Special report: First year After Launch, August 2013
By Andrew Humphreys firstname.lastname@example.org
For the global pharma arena, 2012 is noted as the year of the patent cliff, with roughly $38 billion in prescription drug sales lost due to the exclusivity expiration of some of the all-time best sellers, including Lipitor and Plavix. As a result, total worldwide Rx brand sales uncharacteristically decreased year over year. But overall global sales growth for branded prescription drugs is expected to slightly increase in 2013, and is anticipated to gain better traction and increase by several percentage points during each of the next few years thereafter. Helping spur this sales growth is a variety of innovative medicines that were introduced to the U.S. marketplace during 2011 and performed strongly in 2012, their first full year of availability.
Battle for hepatitis C category share
Though this story concentrates on the 2012 and 2013 market performance of successful products launched in the United States during 2011, the latter is the year of most significance for Incivek. The drug became the fastest prescription medicine to top $1 billion in sales, doing so for developer Vertex Pharmaceuticals between May 2011 and January 2012.
Containing the active chemical telaprevir, Incivek is an orally administered hepatitis C virus (HCV) protease inhibitor. The product is available for adults with genotype 1 HCV infection in combination with pegylated-interferon (peg-IFN) and ribavirin (RBV). Patients are initially treated with Incivek, a weekly injection of peg-IFN, and RBV for 12 weeks. After three months, patients stop receiving Incivek and continue with peg-IFN and RBV for another 12 weeks or 36 weeks of treatment. Incivek is indicated for three-times-daily dosing, with regulatory filings awaiting approval for twice-daily use.
Telaprevir was discovered through a former collaboration between Vertex and Lilly. Approved by U.S. regulators on May 23, 2011, the drug was launched by Vertex in America shortly thereafter. Canadian approval was granted during August 2011, and Incivek was introduced to that market by Vertex two months later. Telaprevir gained regulatory clearance in the third quarter of 2011 in the European Union (branded as Incivo) and Japan (marketed as Telavic). Johnson & Johnson subsidiary Janssen Pharmaceutica is responsible for marketing in Europe and other countries, and Mitsubishi Tanabe Pharma commercializes the medicine in Japan.
Before the arrival of Incivek and Merck’s Victrelis during 2011, patients with genotype 1 HCV infection were treated with a combination of peg-IFN and RBV for 48 weeks. Those new treatment regimens incorporating HCV protease inhibitors offer substantially increased sustained viral response rates – and in many instances shorter treatment durations – for patients with genotype 1 HCV infection, versus peg-IFN and RBV alone.
Incivek attained rapid acceptance in the United States for treating patients with genotype 1 HCV infection. Vertex reported total sales (for the United States and Canada) of $950.9 million in 2011, increasing to $1.16 billion during 2012. But according to Vertex, because of competitive treatment regimens undergoing late-stage clinical development for which there have been reported improved viral cure rates and/or tolerability over available regimens, the marketplace has anticipated the approval of these newer regimens. Between the promising safety and efficacy data reported by Vertex competitors for potential treatment regimen rivals along with other factors, Incivek revenue has been declining since reaching a peak during fourth-quarter 2011. Vertex expected that the drug’s revenue would continue decreasing in 2013 versus its 2012 performance. That projection came to fruition during first-half 2013 as Vertex’s net revenue from Incivek totaled $361.4 million, versus $684.6 million for January-June 2012. The company attributed the reduced revenue to fewer HCV patients initiating treatment in the first half of 2013 compared to the first six months of 2012.
Incivek is patent protected in the United States until 2025. Incivo’s EU patent protection ranges until 2026.
Victrelis (boceprevir) is an innovative oral medicine marketed by Merck for treating certain adults with chronic hepatitis C. The medication is used for patients who still have some liver function, and who either have not been previously treated with drug therapy for their hepatitis C or who have failed such treatment. Victrelis is available for use in combination with peginterferon alfa and ribavirin. Victrelis is taken as a pill three times per day with food. The therapy belongs to a class of medicines referred to as protease inhibitors, which work by binding to the virus and preventing it from multiplying.
The drug was cleared for approval by U.S. regulators during May 2011 and by the European Commission in July 2011. Victrelis is approved in 70 countries and has been introduced in at least 45 of those markets. After generating global sales of $140 million in 2011, the figure reached $502 million for 2012. Merck reported that Victrelis’ 2012 performance was spurred by post-launch growth in the United States and internationally, particularly in Europe.
Victrelis sales for the first three months of 2013 amounted to $110 million, compared to $111 million during January-March 2012. According to Merck, the sales decline included a 2 percent negative impact from foreign exchange. Lower U.S. sales for the oral hepatitis C virus protease inhibitor were partially offset by continued growth in international markets.
Victrelis is patent protected in the United States until 2024 (with pending Patent Term Restoration). Some industry trackers had previously projected full-year 2013 worldwide sales of more than $700 million, with that figure declining in the ensuing years due to the arrival of newer and better competition.
Many companies, including Vertex, are pursuing the development of treatment regimens for HCV infection that could potentially offer improved safety, efficacy and/or tolerability – such as shorter duration therapies, therapies that do not necessitate administration of peg-IFN, and those that do not result in side effects evident with currently approved HCV protease inhibitors. Various companies are investigating combination regimens that bring together one or more of an HCV protease inhibitor, an HCV nucleotide analog, an HCV non-nucleotide polymerase inhibitor or an NS5A inhibitor; each of which inhibit HCV viral replication via different mechanisms of action. Clinical studies of these investigational combination regimens are being carried out in a different types of patient populations, including treatment-naïve and treatment-failure patients, and across all HCV genotypes, which respond differently to various combinations of molecules employing different mechanisms.
Vertex is sponsoring Phase IIIb clinical trials to evaluate telaprevir-based combination treatment regimens for patients with genotype 1 HCV infection who also have HIV infection and for patients who experience recurrent genotype 1 HCV infection following a liver transplant.
The next wave of genotype 1 HCV infection drugs to reach the marketplace are expected to be part of a treatment regimen that includes peg-IFN and RBV, with regulatory approval possible coming in late 2013 or early 2014. All-oral treatment regimens that do not contain the injectable peg-IFN additionally are in late-stage clinical trials, and the first of those treatment regimens could gain U.S. clearance by late 2014.
The biopharma company Gilead Sciences has completed Phase III studies evaluating treatment regimens for patients with HCV infection. During April 2013, Gilead filed for approval with U.S. and EU health regulators for the use of sofosbuvir (product code GS-7977) and ribavirin as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with RBV and pegylated interferon for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection. On May 17, the Marketing Authorisation Application (MAA) for the once-daily oral nucleotide analog inhibitor sofosbuvir was announced as fully validated and under assessment by the European Medicines Agency. Gilead announced in June that FDA had granted priority review for sofosbuvir. The U.S. regulatory agency has set a target review date under the Prescription Drug User Fee Act of Dec. 8, 2013.
Janssen also has a combination treatment for genotype 1 chronic hepatitis C undergoing priority review by FDA, as of May 2013. Simeprevir (product code TMC435) is an investigational NS3/4A protease inhibitor administered as a 150-mg capsule once daily with pegylated interferon and ribavirin for treating genotype 1 chronic hepatitis C in adult patients with compensated liver disease. Jointly developed by Janssen and Medivir, the intended indication for simeprevir includes every stage of liver fibrosis. The drug works by blocking the protease enzyme that allows the hepatitis C virus to replicate in host cells. Janssen has also filed simeprevir for marketing authorization to health regulators in Japan and Europe.
Top-line results reported by Gilead and Janssen from Phase III studies for sofosbuvir and simeprevir suggest that their safety and efficacy profiles will position them to potentially take a significant portion of the market for HCV therapies. Industry analysts have projected that various sofosbuvir-based products could generate more than $9 billion in combined sales during 2018.
As for the development of all-oral treatment regimens for HCV infection, Vertex is studying different options including its HCV nucleotide analog VX-135/ALS-2200 in Phase II trials. VX-135 studies include the drug compound as part of all-oral treatment regimen with ribavirin as well as other direct-acting antivirals. Vertex intends to start pivotal development of VX-135 as part of all-oral treatment regimens in 2014, pending data from the Phase II trials.
The uridine nucleotide analog pro-drug VX-135 is designed to inhibit the replication of HCV by acting on the NS5B polymerase. ALS-2200 has demonstrated pangenotypic activity in vitro. Vertex acquired global rights to ALS-2200 via an exclusive licensing deal inked with Alios BioPharma during June 2011. The pact includes a research program that concentrates on the discovery of additional nucleotide analogs that act on the hepatitis C polymerase. Vertex has the option to choose more compounds for development emerging from the research program.
Gilead is conducting Phase III development an all-oral treatment regimen for HCV infection. The ION-1 study is evaluating a once-daily fixed-dose combo of sofosbuvir and the NS5A inhibitor ledipasvir with and without ribavirin for 12 or 24 weeks among treatment-naïve genotype 1 patients with HCV infection. Sofosbuvir/ledipasvir is additionally being studied in the Phase III ION-2 trial launched during January 2013. Fully enrolled, ION-2 is evaluating sofosbuvir/ledipasvir with RBV for 12 weeks, and with and without RBV for 24 weeks, among 400 treatment-experienced genotype 1 HCV patients. Participants in this clinical trial failed to respond to past therapy containing peg-IFN plus a protease inhibitor.
AbbVie is performing Phase III development for an investigational direct-acting antiviral (DAA) combination with and without ribavirin for treating genotype 1 (GT1) hepatitis C virus infection. The Phase III program for the all-oral, triple-DAA combination consists of more than 2,000 patients with HCV genotype 1, with trial sites in 29 countries. The DAAs in the program include ABT-450/r (protease inhibitor and ritonavir), ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside polymerase inhibitor). Treatment durations being studied are 12 weeks in non-cirrhotic patients, and 12 or 24 weeks in cirrhotic patients. Every patient will be followed for 48 weeks post-treatment. Co-formulated tablets of ABT-450/r and ABT-267 are being used in the Phase III studies.
The interferon-free, direct-acting antiviral combo gained Breakthrough Therapy designation from FDA, as announced by AbbVie during May 2013. This designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. Criteria includes preliminary clinical evidence showing a drug may have substantial improvement on at least one clinically significant endpoint versus available therapy. According to U.S. regulators, Breakthrough Therapy designation conveys all of the fast track program features in addition to more intensive FDA guidance on an efficient drug development program.
The designation is based, in part, on positive data from the company’s clinical development program, including the Phase IIb study M11-652 known as “Aviator.” The Aviator trial was carried out in 571 patients infected with HCV GT1. Results from the treatment arms evaluating ABT-450/r plus ABT-267 plus ABT-333 with and without ribavirin showed that the regimen provided high sustained viral response rates (SVR) with 12 weeks of therapy in patients who had not been previously treated (treatment naive) and in those who had failed previous therapy with pegylated interferon and ribavirin (null responders).
Despite the assumed rivalry between the aforementioned companies and their HCV therapies, a number of them are teaming up to investigate combination regimens of their drug candidates, with or without the addition of RBV. For instance, Vertex entered into separate non-exclusive collaborations to study VX-135 in combination with Janssen’s simeprevir and GlaxoSmithKline’s HCV NS5A inhibitor GSK2336805. Janssen is evaluating simeprevir in combination with Gilead’s sofosbuvir. Janssen additionally is assessing simeprevir in combination with Idenix Pharmaceuticals’ HCV NS5A inhibitor IDX719.
Vertex announced separately in early November 2012 two non-exclusive deals to conduct Phase II proof-of-concept studies of all-oral regimens for treating hepatitis C; one consists of VX-135 with simeprevir, and the other involves VX-135 with GSK2336805. The studies are evaluating safety, tolerability and viral cure rates using a 12-week combination of VX-135/simeprevir and VX-135/GSK2336805. Vertex is jointly sharing costs associated with the different studies between Janssen and GlaxoSmithKline. GSK2336805 is an investigational NS5A replication complex intended for the treatment of hepatitis C.
Idenix revealed in late May 2013 the start of the Phase II HELIX-1 study evaluating an all-oral, direct-acting antiviral HCV combo regimen. The combination regimen consists of Idenix’s once-daily pan-genotypic NS5A inhibitor samatasvir (product code IDX719) and simeprevir. The collaboration, announced in January 2013, is investigating different combinations including samatasvir, simeprevir, and TMC647055. A potent non-nucleoside hepatitis C polymerase inhibitor, TMC647055 has broad genotypic coverage. In addition to the HELIX-1 Phase II study, the companies intend to initiate HELIX-2 to evaluate a three-DAA combination of samatasvir, simeprevir and TMC647055/r, with and without ribavirin. The clinical trials will be carried out by Idenix. The biopharma entity Idenix and Janssen retain all rights to their respective compounds.
Three oncology drugs on their way to blockbuster status
The anti-cancer agent Zytiga nearly generated $1 billion in sales during its first full calendar year on the market. Containing the active chemical abiraterone, Zytiga is available as a treatment for metastatic castration-resistant prostate cancer. The drug is intended for use in combination with the steroid prednisone for patients who have received prior docetaxel (chemotherapy). Zytiga was FDA-approved as the first oral, once-daily medication for this indication on April 28, 2011. Zytiga’s new drug application was reviewed via FDA’s priority-review program, which provides for an expedited six-month review for drugs that may offer major advances in treatment, or provide a treatment when no adequate therapy exists. During fourth-quarter 2012, Zytiga was approved by
U.S. and EU regulators for an expanded indication, allowing for use before chemotherapy. Initial marketing clearance for the product was granted by EU health officials in September 2011.
Available as a pill, abiraterone targets a protein called cytochrome P450 17A1 (CYP17A1). This protein plays a significant role in producing the hormone testosterone. Abiraterone functions by decreasing the production of this hormone that would stimulate cancer cells to continue growing. The oral androgen biosynthesis inhibitor works by inhibiting the CYP17 enzyme complex, which is required for the production of androgens at three sources: testes, adrenal glands, and tumor tissue.
Zytiga is marketed in the United States by the Johnson & Johnson affiliate Janssen Biotech. The drug’s worldwide 2012 sales came to $961 million after producing $301 million during its launch year. Of the 2012 total, $463 million derived from the United States and $498 million was generated in international markets. The strong momentum carried over into 2013 as first-quarter global sales rose to $395 million, up 70.3 percent over January-March 2012.
Another cancer medicine that has been a market success since its 2011 launch is Yervoy. The product was approved by U.S. regulators on March 25, 2011, and by EU health authorities on July 14, 2011, to treat patients with late-stage (metastatic) melanoma. The most dangerous type of skin cancer, melanoma is the No. 1 cause of death from skin disease.
Yervoy is the first therapy for unresectable or metastatic melanoma to show a significant improvement in overall survival based on results from a pivotal randomized, double-blind Phase III trial. The recombinant, human monoclonal antibody is the first FDA-cleared cancer immunotherapy that blocks cytotoxic T-lymphocyte antigen-4. CTLA-4 may have a role in slowing down or turning off the body’s immune system, affecting its ability to fend off cancerous cells. The drug may work by enabling the body’s immune system to recognize, target, and attack cells in melanoma tumors. Containing the active ingredient ipilimumab, Yervoy is administered intravenously.
CTLA-4 acts as a negative regulator of T-cell activation. Ipilimumab binds to cytotoxic T-lymphocyte antigen-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. CTLA-4 blockade has been demonstrated to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, potentially via T-cell mediated anti-tumor immune responses.
Yervoy was discovered by Medarex and jointly developed by that company and Bristol-Myers Squibb. Medarex now operates as a subsidiary of BMS. Yervoy was granted orphan drug status during 2004, a designation provided to medicines that treat rare diseases. In 2006, the biological product gained fast-track designation. During August 2010, Yervoy was given priority-review designation.
Global sales for Yervoy totaled $360 million for 2011 and $706 million during 2012. Of the 2012 amount, $503 million was generated in the United States and $203 million was produced outside America. Sales growth continued throughout first-quarter 2013, with the global figure up 49 percent year over year to $229 million.
Yervoy is being studied for new indications such as lung cancer, adjuvant melanoma, and hormone-refractory prostate cancer. Industry forecasters have estimated Yervoy global sales of more than $1.6 billion for 2020. The product’s basic exclusivity loss is set to occur during 2020 in Canada, 2021 in the European Union, and 2023 in the United States.
The novel, oral small molecule Zelboraf (vemurafenib) gained FDA approval and was launched in the United States during August 2011. The drug is available for treating patients with BRAF V600E mutation-positive inoperable or metastatic melanoma as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test is a DNA-based companion diagnostic used to identify patients whose tumors carry the BRAF mutation. The test was simultaneously FDA-approved with Zelboraf, and is CE marked and commercially available in Europe.
Vemurafenib was discovered via Plexxikon’s structure-guided chemistry platform, and the company started the drug’s clinical development in 2006. Zelboraf was jointly developed through a 2006 license and collaboration deal between Plexxikon and Roche. Plexxikon became a member of the Daiichi Sankyo Group in April 2011. Zelboraf is jointly promoted in the United States by Daiichi Sankyo and the Roche company Genentech. Roche Molecular Diagnostics developed the cobas 4800 BRAF V600 Mutation Test following a 2005 pact with Plexxikon.
As of November 2012, Zelboraf had been used to treat 11,000 patients globally and was approved in 43 countries. The European Commission during February 2012 approved it as the first personalized skin cancer medicine that allows individuals with BRAF V600 mutation-positive metastatic melanoma to live significantly longer. Zelboraf has been proven to help patients with BRAF V600 mutation-positive metastatic melanoma in two significant ways: it stalls the growth or spread of cancer and helps patients survive longer, extending life expectancy beyond one year for many patients.
A mutated form of the BRAF protein takes place in about half of all melanoma patients. After the companion test identifies patients with this specific mutation, Zelboraf sets forth a targeted attack against the tumor. This is the first treatment for this aggressive skin cancer to considerably improve quality of life and prolong survival, according to Roche.
Roche says the product performed well in 2012 and emerged as a key growth driver for the Swiss company. Roche reported Zelboraf sales of SFr234 million ($250 million) for 2012, rising from SFr31 million ($33 million) during 2011.
Roche is building on its extensive clinical experience with the first-in-class BRAF inhibitor Zelboraf to explore various combination approaches. One potential combination is Zelboraf with Roche’s investigational MEK inhibitor GDC-0973. Roche scientists believe that one reason why patients treated with BRAF inhibitors stop responding to therapy is because they have acquired resistance to drugs that inhibit the RAS-RAF pathway. The company has started a Phase III trial investigating the potential of GDC-0973 with Zelboraf.
GDC-0973 (also known by the product code XL518) is a potent, highly selective inhibitor of MEK, which is a serine/threonine kinase that is a component of the RAS/RAF/MEK/ERK pathway. GDC-0973 is being developed by Genentech via a collaboration deal with the biopharmaceutical company Exelixis.
Eye-health market receives a boost
Eylea – also known as VEGF Trap-Eye – is making strong inroads in the eye-care arena. VEGF (Vascular Endothelial Growth Factor) is a naturally occurring protein within the body. VEGF’s normal role in a healthy organism is to trigger formation of new blood vessels (angiogenesis) supporting the growth of tissues and organs. But in certain diseases such as wet age-related macular degeneration, it is additionally associated with the growth of abnormal new blood vessels in the eye, which exhibit abnormal increased permeability that results in edema. Scarring and loss of fine-resolution central vision often takes place. In central retinal vein occlusion and branch retinal vein occlusion, a blockage results in the main blood vessel that transports deoxygenated blood away from the retina. VEGF levels rise in response, contributing to macular edema. For clinically significant diabetic macular edema (DME), VEGF-mediated leakage of fluid from blood vessels in the eye leads to vision interference.
A recombinant fusion protein, Eylea (aflibercept) contains portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 and formulated as an iso-osmotic solution for intravitreal administration. The drug acts as a soluble decoy receptor that binds VEGF-A and placental growth factor (PlGF) and thereby can inhibit the binding and activation of these cognate VEGF receptors. Eylea is specially purified and consists of iso-osmotic buffer concentrations, enabling injection into the eye.
Eylea is marketed in the United States for treating wet AMD and macular edema following CRVO. The product is additionally available in the United Kingdom, Germany, Switzerland, Australia, Japan, and various other countries for treating wet AMD. Regeneron Pharmaceuticals launched the drug in the United States for the wet AMD indication during November 2011 and the macular edema indication as of September 2012. Bayer HealthCare introduced the drug in Europe, Japan, and Australia for treating wet AMD in November 2012. Regulatory filings submitted by Bayer in other countries for the treatment of wet AMD are awaiting clearance. Additionally, Bayer filed applications for marketing authorization for Eylea in Europe during December 2012 and in Japan during January 2013 for macular edema following CRVO.
Since October 2006, Regeneron and Bayer HealthCare have had a worldwide development and commercialization deal for Eylea outside the United States. Bayer is responsible for marketing the medicine outside the United States, where, for countries other than Japan, the companies equally share the profits and losses from Eylea sales. For Japan, Regeneron is entitled to a royalty on the product’s sales. Regeneron holds U.S. exclusive rights to Eylea and is entitled to all profits from those sales.
Regeneron reported Eylea U.S. net product sales of $837.9 million for 2012 and $24.8 million during 2011. The drug’s net sales outside of the United States as recorded by Bayer totaled €14 million ($18 million) in 2012.
Eylea is undergoing Phase III trials for treating DME and macular edema following BRVO. In Asia, the drug is being studied in Phase III for choroidal neovascularization of the retina as a result of pathologic myopia (mCNV).
Some industry trackers expect big things from Eylea, including potential annual peak sales exceeding $4.5 billion.
According to Bayer, the patent expirations for Eylea/Eylia are set for 2020 in Germany, France, the U.K., Italy, Spain, Japan, China, and Canada. The U.S. patent for Eylea is not expected to expire before that year.
The most broadly indicated novel oral anticoagulant
Bayer is also jointly marketing another recent U.S. launch success, the innovative anticoagulant Xarelto (rivaroxaban). The anticipated blockbuster medicine was discovered at Bayer’s Wuppertal Research Center in Germany during 1999. In 2005, after a comprehensive selection process with various top pharma companies, Bayer entered into a collaboration with Janssen to increase the drug’s worldwide potential by expanding its range of indicated uses. The development program for Xarelto is expected to enroll almost 100,000 patients by its completion. Rivaroxaban is the most studied oral, direct Factor Xa inhibitor globally.
Xarelto has been cleared for more indications than any other oral anticoagulant. The product was initially approved for marketing by Canadian health authorities in 2008 for the prevention of venous thromboembolism in adult patients following elective hip or knee replacement surgery. FDA granted approval for the prevention of venous thromboembolism in adult patients following elective hip or knee joint replacement surgery and to reduce the risk of stroke in patients with non-valvular atrial fibrillation during 2011. U.S. regulators via priority review approved Xarelto in the treatment of deep vein thrombosis or pulmonary embolism and in secondary prevention of recurrent VTE during November 2012. Janssen Pharmaceuticals holds the U.S. commercialization rights for Xarelto. Bayer HealthCare supports the Janssen Pharmaceuticals sales team in selected U.S. hospitals and specialty markets.
The drug is registered in 120-plus countries and is marketed for VTE prophylaxis by Bayer HealthCare outside the United States. During 2011 the product was cleared in the European Union for stroke prevention in patients with atrial fibrillation, the treatment of deep-vein thrombosis (DVT), and the prevention of recurring DVT and pulmonary embolism following acute DVT in adult patients. EU marketing authorization was granted in November 2012 for treating pulmonary embolism and the secondary prevention of recurrent deep vein thrombosis and pulmonary embolism. In Japan, Xarelto was approved during January 2012 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, and launched during April 2012.
Xarelto’s annual sales potential has been projected by health-care analysts to reach several billion dollars. Bayer reported Xarelto sales of €86 million ($111 million) in 2011 and €322 million ($414 million) for 2012. According to the company, sales advanced strongly in all regions – particularly in Germany, the United States and Japan – following additional product launches and indication expansions in 2012.
Xarelto’s patent-expiration years include 2020 in Germany, Japan, China and Canada; 2021 in the United States; and 2023 in France, the U.K., Italy and Spain.
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|First year after launch - Product sales|
Posted: August 2013