Future blockbusters 2013


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An upswing in NME approvals is an encouraging sign for an industry trying to overcome mega-brand patent expirations and a lag in research and development productivity.

R&D expenditure growth for the industry as a whole has reached a stagnant state, though many companies remain dedicated to innovation and improving pipeline productivity. For the first time in many years, there was an annual drop-off in the combined R&D expenditure of the leading pharmaceutical/biopharma companies. From 2011 to 2012, a 2.7 percent decrease in R&D spending was produced by the top 10 pharma/biopharmaceutical companies. From 2012 to 2013, the R&D total for those industry leaders is expected to remain about flat year over year. The long-term outlook is forecasted to be more positive though when compared to the 2012 amount, with a predicted 3.8 percent increase for the 2014-2016 period average and a significant 9.2 rise for the 2017-2020 period average.

Industry trackers contend that the ultimate measure of R&D productivity is the amount of new regulatory approvals as well as the commercial value of new molecular entities. The total amount of approved new molecular entities (NMEs) submitted under new drug applications and therapeutic biologics submitted through original biologic license applications (BLAs) to FDA increased from 21 in 2010 to 30 during 2011 to 39 for 2012. The 2012 tally was the highest since 39 new molecular entities were approved during 1997, which followed a one-year record of 53 in 1996.

The recent two-year increase in new molecule approvals is a good sign for the industry during a time in which the patent-expiration losses of some of the best-selling prescription drugs of all-time has occurred. The pharmaceutical arena’s total branded drug sales reportedly are undergoing a yearly decrease as generic competition continues to grow and pharma jobs decrease.

The 39 NME/BLA approvals of 2012 included about a dozen oncology-related products. Oncology will continue to be the most heavily targeted therapeutic field by the industry for years to come due in part to the scientific advances being accomplished for such a vast unmet medical need. Drug makers will also continue to shift R&D more towards biologics based on their higher pricing and lower commercial infrastructure needs, as well as because of less exposure to generic competition. Additionally, pipeline success rates for biologic drugs are much higher than those for small-molecule medicines.

Following is an overview of select new molecular entities expected to be approved by the U.S. Food and Drug Administration during the next 12 months or so that have the potential to generate more than $1 billion in peak annual sales.


The investigational integrase inhibitor dolutegravir (product code GSK1349572) represents another advance in the fight against HIV/AIDS. The product candidate is being evaluated for safety and efficacy without another ‘booster’ drug being added to the regimen. Integrase inhibitors block HIV replication by the prevention of viral DNA from integrating into the genetic make-up of human immune cells (T cells). This process is essential in the HIV replication cycle and is responsible for establishing chronic infection.

Dolutegravir is being developed for treating HIV for use in combination with other human immunodeficiency virus drugs. The compound is intended for HIV infection treatment in adults and children aged 12 years and older. Regulatory applications were filed for the new product candidate during December 2012 in the United States, European Union, and Canada. Dolutegravir has been granted FDA priority-review status and U.S. marketing clearance is expected by Aug. 17, 2013.

The regulatory submissions for dolutegravir were based on Phase III clinical data from the VIKING-3, SAILING, SPRING-2 and SINGLE studies. VIKING-3 (ING112574) is a Phase III, multicenter, open-label, single arm trial to assess the antiviral activity and safety of dolutegravir 50mg twice-daily in treatment-experienced adults with HIV-1 and historical or current evidence of resistance to raltegravir or elvitegravir. SAILING (ING111762) is a multicenter, double blind, double dummy study comparing the efficacy and safety of dolutegravir 50mg once-daily to raltegravir 400mg twice-daily in treatment-experienced, integrase inhibitor-naive adults with HIV-1.

SPRING-2 (ING113086) is a multicenter, double blind, double dummy trial comparing the efficacy and safety of dolutegravir 50mg once-daily to raltegravir 400mg twice-daily in treatment-naïve adults with HIV-1. SINGLE (ING114467) is a multicenter, double blind, double dummy trial to compare the efficacy and safety of once-daily dolutegravir 50mg plus abacavir/lamivudine versus Atripla (tenofovir/emtricitabine/efavirenz). Along with data from a bioequivalence study (ING114580), SINGLE is designed to support additional regulatory submissions for a fixed dose combination of dolutegravir/abacavir/lamivudine.

Discovered by Japanese pharma company Shionogi, dolutegravir was licensed to pharmaceutical giant GlaxoSmithKline during 2003. The product was eventually transferred to ViiV Healthcare, a worldwide company with a sole concentration on HIV that was established during 2009 by GlaxoSmithKline and Pfizer. Shionogi joined ViiV Healthcare during 2012, resulting in the Shionogi-ViiV Healthcare joint venture. In October 2012, ViiV and Shionogi announced a deal revamping their integrase inhibitor relationship. Through the updated pact, ViiV acquired the exclusive worldwide rights to Shionogi-ViiV Healthcare. The assets include dolutegravir and other early-stage integrase inhibitor compounds.

Sanford Bernstein analysts in January 2013 projected that GSK’s share of dolutegravir global sales will amount to £735 million ($1.17 billion) in 2020, based on regulatory approval during 2013. Dolutegravir’s competition will include the biopharma company Gilead Sciences’ various once-daily fixed-dose combo drugs such as Atripla and the quad pill Stribild. Launched in the United States during July 2006, Atripla generated worldwide 2012 sales of $3.57 billion. Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) was introduced to the U.S. market in August 2012 and has annual multi-billion sales potential.


Gilead also has a potential billion-dollar generator in the pipeline in the form of the nucleotide NS5B inhibitor sofosbuvir. Also known by the product code GS-7977, sofosbuvir is being developed in Phase III studies for treating hepatitis C. The drug candidate is on track to become the first purely oral treatment available for hepatitis C.

Top-line results were announced by Gilead in February 2013 from the Phase III FUSION study evaluating 12-week and 16-week courses of therapy with once-daily sofosbuvir plus ribavirin (RBV) in treatment-experienced patients with genotype 2 or 3 chronic hepatitis C virus (HCV) infection who failed prior treatment. The clinical study met its primary efficacy endpoint of superiority versus a predefined historic control sustained virologic response rate of 25 percent. In FUSION, half of the patients (n=50/100) in the 12-week arm and 73 percent of patients (n=69/95) in the 16-week arm attained SVR12 (p<0.001 for both arms).

“This study demonstrates that all-oral therapy with sofosbuvir provides significant efficacy among difficult-to-treat hepatitis C patients who could not be cured by prior regimens containing pegylated interferon and now have limited treatment options,” noted Norbert Bischofberger, Ph.D., executive VP of R&D and chief scientific officer at Foster City, Calif.-based Gilead. “With positive results from all four Phase III trials now in hand, Gilead is on track to meet its goal of filing regulatory applications in the United States and Europe in the second quarter.”

Results from each of sofosbuvir’s four pivotal Phase III trials – FUSION, POSITRON, FISSION and NEUTRINO – will support the initial regulatory submission for sofosbuvir. The regulatory filings are intended for sofosbuvir as part of an all-oral therapy with RBV among genotype 2 and 3 treatment-naïve, treatment-experienced and interferon-intolerant HCV patients, and in combination with RBV and pegylated interferon among treatment-naïve patients with genotypes 1, 4, 5 and 6.

Gilead is also evaluating a once-daily fixed-dose combo tablet containing sofosbuvir and the NS5A inhibitor ledipasvir (product code GS-5885) in several Phase II and III studies. The studies are evaluating sofosbuvir/GS-5885 with and without ribavirin among a range of genotype 1 HCV patient populations. Interim data from the Phase II ELECTRON study were revealed by Gilead in November 2012. The study is examining a 12-week course of therapy with sofosbuvir, ledipasvir, and ribavirin in patients with genotype 1 chronic hepatitis C virus infection. Among treatment-naïve patients receiving this combo therapy, every one (n=25/25) remained HCV RNA undetectable four weeks after completing therapy.

“Since the acquisition of Pharmasset only a year ago, we have fully enrolled four Phase III studies of sofosbuvir and during the first quarter of this year we will have initiated two Phase III studies of the sofosbuvir and GS-5885 fixed-dose combination,” commented Bischofberger during January 2013. “We are on track to submit the initial regulatory filing for sofosbuvir by mid-2013 and to file for approval of the fixed-dose combination of sofosbuvir and GS-5885 in 2014.”

Gilead agreed to buy Pharmasset during November 2011 in a $11 billion cash transaction. The agreement was designed to diversify Gilead away from HIV medicines and give the company a boost in the fast-growing hepatitis C drug arena. Included in the deal was the hepatitis C polymerase inhibitor sofosbuvir. Some industry analysts have projected sofosbuvir franchise global sales of more than $5 billion in 2018.


Bayer is awaiting FDA approval of a new medicine for prostate cancer, which is the second most common cancer among American men after skin cancer. The investigational compound radium Ra 223 dichloride is intended for treating castration-resistant prostate cancer (CRPC) patients with bone metastases. Radium Ra 223 dichloride is an alpha particle emitting pharmaceutical.

Expected to be branded as Alpharadin, Bayer submitted the NDA for the product as announced during December 2012. Radium-223 was granted fast-track designation by the U.S. regulatory agency.

The regulatory filing was based on data from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) study. The Phase III, randomized, double-blind, placebo-controlled international trial compared radium-223 with best standard of care (BSC) versus placebo with BSC in symptomatic CRPC patients with bone metastases. The clinical trial enrolled 921 patients in 100-plus centers in 19 countries. The study treatment contained up to six intravenous administrations of radium-223 or placebo, each separated by a four-week interval.

The study’s primary endpoint was overall survival. Secondary endpoints consisted of time to occurrence of skeletal-related events (SRE), time to total alkaline phosphatase (ALP) and prostate-specific antigen (PSA) progression, total ALP response and normalization, safety, and quality of life.

Sixteen percent of prostate cancer cases are considered regional or distant, which means that the cancer has spread beyond the prostate to nearby or distant regions of the body (metastasis). A majority of men with castration-resistant prostate cancer have radiological evidence of bone metastases. Bone metastases secondary to prostate cancer generally target the lumbar spine, vertebrae and pelvis. Bone metastases are the primary cause of morbidity and death in patients with CRPC.

“If approved, radium-223 has the potential to play a key role in the treatment of men with CRPC that has metastasized to the bone,” commented Pamela A. Cyrus, M.D., VP and head of U.S. medical affairs for Bayer HealthCare Pharmaceuticals. “The development of a compound like radium-223 is an example of Bayer’s commitment to investing in approaches to treat hard-to-treat cancers.”

Bayer inked a deal during September 2009 with Algeta of Oslo, Norway, for the development and commercialization of radium-223. Bayer is developing, applying for health authority approvals globally, and will commercialize the radiotherapy agent worldwide. Bayer and Algeta will jointly promote radium-223 in the United States.

Industry analysts have projected Alpharadin global sales of more than $1 billion for 2018.


The immunomodulator dimethyl fumarate (product code BG-12) is a promising treatment for multiple sclerosis and an anticipated mega-brand for Biogen Idec. The drug is awaiting approval in the United States, European Union, Australia, Canada, and Switzerland for treating relapsing-remitting multiple sclerosis (RRMS). Dimethyl fumarate is the only known investigational compound for treating RRMS that has experimentally shown activation of the Nrf-2 pathway.

Biogen Idec announced in October 2012 that the Food and Drug Administration extended the initial Prescription Drug User Fee Act (PDUFA) date for its review of the new drug application for dimethyl fumarate. The three-month extension – a standard extension time line – was needed to allow extra time for review of the application. The updated PDUFA date is reportedly set for late March 2013.

A pre-specified analysis of integrated data from the Phase III DEFINE and CONFIRM trials for dimethyl fumarate demonstrated statistically significant and clinically relevant effects in reducing MS relapses and progression of disability, as well as reductions in MRI measures of disease activity as announced by Biogen Idec in October 2012. Interim safety data from a Phase III extension trial indicate that continued exposure to dimethyl fumarate did not lead to any new or worsening safety signals, and that the drug’s safety and tolerability profiles were consistent with previous studies.

In a June 2012 report, EvaluatePharma cited BG-12 as the second most valuable R&D project in the industry at that time with a net present value of $9.08 billion. In that report, the analysts projected global 2018 sales of $3.4 billion for the drug.

Anoro and Breo/Relvar

GlaxoSmithKline is awaiting the market arrival of two new-generation COPD treatments to eventually replace its long-time best-seller Advair/Seretide. The London-based company is developing two investigational bronchodilator molecules: the long-acting muscarinic antagonist (LAMA) GSK573719/umeclidinium bromide (UMEC), and the long-acting beta2 agonist (LABA) vilanterol (VI). Intended to be branded as Anoro, the product is administered via the Ellipta inhaler.

A New Drug Application for 62.5/25mcg and 125/25mcg doses of UMEC/VI was submitted to U.S. regulators on Dec. 18, 2012. The NDA is for the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. The PDUFA goal date is set for Dec. 18, 2013.

An EU submission for UMEC/VI was filed on Jan. 8, 2013. The Marketing Authorisation Application was submitted for 55/22mcg and 113/22mcg doses of UMEC/VI with the proposed proprietary name Anoro. The product also was filed with the European Medicines Agency as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. The UMEC/VI doses of 55/22mcg and 113/22mcg are specified as the delivered doses (emitted from the inhaler) that are equivalent to the 62.5/25mcg and 125/25mcg pre-dispensed doses (contained inside the inhaler) filed for FDA approval.

Filings for UMEC/VI will take place in other countries during 2013. Additionally, GlaxoSmithKline plans to commence worldwide regulatory submissions for UMEC monotherapy in the Ellipta inhaler for COPD patients during 2013. UMEC/VI and UMEC monotherapy are two of several late-stage assets in GlaxoSmithKline’s respiratory development arsenal. The portfolio also includes fluticasone furoate/vilanterol (FF/VI), vilanterol monotherapy, MABA (GSK961081), FF monotherapy, and the anti-IL5 MAb mepolizumab.

The once-daily investigational medicine FF/VI is also administered by the new dry-powder inhaler called Ellipta. The product candidate has the proposed trade names Breo in the United States, and Relvar in Europe and Japan.

GSK and Theravance announced during September 2012 that the NDA for FF/VI for COPD patients had been accepted for FDA review. The PDUFA goal date is scheduled for May 12, 2013. The companies announced on July 13, 2012, the filing of U.S. and EU regulatory applications for COPD patients, and a EU regulatory application for asthma. The MAA for FF/VI for COPD and asthma was validated by the European Medicines Agency. GSK additionally filed a Japanese New Drug Application for FF/VI for COPD and asthma patients on Sept. 25, 2012. Breo is undergoing U.S. Phase III trials for asthma treatment.

Anoro, Breo/Relvar, and MaBA (GSK961081) are being developed in collaboration with Theravance. The biopharma company is concentrated on the discovery, development and commercialization of small-molecule medicines across various therapeutic fields such as respiratory disease, bacterial infections, and CNS/pain. GSK holds a reported 27 percent stake in the South San Francisco, Calif.-based company.

Assuming U.S. and EU regulatory clearance during 2013, Sanford Bernstein analysts have projected total Anoro 2020 global sales of £1.37 billion ($2.19 billion). Through Anoro, GSK and Theravance are expected to have the first LABA/LAMA combination product to reach the market. Novartis also has one in the works via QVA149, which combines the long-acting beta2-adrenergic agonist indacaterol with the long-acting muscarinic antagonist NVA237. That combo medicine and projected blockbuster may not be submitted for FDA approval until late 2014 due to the necessity of another study to determine the lowest effective dose and support once-a-day administration.

Based on regulatory approval during 2013, Sanford Bernstein analysts have forecasted Breo/Relvar worldwide sales of £949 million ($1.52 billion) for GSK in 2020. Theravance is reportedly entitled to a 15 percent royalty on the first $3 billion in yearly Breo/Relvar sales and 5 percent thereafter.