Evaluating Late-Stage Pipelines and Potential

How robust is the pipeline of the pharmaceutical majors? That is the crucial question not only for the pharmaceutical majors but also for emerging pharmaceuticals that rely on licensing or product acquisition by the large pharmaceutical companies to fund their development efforts.

(CRISTINA PEDRAZZINI/GETTY IMAGES)

The numbers

The well-chronicled problem of a lack of strong recent product innovation, combined with greater incursion of generic drugs, paints a pessimistic outlook for prescription-drug sales by the pharmaceutical majors. A recent analysis by the market-research firm Datamonitor estimates that growth will slow to 1.3% to 2015 for the branded prescription pharmaceutical industry's leading companies. In contrast, between 2003 and 2009, these same companies had sales growth at a compound annual growth rate (CAGR) of 7.1%. Sharp declines in branded sales following the loss of patent exclusivity will drive the decline in growth.

"The difficulty in developing new products, particularly those that can generate sufficient sales to compensate for blockbuster expiries, has compounded this problem," said Simon King, pharmaceutical company analyst at the market research firm Datamonitor, in a Jan. 20, 2011, press release. "This has driven a steady shift away from blockbuster-centric growth strategies toward diversification into other areas of the market." Datamonitor predicts that those companies insulated from generic competition or those able to offset generic-drug incursion from revenue growth sourced from a high biologics focus or the targeting of niche indications and areas of high unmet need will be the best performers."

Patricia Van Arnum

Datamonitor projects that Bayer, Novartis, Roche, and GlaxoSmithKline will be the only Big Pharma companies generating above average growth through the period to 2015. Of 43 branded companies examined in detail by Datamonitor, 11 are expected to report negative sales CAGR during the period to 2015. Of those expected to deliver positive sales CAGR, only six will exceed the 7.1% average shown between 2003 and 2009.

Inside the pipelines

Pfizer. Pfizer provided an update of its development program, which includes 118 programs from Phase I through registration, as of September 2010. The 118 programs in place was a decline compared with the 133 programs that the company had as of its previous pipeline update in January 2010. The 118 programs reflect 25 drug candidates that are new compounds or other drug that have advanced along the pipeline and 31 programs that were discontinued. The company's pipeline as of its September 2010 update included 26 programs in Phase III development, and nine programs in registration as well as 27 biologics and four vaccines within all phases in development. The company also had 46 projects in Phase I development, and 37 drug candidates in Phase II development.

Pfizer discontinued several late-stage projects when providing an update to its pipeline in September 2010. These withdrawals included several existing drugs that were being developed for additional indications: Sutent (sunitinib) for various oncology indications; Celebrex (celecoxib) for treating gouty arthritis; and Lyrica (pregabalin) for treating restless legs syndrome. The company also discontinued development of a monoclonal antibody in Phase III development, figitumumab, which was being examined for treating non-small-cell lung cancer although the drug continues to be studied for other indications.

Pfizer has several Phase III oncology drug candidates. Some key candidates include PF-00299804, an investigational, oral, pan-HER (pan-human epidermal growth factor receptor) inhibitor. It is an irreversible small- molecule inhibitor of HER-1 (EGFR- epidermal growth factor receptor)-2 and -4 tyrosine kinase designed to treat lung cancer. Neratinib also is a pan-HER inhibitor and is targeted to treat breast cancer. Bosutinib is an investigational oral dual Src and Abl kinase inhibitor. It is believed that bosutinib may inhibit Src and Abl tyrosine kinases in chronic myeloid leukemia cells that allow the cells to grow, survive, and reproduce. Axitinib is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor designed to treat renal-cell carcinoma. And crizotinib (PF-02341066) is an anaplastic lymphoma kinase (ALK) inhibitor for treating patients with advanced non-small-cell lung cancer whose tumors are ALK-positive.

Crizotinib was granted fast-track status by FDA in December 2010. In January 2011, Pfizer initiated the rolling submission of a new drug application (NDA) to FDA for crizotinib and expects to complete the submission in the first half of 2011. Pfizer also plans regulatory submissions to FDA and the European Medicines Agency for two other investigational oncology compounds in 2011, axitinib and bosutinib, according to a Jan. 12, 2011, Pfizer press release.

Another important drug to watch from Pfizer's late-stage pipeline is tasocitinib (CP-690550), an investigational Janus kinase (JAK) inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. Pfizer reported positive Phase III results in 2010. The company said that the mechanism of action is an improvement compared with the mechanisms of other rheumatoid arthritis therapies that are directed at extracellular targets, such as pro-inflammatory cytokines. Tasocitinib targets the intracellular signaling pathways that operate as hubs in the inflammatory cytokine network. Pfizer also is studying orally administered tasocitinib in psoriasis, inflammatory bowel disease (i.e., Crohn's disease and ulcerative colitis), and organ transplant, and topical tasocitinib in both psoriasis and dry eye.

sanofi-aventis. sanofi-aventis had 49 projects in clinical development as of February 2010, of which 17 were either in Phase III, including seven vaccine projects, or pending review for marketing authorization from health authorities. These included nine new molecular entities (NMEs) in Phase III development, and one NME submitted for approval, which was subsequently approved in 2010. Jevtana (cabazitaxel), a novel investigational taxane compound that may be active in cell lines refractory to taxanes, was approved in July 2010 in the US as a second-line use in advanced hormone-refractory prostate cancer in men who have already been treated with docetaxel. The drug was recommended for approval by an EMA advisory committee in January 2011.

Several late-stage NMEs by sanofi- aventis are targeting oncology. These candidates include BSI-201 (iniparib), an investigational targeted therapy, which inhibits poly (ADP-ribose) polymerase (PARP1), an enzyme involved in DNA damage repair. Iniparib is in Phase III trials for treating patients with metastatic triple negative breast cancer (mTNBC) and squamous non-small-cell lung cancer. It also is in Phase II trials for treating patients with ovarian, uterine, and brain cancers. The drug is being developed by sanofi-aventis's subsidiary BiPar Sciences. Iniparib was granted fast-track designation by FDA for mTNBC. The regulatory submissions are planned for the first quarter 2011 in the US and the second quarter 2011 in the European Union, according to a Jan. 5, 2011, BiPhar Sciences press release.

sanofi aventis also is developing aflibercept, a fusion protein specifically designed to bind all forms of vascular endothelial growth factor-A (VEGF-A). VEGF-A is required for the growth of new blood vessels that are needed for tumors to grow and is a regulator of vascular permeability and leakage. In addition, aflibercept binds placental growth factor, which also has been implicated in tumor angiogenesis. sanofi-aventis is developing the drug for several cancer indications with the biopharmaceutical company Regeneron. In January 2011, Regeneron announced that it also started Phase III trials for VEGF Trap-Eye (aflibercept ophthalmic solution) with Bayer Healthcare and the Singapore Eye Research to treat choroidal neovascularisation of the retina as a result of pathologic myopia.

Other late-stage drugs by sanofi include: ombrabulin (AVE8062), which is currently being investigated in Phase III for treating refractory advanced soft tissue sarcoma. Phase III studies also are planned in non-small-cell lung cancer. Another late-stage candidate is alvocidib, a cyclin-dependent kinase (CDK); CDKs are involved in both cell-cycle progression and transcription. sanofi aventis also is partnered with the Danish biopharmaceutical firm Zealand Pharma for lixisenatide, a glucagon-like peptide-1 (GLP-1) drug to treat diabetes. sanofi also is developing otamixaban, an anti-Xa intravenous anticoagulant.

Novartis. Novartis reported in November 2010 that it has 142 pipeline projects in pharmaceuticals at various stages of clinical development, of which more than 35% are in Phase III or registration. The company plans to submit 30 regulatory submissions in pharmaceuticals before the end of 2012, inclusive of NMEs as well as additional indications for existing drugs or new formulations.

Novartis was targeting to complete eight regulatory submissions in 2010. These candidates included: a single-pill combination for Tekturna (aliskiren) and amlodipine for treating hypertension; Lucentis (ranibizumab) for treating visual impairment due to macular edema secondary to retinal vein occlusion; Afinitor (everolimus) for treating subependymal giant-cell astrocytoma associated with tuberous sclerosis; and SOM230, an investigational compound to treat Cushing's disease. In 2011, Novartis expects to complete a further 13 regulatory submissions with an additional nine planned for 2012, according to a Nov. 17, 2010, Novartis press release.

Novartis experienced a setback in its pipeline when it decided in October 2010 to discontinue development of two compounds: albinterferon alfa-2b, a drug being developed with Human Genome Sciences to treat chronic hepatitis C, and Mycograb (efungumab), an antifungal agent. The company took an impairment charge of $590 million in the third quarter 2010 for discontinuing these programs, $230 million for stopping development of albinterferon alfa-2 and $360 million for stopping development of efungumab.

GlaxoSmithKline (GSK). GSK has approximately 30 drug candidates in late-stage development, according to a January 2011 company overview of its portfolio, and the company recently highlighted progress on some of those candidates. In January 2011, GSK started two global Phase III studies in patients with advanced or metastatic melanoma that have a BRAF V600 mutation. The studies will separately assess the efficacy and safety of two investigational agents, GSK2118436 and GSK1120212, to determine their individual ability to stop or slow the progression of skin cancer in patients whose tumors contain a BRAF V600 mutation, which the company said occurs in 50–60% of melanoma patients. GSK also will evaluate these compounds alone and in combination with other agents in other difficult-to-treat forms of cancers, including pancreatic cancer, refractory or relapsed leukemia, and other solid tumors.

Also in January 2011, GSK received a positive recommendation from EMA for Trobalt (retigabine) as an adjunctive treatment for partial onset seizures (i.e., a form of epilepsy where a seizure begins in a specific area in one side of the brain), with or without secondary generalization in adults aged 18 years and older with epilepsy. Retigabine received preliminary approval from the Swiss Agency for Therapeutic Products, Swissmedic, in December 2010. Retigabine, referred to as ezogabine in the US, is being jointly developed by GSK and Valeant.

GSK also began Phase III studies for GSK2402968, an antisense oligonucleotide, to treat a neuromuscular disease, Duchenne muscular dystrophy in ambulant boys who have a dystrophin gene mutation amenable to an exon 51 skip. The drug was granted orphan- drug status in the EU and US and is being developed as part of an alliance between GSK and Prosensa.

Roche. Roche's late-stage pipeline includes potentially 10 regulatory submissions of NMEs through the end of 2013, according to a Dec. 9, 2010, Roche press release Some key compounds are T-DM1 (trastuzumab) and pertuzumab for treating breast cancer and GA101/RG7159, a glyco-engineered Type II humanized anti-CD2-monoclonal antibody to treat relapsed/refractory aggressive non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Aleglitazar is being developed to treat cardiovascular risk in patients with Type II diabetes, and dalcetrapib is being developed to reduce cardiovascular risk and dyslipidemia. RG1678, a glycine-reuptake inhibitor, is being developed to treat the negative symptoms and suboptimally controlled positive symptoms of schizophrenia.

Roche also is evaluating the progress of late-stage compounds to move them either to Phase III development or possible registration. Some compounds include RG7204, which is designed to selectively inhibit the mutated BRAF protein, which can be found in certain cases of metastatic melanoma. MetMAB, a monovalent antibody, is being developed to treat solid cancers. Ocrelizumab, a humanized anti-CD20 antibody, is being studied to treat multiple sclerosis, and RG7201 and taspoglutide are being examined as treatments for Type II diabetes.

Bristol-Myers Squibb. Bristol-Myers Squibb pointed to five key potential product approvals in 2011 based on a company overview presented in January 2011. These candidates include ipilimumab, an anticancer immunotherapy; belatacept, a co-stimulation blocker developed as an alternative therapy in solid-organ transplantation; apixaban, an oral Factor X inhibitor as an anticoagulant; dapagliflozin, an antidiabetes treatment; and a subcutaneous formulation of Orcenia (abatacept) to treat rheumatoid arthritis. The company also highlighted four drug candidates that potentially may move to Phase III development in 2011. These drugs include: elotuzumab, a humanized monoclonal antibody to treat multiple myeloma; a peptide functioning as a gamma secretase inhibitor to treat Alzheimer's disease; PEG-IFN lambda, an interferon to treat hepatitis C; and a small-molecule NS5A inhibitor to treat hepatitis C.

Other companies. AstraZeneca had 10 NMEs as drug candidates in late-stage development (Phase III or in registration) and 12 products being developed as line extensions as of July 29, 2010. Merck & Co. reported on its research pipeline as of Oct. 22, 2010, which included 19 programs in Phase III development. Eli Lilly reported as of October 18, 2010, that it had eight drug candidates in Phase III development and three drugs under regulatory review. One recent setback reported by Eli Lilly on Jan. 12, 2011, was a recommendation of a FDA advisory committee for nonapproval of liprotamase, an oral, nonporcine pancreatic enzyme-replacement therapy for treating exocrine pancreatic insufficiency. The committee had questions about the degree of efficacy of liprotomase and recommended additional studies to be conducted before approval.

Looking ahead

As companies navigate late-stage development, they face moderate industry growth in 2011. The global pharmaceutical market is expected to grow 5–7% in 2011 to reach $880 billion, slightly better than the 4–5% growth in 2010, according to estimates by IMS Health in October 2010. Five potential blockbuster products—defined as those exceeding $1 billion annually in peak sales—are expected to be approved and launched globally by the end of next year, projects IMS. In 2011, products with sales of more than $30 billion are expected to face generic competition in the major developed markets.

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com.