2014 the fixed dose combination drug sofosbuvir/ledipasvir, the latter a viral NS5A inhibitor, was approved; it had also been granted breakthrough status.

Prior to the availability of sofosbuvir, hepatitis C treatments involved 6 to 12 months treatment with an interferon-based regimen that provided cure rates of 70% or less and was associated with severe side effects including anemia, depression, severe rash, nausea, diarrhea, and fatigue. As sofosbuvir clinical development progressed, physicians began to "warehouse" people in anticipation of its availability. Sofosbuvir's U.S. launch was the fastest of any new drug in history. Over 60,000 people were treated with sofosbuvir in its first 30 weeks on the U.S. market, about 5% of the U.S. infected population.

Society and culture

Sofosbuvir is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.

The price of sofosbuvir, quoted in various media sources as $84,000 to $168,000 for a course of treatment in the U.S., £35,000 in the UK for 12 weeks has engendered considerable controversy. However, sofosbuvir is significantly more affordable in Japan and South Korea at approximately $300 and $5900 respectively for a 12-week treatment, with each government covering 99% and 70% of the cost respectively. In 2014, Gilead announced that it would work with generic manufacturers in 91 developing countries to produce and sell sofosbuvir, and that it would sell a name brand version of the product in India for approximately $300 per course of treatment; it had signed agreements with generic manufacturers by September 2015.

Cost

The price has generated considerable controversy.

United States

As of 2016 for a course of treatment it costs about $84,000 in the United States. In 2014 the list price of 12 weeks combination treatment with a sofosbuvir-based regimen sosbuvir ranges from US$84,000 to $94,000. In April 2014 U.S. House Democrats Henry Waxman, Frank Pallone Jr., and Diana DeGette wrote Gilead Sciences Inc. questioning the $84,000 price for sofosbuvir. They specifically asked Gilead CEO John Martin to "explain how the drug was priced, what discounts are being made available to low-income patients and government health programs, and the potential impact to public health by insurers blocking or delaying access to the medicine because of its cost." Sofosbuvir is cited as an example of how specialty drugs present both benefits and challenges.

Sofosbuvir also is an excellent example of both the benefit and the challenge of specialty medications. On one hand, this agent offers up to a 95% response rate as part of an interferon-free treatment regimen for hepatitis C. Generally speaking, it is more effective and better tolerated than alternative treatments. Unfortunately, the current per pill cost—$1,000—results in an $84,000 treatment course, creating barriers to therapy for many. Patients, providers, and payors alike have expressed outrage, and the debate has even drawn the attention of the US Congress. Despite these concerns, sofosbuvir rapidly has become a top seller in the United States…

In February 2015 Gilead announced that due in part to negotiated discounts with pharmacy benefit managers and legally mandated discounts to government payers, the average discount to list price in 2014 was 22%. The company estimated that the average discount in 2015 would be 46%. According to the California Technology Assessment Forum, a panel of academic pharmacoeconomic experts, representatives of managed care organizations, and advocates for people with hepatitis, a 46% discount would bring the average price of treatment to about $40,000, at which price sofosbuvir-based treatment regimens represent a "high value" for people and healthcare systems.

Germany

In Germany negotiations between Gilead and health insurers led to a price of €41,000 for 12 weeks of treatment. This is the same price previously negotiated with the national healthcare system in France, except that additional discounts and rebates apply in France depending on the volume of sales and the number of treatment failures.

Switzerland

In Switzerland the price is fixed by the state every three years. The price is CHF 16,102.50 for 24 pills of 400 mg.

United Kingdom

The price in the United Kingdom is expected to be £35,000 (~US$68,110) for 12 weeks. NHS England has established 22 Operational Delivery Networks to roll out delivery which was approved by the National Institute for Health and Care Excellence in 2015 and proposes to fund 10,000 courses of treatment in 2016-17. Each has been given a "run rate" of how many people they are allowed to treat, which was the NHS’ single biggest new treatment investment in 2016.

Asia

Unlike Western countries, sofosbuvir is more affordable in Japan and South Korea at approximately $300 and $5900 respectively for a 12-week treatment, with each government covering 99% and 70% of the cost respectively.

Developing world

In 2014, Gilead announced that it would seek generic licensing agreements with manufacturers to produce sofosbuvir in 91 developing countries, containing 54% of the world's HCV-infected population and that it would sell a name brand version of the product in India for $300 per course of treatment, approximately double a third party estimate of the minimum achievable cost of manufacture. It had signed licenses with generic manufacturers by September 2015. The leader of one Indian activist group called this move inadequate, but nine companies launched products, which "unleashed a fierce marketing war", according to India's The Economic Times.

Jennifer Cohn of Doctors without Borders and the organization Doctors of the World criticized the price of sofosbuvir as reflecting "corporate greed" and ignoring the needs of people in developing countries. In contrast, the Access to Medicines Index ranked Gilead first among the world's 20 largest pharmaceutical countries in the Pricing, Manufacturing and Distribution category in both 2013 and 2014, citing Gilead's "leading performance in equitable pricing".

In Algeria, as of 2011 about 70,000 people were infected with hepatitis C. As of August 2015, Gilead had licensed its partners in India to sell sofosbuvir in Algeria. It had been criticized for not making the drug available in middle-income countries including Algeria prior to that.

Patent challenges

In January 2015 the Indian Patent Office in Mumbai rejected Gilead's patent application. That decision was overturned on appeal in February 2015.

In February 2015 it was reported that Doctors of the World had submitted an objection to Gilead's patent at the European Patent Office claiming that the structure of sofosbuvir is based on already known molecules. In particular, Doctors of the World argue that the Protide technology powering sofosbuvir has been previously invented by the McGuigan team at Cardiff University in the UK, and that the Gilead drug is not therefore inventive. The group filed challenges in other developing world countries as well.

Research

Combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or ledipasvir, have shown sustained virological response rates of up to 100% in people infected with HCV. Most studies indicate that the efficacy rate is between 94% and 97%; much higher than previous treatment options.