Top 10 Pipelines
This year we are presenting to our readers 10 leading pipelines amongst the entire pharma and biotech arena, and the selections are not just based on which areas of R&D they encompass and which potential blockbusters are undergoing development. The new format also rewards companies that produced headliner new drug approvals during 2014. That was done in part to recap what occurred last year when this special report was on vacation, and additionally because plenty of the most exciting drug prospects never reach the marketplace and drug firms should be acknowledged for what they have recently delivered from their pipelines.
TOP 10 PIPELINES
Though not intentional, each of the companies reviewed in this forum (presented in alphabetical order) rank amongst the top 20 industry research and development spenders. Certain drug makers may not have rated as high on all analysts’ valuations lists as others did, but our research took into account recent strategic efforts and plans involving innovation, including R&D alliances and deals. Pipelines for some of the leading companies that were considered “thin” by industry insiders a year ago deserve another look today (and most companies throughout the industry would not mind having a “thin” Big Pharma R&D program).
Amgen’s late-stage pipeline is poised to deliver organic products with blockbuster potential, which some industry analysts say they have been waiting to occur for years. The Thousand Oaks, Calif.-based biotech leader intends to deliver late-stage data on 10 experimental drugs between 2014 and 2016.
One of those promising medicines is the high cholesterol treatment evolocumab. The investigational fully human monoclonal antibody from Amgen is being developed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver’s ability to remove LDL-C/bad cholesterol from the blood.
Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. Without PCSK9, there are more LDL receptors on the surface of the liver to remove LDL-C from the blood.
Amgen announced during November 2014 new data from three separate analyses of Phase II and III studies evaluating evolocumab. Data from one of the long-term pooled analyses demonstrated that evolocumab significantly reduced lipoprotein(a) (Lp(a)) over 64 weeks. Data from a separate long-term, 52-week pooled analysis demonstrated that adverse events were overall balanced between patients who achieved LDL-C levels of <40 mg/dL and those who achieved LDL-C levels of >40 mg/ dL. Another pooled analysis revealed the two dosing regimens of evolocumab were clinically equivalent.
Amgen’s low-density lipoprotein cholesterol-lowering medication is in a race with Sanofi/RegeneronPharmaceuticals’s alirocumab to reach the marketplace first. Industry analysts forecast billions of dollars of peak annual sales for both products regardless of which is initially approved by health regulators.
Another hot pipeline prospect for Amgen is the cancer vaccine talimogene laherparepvec, also known as T-Vec, which is a treatment for melanoma. Amgen’s investigational oncolytic immunotherapy is designed to selectively replicate in tumors (but not normal tissue) and to initiate an immune response to target cancer cells that have metastasized. Talimogene laherparepvec was designed to work in two significant and complementary ways. First, it is injected directly into tumors where the drug replicates inside the tumor’s cells causing the cell to rupture and die in a process called lysis. Then, the rupture of the cancer cells can release tumor-derived antigens, along with GM-CSF, that can stimulate a system-wide immune response where white blood cells are able to find and target cancer that has spread throughout the body.
Amgen has launched a comprehensive clinical development program for talimogene laherparepvec in metastatic melanoma, which includes joint studies with checkpoint inhibitors in patients with late-stage disease and monotherapy before surgery (neoadjuvant) in patients with resectable disease. Based on its mechanism of action, talimogene laherparepvec has the potential to be studied in various solid tumor types.
In December 2014, Amgen announced the start of a trial of talimogene laherparepvec in combination with an investigational use of Merck’s FDA-approved, anti-PD-1 therapy Keytruda (pembrolizumab) in patients with regionally or distantly metastatic melanoma. The study will evaluate the combination of these two therapies in 110 patients across 35 clinical trial sites in the United States, Australia and Europe.
Brodalumab is another possible market success for Amgen that is being developed in collaboration with AstraZeneca. The novel human monoclonal antibody binds to the interleukin-17 (IL-17) receptor and inhibits inflammatory signaling by blocking the binding of several IL-17 ligands to the receptor. By stopping IL-17 ligands from activating the receptor, brodalumab prevents the body from receiving signals that may result in inflammation. The IL-17 pathway plays a main role in inducing and promoting inflammatory disease processes.
Brodalumab is the first investigational treatment being developed that binds to the IL-17 receptor and inhibits inflammatory signaling by blocking the binding of several IL-17 cytokines (A, F and A/F) to the receptor. Brodalumab studies include moderate-to-severe plaque psoriasis (Phase III), psoriatic arthritis (Phase III) and asthma (Phase II).
The AMAGINE program consists of three pivotal Phase III trials designed to assess the efficacy and safety of brodalumab in more than 4,200 patients with moderate-to-severe plaque psoriasis. Positive top-line results from AMAGINE-1 were revealed during May 2014. Positive top-line results from AMAGINE-2 and AMAGINE-3, comparing brodalumab with Johnson &Johnson’s blockbuster immunosuppressant Stelara(ustekinumab) as well as placebo, were made public in November 2014. AMAGINE-2 and AMAGINE-3 are identical in design.
Amgen management is encouraged by the emerging data from this program and anticipates initiating worldwide regulatory filings during 2015.
The company is looking to expand the label for the already-approved anticancer agent Kyprolis, which Amgen acquired via the purchase of OnyxPharmaceuticals in 2013 for about $10.4 billion. Kyprolis is marketed as a third-line treatment for multiple myeloma, a cancer that develops in bone marrow. Amgen is seeking Kyprolis approval for a second-line indication, which represents a more lucrative market.
In December 2014, Amgen and its subsidiary Onyx revealed the results of the Phase III ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) study that evaluated Kyprolis injection plus Revlimid(lenalidomide) and dexamethasone (KRd) compared with Revlimid and dexamethasone (Rd) in patients with relapsed multiple myeloma. As previously reported, the ASPIRE study met its primary endpoint by showing that KRd significantly extended the time patients lived without their disease worsening, or progression-free survival (PFS), by 26.3 months compared to 17.6 months with Rd (HR=0.69; 95 percent CI: 0.57-0.83; p<0.0001), an 8.7 month improvement in PFS.
Amgen officials say the results from the Phase III ASPIRE trial bring the company one step closer to establishing Kyprolis as a backbone of therapy in treating multiple myeloma. Results from the ASPIRE trial will form the foundation for global regulatory submissions starting during first-half 2015. In the United States, the data may support the conversion of accelerated approval to full approval and expand the current indication.
AstraZeneca’s late-stage pipeline has transformed well ahead of plan, according to company management, via increased R&D productivity, accelerated programs and targeted business development. AstraZeneca had 14 new molecular entities in Phase III or registration as of November 2014, compared to the original target of eight. A potential 14 to 16 submissions and eight to 10 approvals of new molecular entities and major-line extensions could take place during 2015-2016. Also during that time period, AstraZeneca is anticipating 12 to 16 Phase II starts. In addition to the late-stage acceleration, the early-stage pipeline has grown rapidly via a concentration on novel biology and technologies, providing a sustainable discovery engine behind all core therapeutic fields.
Company executives note that the near-term delivery and longer-term sustainability of AstraZeneca’s pipeline will be reinforced by shifting the focus from rebuilding the late-stage pipeline to supporting regulatory submissions and approvals, while continuing to transition high-quality programs to late-stage development as rapidly as possible.
According to the company, the progressive changes AstraZeneca has introduced since 2013 continue to fuel the transformation of its pipeline through scientific discoveries and accelerated clinical programs. Leadership says strong progress has been made towards achieving scientific leadership in three core therapeutic fields – respiratory, inflammation and autoimmunity (RIA); cardiovascular and metabolic disease; and oncology.
“We more number of potential medicines in our late-stage pipeline since 2012 and we are on track to return to growth by 2017,” commented Pascal Soriot, AstraZeneca CEO. “Fueled by a very exciting portfolio of new products, oncology is set to become AstraZeneca’s sixth growth platform and play a large part in supporting our efforts to bring life-changing medicines to patients as well as delivering long-term growth.”
AstraZeneca is driven by five growth platforms –Brilinta, diabetes, respiratory, Emerging Markets and Japan – which account for more than half of worldwide revenue. Oncology will become the sixth growth platform, with several potential regulatory filings anticipated in 2015-2016. Company managers expect this segment to contribute the largest proportion of pipeline-driven revenue growth and has the potential to grow to a quarter of AstraZeneca’s sales by 2023 (which are projected to exceed $45 billion). The company’s pipeline of promising anti-cancer agents was one of the enticements that persuaded Pfizer to unsuccessfully try to acquire the London-based drug firm during first-half 2014 for up to about $118 billion.
Biologics represent nearly 50 percent of AstraZeneca’s pipeline. According to management, a portfolio balance of primary and specialty care will boost the company’s profitability.
Additionally, AstraZeneca managers say disciplined capital allocation framework balances R&D investment with a progressive dividend policy, value enhancing business development and an efficient capital structure. The company’s business model includes value creation via partnerships and licensing in neuroscience and infection.
The acquisition of Definiens will help accelerate additional clinical programs via precise predictive and prognostic biomarker testing. Using biomarkers to choose patients for development studies could potentially shorten clinical timelines and increase response rates. The technology is expected to serve as a significant tool in the advancement of the most promising combo therapies across AstraZeneca’s combined small molecule and biologics pipeline, of which about 80 percent has a personalized healthcare approach.
MedImmune, AstraZeneca’s global biologics R&D arm, completed the acquisition of Definiens during late November 2014. A privately held company, Definiens has pioneered a world-leading imaging and data analysis technology called Tissue Phenomics. The technology dramatically improves biomarker identification in tumor tissue.
According to leadership, the oncology field will be potentially transformational for the company’s future. By 2020, AstraZeneca is striving to bring six new cancer medicines to the marketplace. The broad oncology pipeline of next-generation medicines is concentrated on four main disease areas: breast, ovarian, lung and hematological cancers. These areas are being targeted via four key platforms: immunotherapy, the genetic drivers of cancer and resistance, DNA damage repair and antibody drug conjugates (ADCs). an industry-leading immuno-oncology portfolio with 13 combination studies under way and 16 others are planned. The quickly developing mid-stage small molecule oncology pipeline has a strong concentration on tumor drivers and resistance, as well as DNA damage response.
The most heralded drug prospect throughout the entire AstraZeneca late-stage pipeline is MEDI4736, which is reportedly believed by the company to have peak annual sales potential of $6.5 billion. The human monoclonal antibody is directed versus programmed cell death ligand 1 (PD-L1). Signals from PD-L1 assist tumors in avoiding detection by the immune system. MEDI4736 blocks such signals, countering the tumor’s immune-evading tactics. The drug compound is being developed to empower a patient’s immune system and attack the cancer.
MEDI4736 is being studied in 12 of AstraZeneca’s 29 immuno-oncology combination trials. Those studies include continuing Phase I development for a ‘triplet’ combination alongside BRAF and MEK inhibitors in melanoma, with results expected during first-half 2015. Combination trials of MEDI4736 with small-molecule immuno-oncology assets (STAT3 and CXCR2) were on pace to begin during early 2015.
Early-stage studies are additionally intended for MEDI4736 in combination with the oral Bruton’s tyrosine kinase inhibitor ibrutinib for patients with hematological cancers.
MEDI4736 is also being investigated in Phase II as a monotherapy in head and neck cancer, and in Phase III as a monotherapy in non-small cell lung cancer, including in adjuvant setting for NSCLC via a worldwide study launched in November 2014 by the NCIC Clinical Trials Group. Phase III trials of MEDI4736 in combination with tremelimumab in both of these cancer types were on track to begin during early 2015.
A U.S. regulatory filing is expected during second-quarter 2015 for AZD9291 as a second-line treatment for patients with certain types of non-small cell lung cancer. Impressively, just over two years would be the time line from the drug prospect’s first patient dosing to its NDA filing (if that remains on schedule). AstraZeneca additionally planned to launch a Phase III study for AZD9291 in the first-line setting for NSCLC in fourth-quarter 2014.
AZD9291 has been granted Breakthrough Therapy designation, Orphan Drug, and Fast Track status by the U.S. regulatory agency. AstraZeneca believes that the drug compound could generate annual peak sales of $3 billion.
Lynparza (olaparib) gained marketing clearance in the United States and European Union during December 2014, with accelerated approval coming from FDA. Administered as a 400-mg twice-daily capsule, FDA approved Lynparza as the first monotherapy for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer, who have been treated with three or more prior lines of chemotherapy.
Additional studies are under way for the drug in breast, gastric and pancreatic cancers, and it has demonstrated promising early-stage activity in prostate cancer. Lynparza reportedly has been projected by AstraZeneca to have peak yearly sales potential of $2 billion.
AstraZeneca says rapid progress with anti-PD-L1, anti-CTLA-4 and novel approaches such as the OX40 biologics, combined with each other and small-molecule assets, are opening up new opportunities to target various immune pathways ‘hijacked’ by tumor cells.
In January 2015, MedImmune agreed to a licensing pact with Omnis Pharmaceuticals, a privately held biotech company concentrated on developing oncolytic viruses. The deal enables MedImmune to combine key agents from its investigational immunotherapy portfolio with Omnis’ lead investigation-al oncolytic virus program, a genetically engineered strain of vesicular stomatitis virus (VSV). The program is being evaluated in a Phase I study as a monotherapy for treating hepatocellular carcinoma and other cancers that have metastasized to the liver.
Significant advancement is being made across AstraZeneca’s RIA pipeline, which includes six programs in Phase III or registration. In particular, the company is leveraging biologics in severe asthma and COPD as well as developing several promising assets in inflammatory and autoimmune disease areas including dermatology, gout, systemic lupus and rheumatoid arthritis.
Mentioned previously in this story’s Amgen pipeline review, the novel human monoclonal antibody brodalumab is regarded as a future blockbuster medicine. Brodalumab is the first investigational treatment being developed that binds to the interleukin-17 receptor and inhibits inflammatory signaling by blocking the binding of several IL-17 cytokines (A, F and A/F) to the receptor. By preventing IL-17 ligands from activating the receptor, brodalumab halts the body from receiving signals that may result in inflammation. The IL-17 pathway has a central role in inducing and promoting inflammatory disease processes. Brodalumab is being studied for moderate-to-severe plaque psoriasis (Phase III), psoriatic arthritis (Phase III) and asthma (Phase II).
AstraZeneca and Amgen’s AMAGINE program for brodalumab consists of three pivotal Phase III trials. The studies are designed to assess the efficacy and safety of brodalumab in more than 4,200 patients with moderate-to-severe plaque psoriasis. The AMAGINE-3 Phase III study met all primary and key secondary endpoints. Brodalumab, demonstrated superiority to Stelara in achieving total skin clearance (PASI 100) and met co-primary end-points versus placebo. AstraZeneca and Amgen intend to initiate worldwide regulatory submissions for brodalumab during 2015.
Amgen and AstraZeneca formed a collaboration during April 2012 to jointly develop and commercialize five monoclonal antibodies from Amgen’s clinical inflammation portfolio. With oversight from joint governing bodies, Amgen heads clinical development and commercialization for brodalumab and AMG 557/MEDI5872 (Phase Ib studies for autoimmune diseases, including systemic lupus erythematosus). AstraZeneca, through its biologics arm MedImmune, is in charge of clinical development and commercialization for MEDI7183/AMG 181 (Phase II trials for ulcerative colitis and Crohn’s disease), MEDI2070/AMG 139(Phase II studies for Crohn’s disease) andMEDI9929/AMG 157 (Phase II trials for asthma).
During the American College of Rheumatology annual meeting in November 2014, more than 15 abstracts for AstraZeneca drug prospects demonstrated the company’s continued RIA advancement. Positive data were presented across a range of investigational therapies, such as top-line results from the CLEAR1 and CLEAR2 pivotal Phase III studies exploring the potential of lesinurad for treating gout. EU and U.S. submissions were intended by year-end 2014 for use of lesinurad as a combination therapy with the xanthine oxidase (XO) inhibitor allopurinol. Also, sifalimumabwas the subject of the first Phase II study to show efficacy in moderate-to-severe systemic lupus patients across multiple endpoints with an anti-interferon molecule. Additionally, positive data supported a Phase IIb trial for mavrilimumab as a first-in-class anti-GMCSFR antibody for treating rheumatoid arthritis.
AstraZeneca’s strategy in cardiovascular and metabolic disease concentrates on approaches to reduce morbidity, mortality and organ damage by addressing multiple risk factors across cardiovascular disease, diabetes and chronic kidney disease indications. AstraZeneca says this patient-centric method is reinforced by science-led life-cycle management programs and technologies, including early research into regenerative methods.
The company’s diabetes strategy concentrates on shifting the treatment paradigm towards early use of combination therapies, to help accelerate the achievement of goals for patients and potentially delay their disease progression.
Forxiga (dapagliflozin) is undergoing Phase III development for type 1 diabetes. Forxiga is already marketed as the first SGLT2 inhibitor for treating type 2 diabetes. Developed in partnership with Bristol-Myers Squibb, FDA clearance was granted on Jan. 8, 2014. Forxiga is a highly selective and reversible inhibitor of sodium-glucose cotransporter 2 that works independently of insulin to aid in the removal of a body’s excess glucose.
Regulatory filings for the saxagliptin and dapagliflozin fixed-dose combo are anticipated in the United States and European Union during early 2015. Marketed asOnglyza, saxagliptin belongs to the class of medicines known as DPP-4 inhibitors. Those inhibitors act by increasing the activity of the incretin hormones, increasing the release of insulin when glucose levels are elevated and reducing the levels of sugar produced by the liver (glucagon).
Roxadustat is undergoing Phase III development and has the potential to become the first oral treatment for anemia in patients with chronic kidney disease. The drug’s first filing is expected during 2016 in China.
The PARTHENON development program is evaluating Brilinta’s (ticagrelor’s) potential for the long-term treatment of patients with a prior myocardial infarction, for treating patients with peripheral arterial disease, ischemic stroke and transient ischemic attack, and for the prevention of cardiovascular events in patients with diabetes and coronary atherosclerosis.
Top-line results for the PEGASUSTIMI 54 trial, investigating ticagrelor for the long-term prevention of atherothrombotic events in patients who suffered a heart attack one to three years before study enrollment, were revealed during January 2015. Ticagrelor successfully met its primary efficacy endpoint in the large-scale outcomes study involving more than 21,000 patients. The trial evaluated Brilinta tablet at either 60mg twice daily or 90mg twice daily plus low-dose aspirin for the secondary prevention of atherothrombotic events.
AstraZeneca and Eli Lilly announced on Dec. 1, 2014, enrolment of the first patient into the AMARANTH study. The Phase II/III trial is evaluating an oral beta secretase cleaving enzyme (BACE) inhibitor as a potential treatment for Alzheimer’s disease. AZD3293/LY3314814 has been shown in Phase I studies to reduce levels of amyloid-beta in the cerebro-spinal fluid of Alzheimer’s patients and healthy volunteers.
The advancement of Alzheimer’s disease is characterized by amyloid plaque accumulation in the brain. BACE is an enzyme associated with beta-amyloid development. Inhibiting BACE is expected to prevent the formation of amyloid plaque and eventually slow disease progression.
Various industry insiders are high on the widening pipeline of leading MS biotech company Biogen Idec. According to an EvaluatePharma June 2014 report, Biogen Idec is forecast to grow its R&D expense the most rapidly out of the top 20 pharmaceutical companies, rising 10 percent a year from $1.4 billion during 2013 to $2.8 billion in 2020.
One of Biogen Idec’s most intriguing pipeline prospects is its anti-LINGO-1 for an eye disease. In January 2015, the company revealed top-line results from the Phase II acute optic neuritis (AON) RENEW trial. In the study, treatment with anti-LINGO-1 demonstrated evidence of biological repair of the visual system. Anti-LINGO-1 showed an improvement in the study’s primary endpoint, recovery of optic nerve latency (time for a signal to travel from the retina to the visual cortex), as measured by full field visual evoked potential (FF-VEP), relative to placebo. The trial demonstrated no effect on secondary endpoints, including change in thickness of the retinal layers (optic nerve neurons and axons) and visual function, as measured by spectral domain optical coherence tomography (SD-OCT) and low contrast letter acuity, respectively.
AON damages the optic nerve, resulting in loss of the myelin sheath and axonal injury, and may lead to loss of visual function. AON is believed to be a good clinical model to measure the hypothesized mechanisms of action of anti-LINGO-1, remyelination and neuroprotection. RENEW was designed to study anti-LINGO-1’s ability to allow for the repair of an optic nerve lesion through axonal remyelination following the onset of a first episode of AON. RENEW is part of the anti-LINGO-1 Phase II development program, which includes the SYNERGY study in multiple sclerosis.
The January 2015 trial results announcement has been met with mixed reviews. Biogen Idec management believes that the RENEW results are encouraging as this is the first clinical trial to provide evidence of biological repair in the central nervous system by facilitating remyelination following an acute inflammatory injury. The company is looking forward to the SYNERGY results in 2016 to further advance its understanding of this molecule in MS, including a full dose response. The totality of the data from the two Phase II studies may provide Biogen Idec with a clearer understanding of anti-LINGO-1’s clinical potential, company managers say.
During a time in which many pharma companies have departed the CNS drug development arena, Biogen Idec has been stepping up its efforts in that difficult R&D field, including Alzheimer’s disease which has a 99 percent failure rate among treatments. Biogen Idec has four Alzheimer’s drugs in development, including two with collaborator Eisai.
Biogen Idec’s lead candidate against Alzheimer’s,BIIB037, recently skipped ahead to Phase III trials due to promising early results. On the other hand, top-line data for the drug compound is not expected to become available until 2018-2019. The wait could very well be worth it though considering that some analysts project BIIB037 as a $5 billion to $10 billion market opportunity. The fully human immunoglobulin gamma 1 (IgG1) monoclonal antibody is being developed by Biogen Idec as a disease-modification treatment for Alzheimer’s disease.
Biogen Idec agreed during January 2015 to acquire U.K.-based Convergence Pharmaceuticals, a clinical-stage biopharma company with an innovative portfolio of ion channel-modulating product candidates for neuropathic pain. Biogen Idec plans to leverage Convergence’s expertise in chronic pain research and clinical development to accelerate the growth of its own pain franchise.
The acquisition is centered on the development of Convergence’s Phase II clinical candidateCNV1014802, which has shown clinical activity in proof of concept studies for trigeminal neuralgia. TGN is a chronic orphan disease consisting of debilitating, episodic facial pain. The novel small molecule state-dependent sodium channel blocker CNV1014802 preferentially inhibits Nav 1.7 ion channels. The Nav 1.7 ion channel is a genetically validated target for human pain. CNV1014802 has also shown proof of concept for treating pain associated with lumbosacral radiculopathy, more commonly known as sciatica, and has potential applicability in several other neuropathic pain states.
Biogen Idec and Columbia University Medical Centerformed a $30 million strategic alliance in January 2015 to perform genetics discovery research on the underlying causes of disease and to identify new treatment approaches. A sequencing and analysis facility and shared postdoctoral program will be established at Columbia to support collaborative genetics studies. The transaction will integrate genomics research conducted at Columbia with Biogen Idec’s understanding of disease mechanisms and pathways, and expertise in discovering new medicines.
The new facility will have extensive genetic research capabilities and the capacity to launch and complete whole-genome sequencing projects quickly. The site will enable rapid population-scale DNA sequencing across a broad range of disease fields, concentrating on diseases with significant unmet clinical need including amyotrophic lateral sclerosis (ALS) and idiopathic pulmonary fibrosis.
Two leading neuroscientists joined Biogen Idec, as announced in October 2014, to advance the company’s research in neurodegenerative diseases. Christopher Henderson, Ph.D., joined as VP, Neurology. Richard Ransohoff, M.D., came on as senior research fellow, Neuroimmunology. The addition of these top researchers bolsters Biogen Idec’s discovery engine, according to management.
U.S. regulators approved Plegridy as a new treatment for people with relapsing forms of multiple sclerosis during August 2014. One month earlier, the company received marketing authorization from the European Commission for the pegylated interferon administered subcutaneously once every two weeks for adults with RRMS.
Plegridy is considered by many analysts to be one of the most promising drug compounds to be approved during 2014. The interferon beta drug joins Biogen Idec’s MS treatment Tecfidera (dimethyl fumarate), which gained U.S. regulatory clearance in March 2013, as prominent members of the company’s next generation of sales leaders. Each product has the potential to generate multi-billion yearly sales.
New York-based Bristol-Myers Squibb possesses top-tier research and development capabilities. The company’s “String of Pearls” strategy of innovative alliances, partnerships, and acquisitions further enhances its development capabilities. Industry analysts are high on the well-touted pipeline that reportedly contains eight drugs in marketed product development and three more in Phase III studies, along with a large amount of high-potential products in Phase I and Phase II development.
“We continue to build a solid foundation for our future as a Diversified Specialty BioPharma by advancing our own R&D efforts and investing in strategic business development to build a sustainable pipeline,” says Lamberto Andreotti, CEO of Bristol-Myers Squibb. Effective May 5, 2015, Giovanni Caforio will take over as CEO. Mr. Andreotti will become executive chairman of the board of directors on May 5 and will continue to remain as chairman after his retirement on Aug. 3, 2015.
Bristol-Myers Squibb has become a leader in an innovative area of cancer research and treatment known as immuno-oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is investigating various compounds and immunotherapeutic approaches for patients with different forms of cancer, including researching the potential of combining immuno-oncology agents that target different and complementary pathways in treating cancer.
Bristol-Myers Squibb secured perhaps the most market-promising new drug approval during 2014. The immunotherapy Opdivo (nivolumab) injection is indicated for treating patients with unresectable or metastatic melanoma and disease progression followingYervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication was approved in December 2014 under FDA’s accelerated approval based on tumor response rate and durability of response. FY2016 sales from Opdivo have been projected by J.P. Morgan analysts to total about $1.7 billion.
Opdivo is the first PD-1 targeting cancer immunotherapy that has shown efficacy in a Phase III, pivotal study with advanced melanoma in patients who had been previously treated and progressed with Yervoy and, if BRAF mutation positive, a BRAF inhibitor. The human programmed death receptor-1 blocking antibody Opdivo, for intravenous use, works by binding to the PD-1 receptor expressed on activated T-cells.
Bristol-Myers Squibb has a broad, worldwide development program to study Opdivo in multiple tumor types consisting of over 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled globally.
In January 2015, Bristol-Myers Squibb and Eli Lilly announced a clinical study collaboration. The companies are teaming up to evaluate the safety, tolerability and preliminary efficacy of Opdivo in combination with Lilly’s galunisertib (product code LY2157299). The Phase I/II study is assessing the investigational combination of Opdivo and galunisertib as a potential treatment option for patients with advanced (metastatic and/or unresectable) glioblastoma, hepatocellular carcinoma and non-small cell lung cancer. The TGF beta R1 kinase inhibitor galunisertib in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system and elevates the ability of tumors to spread in the body. This collaboration will address the hypothesis that joint inhibition of PD-1 and TGF beta negative signals may result in enhanced anti-tumor immune responses than inhibition of either pathway alone.
Bristol-Myers Squibb entered into another January 2015 deal regarding Opdivo. The clinical study agreement will evaluate the investigational combination of Seattle Genetics’ antibody-drug conjugate (ADC) Adcetris(brentuximab vedotin) with Opdivo in two planned Phase I/II studies. The first study will assess the combination of Adcetris and Opdivo as a potential treatment option for patients with relapsed or refractory Hodgkin lymphoma (HL). The second trial will concentrate on patients with relapsed or refractory B-cell and T-cell non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL).
Adcetris is an ADC directed to CD30, a defining marker of classical HL, which joins together the targeting ability of a monoclonal antibody with the potency of a cell-killing agent. The trials are expected to start during 2015, with Seattle Genetics conducting the HL study and Bristol-Myers Squibb carrying out the NHL study.
CheckMate -017, a Phase III trial of Opdivo compared to docetaxel in patients with second-line squamous cell non-small cell lung cancer, stopped early for a good reason as revealed during January 2015. The study ended early because an assessment conducted by the independent data monitoring committee concluded that the trial met its endpoint, showing superior overall survival in patients receiving Opdivo versus the control arm. This study was the first to indicate a survival advantage with an anti-PD1 immune checkpoint inhibitor in lung cancer.
The open-label, randomized Check-Mate -017 trial pitted Opdivo against docetaxel in previously treated patients with advanced or metastatic squamous cell NSCLC. The study randomized 272 patients to receive either nivolumab 3 mg/kg intravenously every two weeks or docetaxel 75 mg/m2 intravenously every three weeks. The primary endpoint is overall survival, and secondary endpoints include objective response rate and progression free survival.
Positive results were reported in December 2014 from a cohort of patients in the Phase Ib CheckMate -039 study evaluating the PD-1 immune checkpoint inhibitor in patients with relapsed or refractory hematological malignancies (n=23). Results demonstrated high levels of response in patients with relapsed or refractory classical HL, with an overall response rate of 87 percent (n=20) and stable disease in 13 percent (n=3).
In the CheckMate -066 randomized double-blind trial comparing Opdivo to chemotherapy in treatment-naïve advanced melanoma patients, the drug became the first PD-1 immune checkpoint inhibitor to demonstrate a survival benefit in a Phase 3 study. Opdivo showed superior overall survival compared to dacarbazine with a one-year survival rate of 73 percent versus 42 percent and a 58 percent decrease in the risk of death (Hazard Ratio [HR] = 0.42, P<0.0001). The objective response rate was higher for Opdivo than dacarbazine (40 percent against 14 percent), including a higher percentage of complete responses (7.6 percent versus 1 percent). Safety and tolerability were well-characterized with fewer treatment-related Grade 3/4 adverse events observed with Opdivo compared to dacarbazine (11.7 percent versus 17.6 percent).
During December 2014, BMS, Ono Pharmaceutical andKyowa Hakko Kirin agreed on a clinical trial collaboration. The companies are performing a Phase I combination study with Opdivo and mogamulizumab, an anti-CCR4 antibody. The study, which will be carried out in Japan, will concentrate on evaluating the safety, tolerability and anti-tumor activity of combining Opdivo and mogamulizumab as a potential treatment option for patients with advanced or metastatic solid tumors.
Opdivo was introduced in Japan during September 2014 for treating patients with unresectable melanoma. Mogamulizumab was launched in Japan during May 2012 for treating relapsed or refractory CCR4-positive Adult T-cell Leukemia-Lymphoma (ATL), and was granted an expanded indication expansion in March 2014 for relapsed or refractory CCR4-positive Peripheral T-Cell Lymphoma (PTCL) and Cutaneous T-Cell Lymphoma (CTCL). Clinical studies with mogamulizumab in ATL, PTCL, and CTCL are under way in the United States, European Union, and other countries.
BMS and The University of Texas MD Anderson Cancer Center revealed in October 2014 a clinical research collaboration to assess Yervoy, Opdivo and three early-stage clinical immuno-oncology assets as potential treatment options for acute and chronic leukemia as well as other hematologic malignancies. Also that month, the company announced a clinical trial collaboration to evaluate the safety, tolerability and preliminary efficacy of combining Opdivo with three molecularly targeted oncology therapies from Novartis –Zykadia (ceritinib), INC280 and EGF816 – to treat NSCLC.
In August 2014, BMS and Celgene agreed on the establishment of a clinical study collaboration to investigate the safety, tolerability and preliminary efficacy of a combination regimen of Opdivo and Celgene’s nab technology-based chemotherapyAbraxane (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) in Phase I development. Multiple tumor types will be evaluated in the clinical study.
In other Bristol-Myers Squibb research news, the company agreed to a global research collaboration in early January 2015 with the California Institute for Biomedical Research. BMS and Calibr are joining forces to develop novel small-molecule anti-fibrotic therapies. Also, Bristol-Myers Squibb entered into an exclusive license deal that enables the company to develop, manufacture and commercialize Calibr’s preclinical compounds resulting from the collaboration.
A key part of Bristol-Myers Squibb’s R&D strategy is identifying novel medicines to halt or slow the progression of fibrotic disease and improve upon the current standard of care. The independent, not-for-profit organization Calibr was established to accelerate the translation of basic biomedical discoveries into innovative new medicines. Calibr brings to the collaboration substantial expertise in identifying and optimizing small molecules with anti-fibrotic activity via its high-throughput screening, target identification, and preclinical drug discovery infrastructure.
Bristol-Myers Squibb is dedicated to addressing the unmet need in fibrosis, a strategic field of focus for the company, by identifying novel medicines to halt or slow the progression of fibrotic disease. Assets in Bristol-Myers Squibb’s fibrosis portfolio include BMS-986020, a lysophosphatidic acid 1 (LPA1) receptor antagonist in Phase II studies for treating idiopathic pulmonary fibrosis (IPF), and a CCR2/5 dual antagonist in Phase II trials for diabetic kidney disease.
Additionally in this research area, a deal was struck in November 2014 providing Bristol-Myers Squibb the exclusive option to acquire Galecto Biotech. The transaction includes Bristol-Myers Squibb obtaining worldwide rights to Galecto Biotech’s lead asset TD139. The novel inhaled inhibitor of galectin-3 is undergoing Phase 1 development for treating IPF and other pulmonary fibrotic conditions.
BMS December 2014 results of the first human study evaluating the reversal of the anticoagulant effect ofEliquis by 4-factor prothrombin complex concentrates (PCCs) in healthy subjects. The study results showed that both PCCs – Sanquin’s heparin-free formulationCofact and CSL Behring’s heparin-containing Beriplex P/N – reversed the steady-state pharmacodynamic effects of Eliquis in several coagulation assessments. These assessments include endogenous thrombin potential (ETP). Cofact and Beriplex P/N are used to stop severe bleeding in patients taking vitamin K antagonists, including warfarin, or with a blood clotting factor deficiency.
As a novel oral anticoagulant that contains the active chemical apixaban, Eliquis specifically inhibits Factor Xa. There are no marketed reversal agents for Eliquis or other direct Factor Xa inhibitors. By inhibiting the key blood clotting protein Factor Xa, Eliquis decreases thrombin generation and blood-clot formation. Eliquis is approved for multiple indications in the United States, including: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the prophylaxis of deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for treating DVT and PE; and to reduce the risk of recurrent DVT and PE following initial therapy.
Bristol-Myers Squibb, Portola Pharmaceuticals, and Pfizer announced during November 2014 statistically significant results from the first part of the Phase III ANNEXA-A studies with the investigational agentandexanet alfa with Eliquis. ANNEXA-A stands for Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors – Apixaban.
The results showed that andexanet alfa produced rapid and nearly complete reversal (by 94 percent, p value <0.0001) of the anticoagulant effect of Eliquis in healthy volunteers ages 50-75 years old. This first part of the Phase III ANNEXA-A study achieved all primary and secondary endpoints with statistical significance (p value <0.0001). Andexanet alfa could become the first universal Factor Xa inhibitor antidote approved for anticoagulated patients who are experiencing a major bleeding event or those needing emergency surgery.
A deal for an exclusive clinical collaboration was reached in November 2014 between Bristol-Myers Squibb and Five Prime Therapeutics. The companies agreed to evaluate the safety, tolerability and preliminary efficacy of combining Opdivo with FPA008, Five Prime’s monoclonal antibody that inhibits colony stimulating factor-1 receptor (CSF1R). The Phase Ia/IIb study will investigate the combination of Opdivo and fellow immunotherapy FPA008 as a potential treatment option for patients with NSCLC melanoma, head and neck cancer, pancreatic cancer, colorectal cancer and malignant glioma.
Bristol-Myers Squibb revealed results in November 2014 of several new sub-analyses of the Phase IIIb AVERT (Assessing Very Early Rheumatoid arthritis Treatment) study investigating use of Orencia plus methotrexate (MTX) in biologic and MTX-naïve citrullinated protein (CCP)-positive early moderate to severe rheumatoid arthritis (RA) patients. The BMS medicine is already approved in adults for moderate to severe RA.
First-line therapy with Orencia in combination with MTX resulted in patients with early RA achieving significantly higher rates of stringent measures of remission, including 37 percent of patients achieving Boolean-defined remission and 42 percent of patients achieving CDAI- and SDAI-defined remission at 12 months compared to patients on MTX alone (22.4 percent, 27.6 percent, and 25 percent, respectively; P<0.05 for all three measures). Analysis demonstrated treatment with Orencia plus MTX reduced the development of anti-CCP antibodies, an indicator of more severe, persistent and erosive disease in patients with early rapidly progressing RA. Sustained improvements on MRI endpoints were additionally observed showing Orencia with MTX improved synovitis and osteitis scores at 12 months, and improved joint erosion scores at 12 and 18 months, versus MTX alone. were reported the landmark ALLY Trial investigating a ribavirin-free 12-week regimen of daclatasvir (DCV) in combination with sofosbuvir (SOF) in genotype 3 hepatitis C (HCV) patients, a patient population that has emerged as one of the most difficult to treat. Genotype 3 is the No. 2 most common genotype globally. The results of the trial demonstrated sustained virologic response 12 weeks after treatment (SVR12) in 90% of treatment-naïve and 86% of treatment-experienced patients. ALLY-3 is the first Phase III trial of an all-oral, ribavirin-free treatment regimen for genotype 3 HCV patients with a 12-week treatment duration.
Also revealed during November 2014 were data from the Phase III UNITY studies showing high cure rates for the investigational, all-oral daclatasvir TRIO fixed-dose combination in genotype 1 hepatitis C patients, including those with cirrhosis. According to the data, daclatasvir TRIO achieves a 98 percent cure rate in treatment-naïve and a 93 percent cure rate in treatment-experienced genotype 1 patients with cirrhosis when used with ribavirin. The 12-week, all-oral treatment cuts in half the current regimen duration for hard-to-manage treatment-experienced genotype 1 patients with cirrhosis. The fixed-dose regimen additionally produced 91 percent SVR rates in non-cirrhotic genotype 1 patients without requiring use of ribavirin.
Bristol-Myers Squibb F-star Alpha reached a deal in October 2014. Bristol-Myers Squibb is provided with the exclusive option to acquire F-star Alpha and gain global rights to its lead asset FS102. The drug prospect is a novel Phase I ready Human Epidermal growth factor Receptor 2 (HER2)- targeted therapy. FS102 is undergoing development for treating breast and gastric cancer among a well-defined population of HER2-positive patients who do not respond or become resistant to current therapies.
During October 2014, BMS announced a clinical trial collaboration deal with Janssen and Pharmacyclics. The companies are evaluating the safety, tolerability and preliminary efficacy of Opdivo with Janssen and Pharmacyclics’ oral Bruton’s tyrosine kinase inhibitorImbruvica (ibrutinib) to treat patients with non-Hodgkin lymphoma.
BMS and Allied Minds announced during August 2014 the formation of Allied-Bristol Life Sciences. The jointly owned enterprise was created to identify and foster research and pre-clinical development of biopharma innovations from leading U.S. university research institutions. The new enterprise is concentrating on converting discoveries from university research institutions into therapeutic candidates for clinical development and, ultimately, approved therapies that address serious diseases.
Celgene Corp. is rising up through the ranks of the world’s leading drug manufacturers. The Summit, N.J.-based integrated global pharma company is engaged primarily in the discovery, development and commercialization of innovative therapies for treating cancer and inflammatory diseases via gene and protein regulation. The company’s 2015 total net product sales are expected to range between $9 billion and $9.5 billion, which would represent a 22 percent year-over-year increase based on the mid-point of the range. In 2020, net product sales are anticipated to top $20 billion, due in no small part to a promising drug pipeline focused on existing products as well as new medicine opportunities. Celgene reportedly has more than 40 medicines ranging from preclinical to Phase III testing. company making significant investments to sustain growth beyond 2020. These investments include the filing of three IND’s: the anti-CD47 MAb CC-90002, CC-90003 for ERKi, and the anti-DLL4/VEGF MAb OMP-305B83. Celgene has 10 new R&D partnerships with emerging companies and leading academic institutions, and is expanding existing collaborations. The company is focusing resources on enhanced established protein homeostasis, epigenetic and immuno-oncology platforms to accelerate development. Also, Celgene intends to advance 12 early-to-mid stage clinical programs to critical decision points over the next two years.
A recent by-product of the company’s strong pipeline isOtezla, an oral selective inhibitor of phosphodiesterase 4. PDE4 inhibition leads to increased intracellular cAMP levels, which is believed to indirectly modulate the production of inflammatory mediators. Otezla (apremilast) is the first in a new class of drugs for treating psoriasis and psoriatic arthritis, two diseases involving dysregulated immune system activity. Otezla is the first oral treatment in 20 years to gain approval for patients with psoriasis and during the past 15 years to receive clearance for psoriatic arthritis.
In January 2015, the European Commission granted marketing authorization for Otezla for treating moderate-to-severe chronic plaque psoriasis and active psoriatic arthritis (PsA). The drug has demonstrated a favorable safety profile, with no European labeling requirement for drug-specific pre-screening or ongoing laboratory monitoring. The marketing authorization was based on efficacy and safety data from two Phase III programs showing a maintained clinical response among patients with psoriasis (ESTEEM) and psoriatic arthritis (PALACE) treated with Otezla through 52 weeks, across multiple endpoints.
Otezla was approved by U.S. regulators on March 21, 2014, for treating adults with active psoriatic arthritis. FDA marketing clearance then came on Sept. 23, 2014, for treating patients with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy. As of January 2015, marketing authorization applications were under way in other countries, including Australia and Switzerland.
Celgene’s oncology drug Revlimid (mentioned earlier in this story’s Amgen pipeline review) will continue to increase is blockbuster sales presence through newly approved indications. Current indications approved in various major markets include the treatment of patients with multiple myeloma who have received at least one prior therapy; transfusion-dependent anemia; and mantle cell lymphoma. Another indication appears ready to gain marketing clearance in 2015, as the European Medicines Agency’s Committee for Medicinal Products for Human Use in December 2014 adopted a positive opinion for continuous oral treatment with Revlimid containing lenalidomide in adult patients with previously untreated multiple myeloma who are not eligible for stem cell transplantation. Revlimid has not yet been approved for treating newly diagnosed multiple myeloma in any country.
In December 2014, Celgene announced results from a Phase II/III study (DLC-001) of Revlimid compared with investigators’ choice (IC) of therapy in patients with relapsed/refractory diffuse large b-cell lymphoma (DLBCL). Data suggest improved response rates, progression-free survival and overall survival with lenalidomide versus IC in the non-germinal b-cell (GCB) population as defined by immunohistochemistry (IHC). These improved outcomes were evidently more pronounced in the activated b-cell (ABC) sub-type when assessed by gene expression profiling. Not yet approved in any country for DLBCL, the Phase III ROBUST program will evaluate Revlimid plus R-CHOP in hard-to-treat patients. R-CHOP is a combination of rituximab, cyclophosphamide, doxorubicin, prednisone and vincristine.
Additionally, Celgene revealed in December 2014 results from an international Phase III study of Revlimid compared with placebo in patients with red-blood cell (RBC) transfusion dependent low-risk myelodysplastic syndromes (MDS) who were unresponsive or refractory to erythropoietin stimulating agents (ESA) and did not have a deletion 5q cytogenic abnormality. The trial showed that significantly more patients treated with lenalidomide achieved RBCtransfusion independence of at least 56 days compared with placebo (26.9 percent, [43/160 patients] versus 2.5 percent,[2/79 patients]; p < 0.001), the primary endpoint of the study. Most patients (90 percent) with transfusion independence responded within 16 weeks of treatment. For patients who became transfusion independent, the median duration of transfusion independence totaled 8.2 months (range 5.2-17.8).
Also, results of the MCL-002 (SPRINT) study showed significantly longer progression-free survival for lenalidomide versus the investigators’ choice in relapsed/refractory mantle cell lymphoma (MCL). Meanwhile, the combination of lenalidomide and rituximab demonstrated a 84.2 percent response rate in previously untreated MCL. The SPRINT trial provided the first head-to-head, randomized, controlled study of single-agent lenalidomide versus a range of single-agent comparators in previously treated MCL. was a busy news month for Revlimid as positive results were presented from multiple post-hoc analyses of the pivotal Phase III FIRST (MM-020/IFM 07-01) study. The clinical trial compared continuous Revlimid plus low-dose dexamethasone (continuous Rd) to a fixed duration of 18 cycles of Rd (Rd18) or 12 cycles of melphalan, prednisone and thalidomide (MPT) for treating newly diagnosed, transplant-ineligible multiple myeloma. The trial met the primary endpoint of progression-free survival in the intent-to-treat analysis of all randomized patients (Median PFS 21.2 months MPT versus 25.5 months Rd, Hazard Ratio (HR) 0.72, p < 0.01). Continuous Revlimid plus low-dose dexamethasone increased PFS compared with fixed duration of Rd or melphalan, prednisone and thalidomide regardless of age, renal impairment, or depth of response.
Pomalyst/Imnovid, which contains the active ingredient pomalidomide, is a newer multiple myeloma medicine in Celgene’s portfolio. Pomalyst was initially FDA-approved on Feb. 8, 2013, and Imnovid gained EU clearance on Aug. 5, 2013. In the United States, Pomalyst is available for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have shown disease progression on or within 60 days of completion of the last therapy. During 2015, approval is expected for Pomalyst/Imnovid in Japan for relapsed and/ or refractory multiple myeloma
Pomalyst/Imnovid sales were projected to be about $680 million for 2014, representing a 123 percent year-over-year increase. Net product sales in 2017 are projected by Celgene to land at $1.5 billion. In an effort to meet or exceed that forecast, the company is studying Pomalyst/Imnovid in combination with other medicines for multiple myeloma. Among those studies is a Phase III trial of pomalidomide plus low-dose dexamethasone in patients with relapsed and refractory multiple myeloma.
Celgene is additionally exploring new uses for Istodax(romidepsin) for injection. The medicine is indicated for treating peripheral T-cell lymphoma in patients who have received at least one prior therapy. Istodax is also indicated for treating cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. In December 2014, data were announced by Celgene from a Phase Ib/II trial of Istodax combined with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with peripheral t-cell lymphoma. Fifty-one percent of patients (18/35) in the trial achieved a complete response. Company officers said the results support additional study via the Phase III comparison of RO-CHOP and CHOP alone in this area of disease.
Celgene is also trying to expand the franchise forVidaza, which is already FDA-approved for refractory anemia and chronic myelomonocytic leukemia. In Phase III results announced in December 2014, compared with conventional care regimens, Vidaza doubled overall survival times in subsets of patients with poor-risk cytogenetics and in patients with morphologic dysplasticrelated changes.
Celgene’s marketed medicine Abraxane – mentioned previously in this story’s BMS pipeline review – is also undergoing development for new indications. The drug is marketed for treating breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy; first-line treatment of locally advanced or metastatic NSCLC in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy; and first-line treatment of metastatic adenocarcinoma of the pancreas in combination with gemcitabine.
Abraxane is awaiting approval in Europe in combination with carboplatin for locally advanced or metastatic non-small cell lung cancer. An opinion from the EU’s CHMP is expected during first-half 2015. A Phase II study, known as abound.2L, with Abraxane in combination withCC-486 compared to Abraxane monotherapy in patients with second-line advanced nonsquamous NSCLC started enrollment in third-quarter 2014. The abound study program will include additional trials in non-small cell lung cancer such as elderly patients, second-line NSCLC and patients with poor performance status.
Celgene’s collaboration partner OncoMed presented data at the European Society for Medical Oncology meeting in September 2014 from two Phase Ib studies of demcizumab in combination with gemcitabine and Abraxane in patients with first-line pancreatic cancer and in combination with pemetrexed and carboplatin in patients with advanced NSCLC.
Celgene has a variety of new product opportunities that are expected to be growth drivers in the 2018-2020 period. One of those products is GED-0301, which is in a registration program for Crohn’s disease. Celgene has established clinical proof-of-concept to advance these prospects into pivotal trials: AG-221 for IDH2 mutant AML with initiation of a pivotal program expected in 2015, and sotatercept or luspatercept in beta-thalassemia and MDS, with beta-thalassemia Phase III trial initiation potentially occurring in 2015. Also, promising new drug candidate CC-486 has advanced into Phase III studies in AML and MDS.
Foster City, Calif.-based Gilead is well known for its successful portfolio of antiviral medicines and hepatitis drugs. For example, the hepatitis C product Sovaldi – which was FDA-approved in December 2013 – has broken the launch sales record to already become one of the industry’s top-selling products. Anticipated future blockbusters Zydelig and Harvoni joined the marketplace in 2014, and Gilead’s pipeline is on track to deliver more approved gems in the years ahead. The company’s clinical program includes ongoing studies for six potential blockbuster indications, such as nonalcoholic steatohepatitis and blood-based disorders.
Gilead started off 2015 by purchasing a development program – which concentrates on what is considered one of the industry’s hottest fields – from a small private German biotechnology company. Gilead obtained Phenex’s Farnesoid X Receptor (FXR) program consisting of small-molecule FXR agonists for treating liver diseases such as nonalcoholic steatohepatitis (NASH). Gilead is responsible for an up-front payment along with additional payments based upon achievement of certain development milestones that may potentially be valued up to $470 million. promising drug the Phenex pipeline is Px-102, which is undergoing Phase II trials to treat NASH. Discovered by Phenex, Px-102 is a novel fully synthetic, non-steroidal and potent FXR agonist. Some industry insiders believe that Px-102 could be an annual $1 billion sales generator. The deal makes Gilead a leader in the area of liver disease research.
NASH is a common, serious chronic liver disease characterized by inflammation and excessive fat accumulation in the liver that may result in progressive fibrosis, cirrhosis and liver failure. NASH is estimated to affect 10 to 20 percent of the developed world population. There are no marketed therapies to treat NASH. The nuclear hormone receptor FXR regulates bile acid, lipid and glucose homeostasis, which can help reduce liver steatosis and inflammation, and may aid in preventing liver fibrosis.
Gilead in late December 2014 announced an expanded agreement with Janssen R&D Ireland for the development and commercialization of a new once-daily single tablet regimen. The combo tablet combines Gilead’s tenofovir alafenamide (TAF) and emtricitabine – which is an active ingredient in several Gilead medicines already on the market – and Janssen’s rilpivirine. The initial pact was established during 2009 for the development and commercialization ofComplera (marketed as Eviplera in the European Union), which combines tenofovir disoproxil fumarate, emtricitabine and rilpivirine in a once-daily tablet. Gilead is expected to initiate Phase II trials of emtricitabine/rilpivirine/TAF in the near term. Pending the drug’s approval, Gilead is responsible for the manufacturing, registration, distribution and commercialization of the regimen in most countries, while Janssen will distribute in 17 markets.
TAF is a novel nucleotide reverse transcriptase inhibitor that has shown high antiviral efficacy at a dose 10 times lower than Gilead’s marketed hepatitis B drugViread (tenofovir disoproxil fumarate), as well as an improved renal and bone safety profile. TAF is an investigational, novel prodrug of tenofovir.
In November 2014, a once-daily single tablet regimen containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and TAF 10 mg (E/C/F/ TAF) for treating HIV-1 infection in adults was submitted for FDA approval. Gilead expected to file a regulatory application for E/C/F/TAF in the European Union by year-end 2014.
“We believe that TAF’s efficacy and safety advantages may make it a strong backbone of new fixed-dose combinations and single tablet regimens,” said Norbert Bischofberger, Ph.D., executive VP of R&D and chief scientific officer of Gilead.
Gilead and Janssen additionally amended a licensing deal for the development and commercialization of a once-daily single tablet regimen for HIV containing Gilead’s TAF, emtricitabine and cobicistat, and Janssen’s darunavir. Janssen is now responsible for further development of the regimen and, subject to regulatory approval, the manufacturing, registration, distribution and commercialization of the product globally.
In another December 2014 transaction with a top pharma company, Gilead and Ono Pharmaceutical announced an exclusive license pact for the development and commercialization of ONO-4059. Ono’s oral Bruton’s tyrosine kinase inhibitor is being developed for treating B-cell malignancies and other diseases. Gilead owes Ono an up-front payment along with additional payments based upon achievement of certain development, regulatory and commercial milestones. The companies will collaborate jointly on worldwide development of ONO-4059. Gilead holds exclusive rights to develop and commercialize the new drug candidate in all countries of the world outside of Japan, South Korea, Taiwan, China and the Association of Southeast Asian Nations (ASEAN) countries, where ONO retains development and commercialization rights.
ONO-4059 is a selective, once-daily, oral inhibitor of BTK, which has been demonstrated to play a role in the survival and proliferation of malignant B-cells. Osaka, Japan-based Ono has presented preliminary Phase I data demonstrating clinical activity in chronic lymphocytic leukemia (CLL) and NHL at several scientific conferences. Ono and Gilead intend to develop ONO-4059 for treating B-cell malignancies and other diseases as a monotherapy and in combination with approved and investigational agents, including combinations with kinase inhibitors in Gilead’s portfolio.
“With this agreement, Gilead now has compounds targeting four unique signaling pathways associated with B-cell malignancies – PI3K delta, Syk, JAK and BTK,” Dr. Bischofberger noted. “In addition to evaluating ONO-4059 in combination with standards of care, we believe there is an opportunity to combine this compound with Gilead’s other kinase inhibitors with a goal of achieving more pronounced and more durable response rates. We look forward to working with Ono to move the ONO-4059 development program forward as quickly as possible.”
The European Commission during November 2014 granted marketing authorization for Harvoni (ledipasvir 90 mg/sofosbuvir 400 mg) as the first once-daily single tablet regimen to treat the majority of chronic hepatitis C genotype 1 and 4 infection in adults. Harvoni joins together the NS5A inhibitor ledipasvir (LDV) with the nucleotide analog polymerase inhibitor sofosbuvir, which was cleared for marketing by the European Commission under the trade name Sovaldi during January 2014. The once-daily single-tablet combination eliminates the need for interferon and ribavirin for patients with genotype 1 and 4 hepatitis C without cirrhosis or with compensated cirrhosis.
The marketing authorization is based on the clinical development program that included 2,000-plus patients with HCV infection, and follows an accelerated assessment by the European Medicines Agency – a designation that is granted to new medicines of major public health interest. The approval enables the marketing of Harvoni in all 28 EU countries.
Marketing authorization was supported primarily by data from three Phase III trials: ION-1, ION-2 and ION-3. These trials evaluated eight, 12 or 24 weeks of treatment with Harvoni, with or without ribavirin, among nearly 2,000 genotype 1 HCV patients with compensated liver disease.
Harvoni received marketing approval in the United States and Canada during October 2014 and in New Zealand during November 2014. Regulatory filings for Harvoni are awaiting clearance in Japan and Switzerland. Sovaldi as a single agent is approved for marketing in the United States, European Union, Canada, Australia, New Zealand, Egypt, Switzerland and Turkey.
Gilead revealed positive data during November 2014 from several Phase II and Phase III trials evaluating investigational uses of Harvoni for treating chronic hepatitis C virus infection in patients with limited or no treatment options. These included patients with decompensated cirrhosis, patients with HCV recurrence following a liver transplant and patients who failed previous treatment with other direct acting antivirals. The results showed that Harvoni provides high cure rates for patients with advanced liver disease, as well as for those who failed prior treatment with other antivirals, including sofosbuvir-based regimens.
As for Sovaldi, in November 2014 Gilead announced positive data from three Phase II open-label trials. The studies evaluated the safety and efficacy of an investigational all-oral pan-genotypic regimen containing the nucleotide analog polymerase inhibitor sofosbuvir and the investigational NS5A inhibitor GS-5816 for treating chronic HCV infection. The once-daily combo achieved high SVR12 rates across multiple HCV genotypes.
All three trials studied SOF 400 mg in combination with GS-5816 25 or 100 mg, with and without ribavirin (RBV), for eight or 12 weeks. Rates of sustained virologic response (SVR12) varied from 88 percent to 100 percent among those receiving SOF plus GS-5816 100 mg for 12 weeks – the regimen selected for Phase III trials. Patients who attain SVR12 are considered cured of HCV infection.
“There continues to be a need for simple, interferon-free and ribavirin-free treatment regimens that are effective for all hepatitis C patients, regardless of genotype,” Dr. Bischofberger remarked. “These data demonstrate the high efficacy and tolerability of sofosbuvir plus GS-5816 among patients with varying genotypes and disease progression and we look forward to providing Phase III data on the combination across all six genotypes.”
During third-quarter 2014, Gilead announced the inking of non-exclusive licensing deals with seven India-based generic pharmaceutical manufacturers to expand access to its chronic HCV medicines in developing countries. The agreements enable the companies to manufacture SOF and the single-tablet combo of LDV/SOF for distribution in 91 developing countries.
Also announced during the third quarter was a new pact with the Medicines Patent Pool (MPP) to expand access to TAF for HIV and hepatitis B, contingent on the medicine’s FDA approval. The MPP can sub-license TAF to generic drug firms in India and China, who may manufacture and distribute it in 112 developing countries.
U.S. regulatory approval – ing September 2014 for Zydelig as a treatment for three B-cell blood cancers. The new medicine is available in combination with rituximab for patients with relapsed chronic lymphocytic leukemia for whom rituximab alone would be considered appropriate therapy and as monotherapy for patients with relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.
The European Commission also granted marketing authorization for Zydelig for CLL and FL during September 2014. For treating CLL, Zydelig has been approved for use in combination with rituximab for patients who have received at least one prior therapy; or in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. For treating FL, Zydelig has been cleared as a monotherapy in patients who are refractory to two prior lines of treatment.
Zydelig is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, which is a protein that has a part in the activation, proliferation and viability of B cells, a crucial component of the immune system. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and by inhibiting the protein, Zydelig (idelalisib) inhibits several cellular signaling pathways that drive B-cell viability.
The clinical development program for idelalisib includes six ongoing or completed Phase III studies for B-cell cancers. Idelalisib is one of several drugs that target the PI3K signaling pathway and are believed to possess blockbuster potential.
Also during September 2014, Gilead unveiled positive results from the AMBITION trial that was performed in collaboration with GlaxoSmithKline. AMBITION is a randomized, double-blind, multicenter study of first-line combination therapy with AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION). In AMBITION, first-line treatment of pulmonary arterial hypertension with the combination of ambrisentan 10 mg and tadalafil 40 mg cut down the risk of clinical failure by 50 percent versus the pooled ambrisentan and tadalafil monotherapy arm. The combination was statistically significant compared to the individual ambrisentan and tadalafil monotherapy groups for the primary endpoint.
Simtuzumab is a promising Phase II drug prospect that Gilead is researching for a variety of indications. The investigational monoclonal antibody is highly selective for LOXL2, an enzyme that modifies the extracellular matrix by promoting the cross-linking of collagen fibers. LOXL2 is believed to play a significant role in tumor progression and metastasis as well as in the development of fibrotic diseases. Phase II studies include: in combination with FOLFIRI for advanced colorectal cancer, in combination with ruxolitinib for myelofibrosis, as monotherapy for the rare lung disease idiopathic pulmonary fibrosis, and for liver fibrosis resulting from non-alcoholic steatohepatitis and primary sclerosing cholangitis (PSC).
Another promising Phase II prospect for Gilead is GS-4997. The ASK-1 inhibitor is being developed to treat diabetic nephropathy and pulmonary arterial hypertension. ASK-1 activation mediates inflammation and fibrosis, and an inhibitor has the potential to treat various cardio-renal and fibrotic diseases.
MERCK & CO.
The Whitehouse Station, N.J.-based pharma power hit payday during 2014 with seven new medicine approvals, highlighted by the market arrival of Keytruda (mentioned previously in the Amgen pipeline review). Merck’s humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blockading the interaction with the receptor ligands, Keytruda releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. The medicine is FDA-approved at a dose of 2 mg/kg every three weeks for treating patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The Keytruda franchise has been forecasted to generate at least $4 billion in peak sales.
Merck revealed early study findings in December 2014 showing an overall response rate of 18.5 percent with Keytruda as assessed by RECIST v1.1, central review (n=5/27), in PD-L1 positive, advanced triple-negative breast cancer – one of the most aggressive types of breast cancer. These early findings stem from the ongoing Phase Ib KEYNOTE-012 trial. The multi-center, non-randomized Phase Ib study is evaluating the safety, tolerability, and anti-tumor activity of Keytruda monotherapy in patients with advanced triple-negative breast cancer (TNBC), advanced head and neck cancer, advanced urothelial (bladder) cancer, or advanced gastric cancer. The primary endpoints of the trial include overall safety, tolerability and anti-tumor activity (as measured by RECIST v1.1 assessed by independent radiology review) in PD-L1 positive tumors; secondary endpoints include progression-free survival (PFS), overall survival (OS) and duration of response. During 2014, early findings were presented for all four cohorts of the Phase Ib KEYNOTE-012 trial. A Phase II trial is planned for first-half 2015 and viewed by Merck officials as a significant next step for the company’s breast cancer clinical program.
Merck’s anti-PD-1 therapy is being investigated for use in 30-plus tumor types of cancers, as monotherapy and in combination. One of the combinations involves GlaxoSmithKline’s Votrient (pazopanib) in kidney cancer.
Merck and Eli Lilly have struck together an oncology clinical trial collaboration to evaluate the safety, tolerability and efficacy of Keytruda in combination with Lilly compounds in multiple studies, as announced in January 2015. Merck is conducting a Phase II trial examining the combination of pembrolizumab with pemetrexed (marketed by Lilly as Alimta) in first-line non-squamous, non-small cell lung cancer. This trial is enrolling patients. Lilly will carry out a multiple-arm Phase I/II study examining the combination of ramucirumab (marketed by Lilly as Cyramza) with pembrolizumab in multiple tumors. This study is expected to launch during 2015. Lilly will also perform a Phase I/ II study examining the combination ofnecitumumab with pembrolizumab in NSCLC. That trial also will begin in 2015.
“Our understanding of the immune system’s role and its impact in the treatment of cancer continues to grow,” noted Eric Rubin, M.D., VP, global clinical development, oncology, Merck Research Laboratories. “Collaborations such as this one are important in advancing the investigation of novel immuno-oncology combinations in different cancers, and to achieving our shared goal of bringing meaningful benefits to patients facing cancer.” management recently – edged that the company needs to speed up its development efforts. “The tempo has changed,” stated Merck Research Laboratories President Roger Perlmutter. “What we are doing is focusing our efforts more profoundly, increasing the speed at which we complete things.” Merck intends to file for another indication for Keytruda by mid-2015, for treating non-small cell lung cancer, the most common form of the disease. The company expects to file its NDA for grazoprevir/elbasvir for treating HCV infection in first-half 2015.
Grazoprevir/elbasvir (product codes MK-5172/MK-8742) is an investigation-al, oral, once-daily, fixed-dose combination chronic HCV treatment. Grazoprevir is an investigational oral, once-daily HCV NS3/4A protease inhibitor. Elbasvir is an investigational oral, once-daily HCV NS5A replication complex inhibitor. During October 2013, Merck announced that U.S. regulators granted Breakthrough Therapy designation to grazoprevir/elbasvir for treating chronic HCV infection.
Merck revealed in November 2014 results from a multi-arm Phase II study evaluating grazoprevir/elbasvir with or without ribavirin (RBV) in treatment-naïve and previously-treated (with peg-interferon/ribavirin [PR]) patients with chronic HCV genotype 1 (GT1) infection – the C-WORTHy trial (Parts A and B). The results of the C-WORTHy study supported the advancement of grazoprevir/elbasvir into the Phase III program known as C-EDGE. The C-EDGE program is evaluating grazoprevir/elbasvir with and without RBV in various genotypes and across a wide range of patient populations with chronic HCV infection. Merck launched the first C-EDGE study during April 2014, and the grazoprevir/ elbasvir registration studies within the C-EDGE program – including C-EDGE TN (treatment-naïve), C-EDGE CO-INFXN (HIV/HCV co-infected) and C-EDGE TE (treatment-experienced) – are fully enrolled. Results from these studies are expected during the first half of 2015.
In October 2013, Merck launched a worldwide initiative to transform itself into a more competitive and innovative company and to build a platform for sustained future growth. During January 2015, management provided an update on the continuing execution of Merck’s multi-year, strategic initiative to sharpen commercial and R&D focus, redesign its operating model and reduce its cost base.
“Over the past 15 months, we’ve seen the results of our transformation strategy, including advancing major pipeline candidates, completing multiple business development actions and securing first-in-class product approvals,” commented Merck Chairman and CEO Kenneth C. Frazier. “As a result of our strong and continued commitment to the pursuit of science and R&D, our labs are focused on many of the most innovative areas in biomedical research today, which we believe is the best way to create intrinsic value for both society and for our shareholders.”
As a result of prioritizing research efforts in the core fields where it can make the most impact on addressing critical areas of unmet medical need, Merck is now concentrated on many of the most urgent global health challenges, including immuno-oncology, hepatitis C, cardiometabolic disease, antimicrobial resistance and Alzheimer’s disease. Merck accelerated several of its key clinical programs throughout 2014, positioning the company for long-term growth.
Merck strengthened its hepatitis pipeline during 2014 by acquiring Idenix Pharmaceuticals for a transaction value of $3.85 billion. As a result, the Phase II C-CREST studies (NCT02332707 and NCT02332720) have begun to study combination regimens of grazoprevir and MK-3682 (formerly IDX21437) with either elbasvir or MK-8408 for treating HCV infection.
Idenix is a biopharma company engaged in the discovery and development of medicines for treating human viral diseases, whose primary focus is on developing next-generation oral antiviral therapeutics to treat HCV infection. Idenix had three HCV drug candidates in clinical development: the nucleotide prodrugs IDX21437 and IDX21459, and the NS5A inhibitor samatasvir. These novel candidates are being studied for their potential inclusion in the development of all oral, pan-genotypic fixed-dose combination regimens.
Merck has more than 10 Phase III programs in its core therapeutic areas, as well as in other fields with significant potential including Alzheimer’s disease, and has multiple strategic collaborations.
The company recently initiated its first Phase III trials (NCT02275780) of the investigational HIV medicinedoravirine/product code MK-1439.
In addition to oncology collaborations, Merck started several other clinical research collaborations during 2014. Among them, Merck is working with NewLink Genetics on the development of an investigational Ebola vaccine and a cardiovascular-focused collaboration with Bayer.
Merck bolstered its product portfolio in 2014 with its announced acquisition of Cubist Pharmaceuticals. Cubist is a worldwide leader in the discovery, development and supply of antibiotics to treat serious and potentially life-threatening infections. Following completion of the Cubist transaction during first-quarter 2015, Merck intends to launching Zerbaxa(ceftolozan/tazobactam), a recently approved antibiotic to treat Gram-negative bacteria, a key cause of in-hospital infections.
The Cubist deal has an equity valuation of $8.4 billion and includes $1.1 billion in net debt (based on projected cash balances) and other considerations for a total transaction value of $9.5 billion. Cubist’s in-line and late-stage pipeline of anti-infective medicines, including Zerbaxa, will enhance Merck’s hospital acute care business in various therapeutic fields such as Gram-positive and Gram-negative multi-drug resistant infections.
Merck officials expect the acquisition to add more than $1 billion of revenue to the company’s 2015 base. Cubist complements Merck’s strategy and its worldwide initiative, especially in the area of sharpening its commercial focus on key therapeutic fields that have the potential to deliver the greatest return on investment. With the company’s long-standing leadership in anti-infectives as well as its customer-focused operating model, Merck identified the hospital acute care segment as one of its main priority areas believed to have the largest impact in addressing significant unmet medical needs while delivering the greatest value to customers and society.
Merck’s oncology portfolio expanded in December 2014 via another acquisition, the purchase of OncoEthix. The Swiss-based privately held biotech company specializes in oncology drug development. Through OncoEthix, Merck lands the investigational, novel oral BET (bromodomain) inhibitor OTX015. The new product candidate is undergoing Phase Ib studies as a treatment of hematological malignancies and advanced solid tumors. OTX015 was in-licensed from Mitsubishi Tanabe Pharma during March 2012 after completion of Phase I studies.
BET proteins are believed to be potential therapeutic targets in cancer, as they play a pivotal role in regulating the transcription of key regulators of cancer cell growth and survival, including c-Myc. Interim data from Phase I studies of OTX015 have shown meaningful clinical activity in patients with hematological malignancies. An international, open-label Phase I study assessing OTX015 in five different solid tumors was launched during November 2014.
Novartis possesses one of the deepest and most productive pipelines in the industry. The Swiss pharma giant has 141 projects in clinical development, many of which are new molecular entities. Novartis in recent years has been regarded as a leader in pharmaceutical drug innovation. That innovation is delivering to the marketplace two more anticipated future blockbusters,LCZ696 and Cosentyx (secukinumab).
As this issue was nearing press time, secukinumab was approved under the trade name Cosentyx by U.S. and EU regulators. The human monoclonal antibody was cleared by the two health bodies for treating moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy (a drug that is absorbed into the bloodstream and distributed to all parts of the body) or phototherapy (light therapy). Cosentyx is the first approved psoriasis prescription product to selectively bind to IL-17A and inhibit interaction with the IL-17 receptor. Cosentyx is the only biologic that can be used as first-line systemic therapy in treating psoriasis and as an alternative to treatments that have significant side effects; all other marketed biologics are recommended for second-line therapy in Europe.
The marketing approvals are based on the efficacy and safety outcomes from 10 Phase II and Phase III studies, including more than 3,990 adult patients with moderate-to-severe plaque psoriasis. The studies showed that Cosentyx resulted in clear or almost clear skin in the majority of patients and had an acceptable safety profile. In the Phase III program for Cosentyx 300 mg, the drug’s overall safety profile was favorable, with minimal differences evident between etanercept (which is marketed as Enbrel by Amgen and Pfizer) and ustekinumab in head-to-head comparison. Enbrel and Stelara are both blockbuster medicines.
“The FDA’s approval of Cosentyx signifies a turning point for psoriasis patients, who can now benefit from the first and only approved treatment targeting the IL-17 pathway, which is proven to play a key role in the development of plaque psoriasis,” stated David Epstein, Division Head, Novartis Pharmaceuticals. “This important milestone will now allow patients to receive a treatment that has the proven ability to offer clear or almost clear skin.”
Cosentyx has been approved in Australia for treating moderate-to-severe plaque psoriasis and in Japan for treating moderate-to-severe plaque psoriasis and active psoriatic arthritis.
In addition to psoriasis, Cosentyx is undergoing clinical development for treating PsA and ankylosing spondylitis (AS). Worldwide regulatory applications for secukinumab in AS and PsA are intended for 2015. With marketing clearance for these additional indications, Cosentyx is expected to be a billion-dollar-per-year brand by 2020.
LCZ696 is a twice-daily product being developed for heart failure. The new drug compound acts to enhance the protective neurohormonal systems of the heart (NP system) while simultaneously suppressing the harmful system (the RAAS). Already-marketed drugs for HFrEF only block the harmful effects and mortality remains very high with up to 50% of patients dying within five years of a heart failure diagnosis.
An ARNI (Angiotensin Receptor Neprilysin Inhibitor), LCZ696 has a unique mode of action believed to reduce the strain on a failing heart. The drug harnesses the body’s natural defenses against heart failure, simultaneously acting to enhance the levels of natriuretic and other endogenous vasoactive peptides, while additionally inhibiting the renin-angiotensin-aldosterone system (RAAS).
LCZ696 has been granted Fast Track designation by the U.S. regulatory agency, and the rolling submission was anticipated to be completed by year-end 2014. The Committee for Medicinal Products for Human Use granted accelerated assessment to LCZ696 for patients with heart failure with reduced ejection fraction (HFrEF) in November 2014. Novartis intends to submit the drug for EU marketing authorization during early 2015. The filing is planned to be based on results from the landmark PARADIGM-HF study, the largest ever carried out in heart failure. The study demonstrated that LCZ696 was superior to the ACE-inhibitor enalapril on key endpoints, including significantly reducing the risk of CV death or heart failure hospitalization.
Other successful pipeline-to-market developments for Novartis in January 2015 included positive top-line results from the pivotal Phase III programs for QVA149(indacaterol/glycopyrronium bromide) and NVA237(glycopyrronium bromide) to support New Drug Applications with FDA for the long-term maintenance treatment of chronic obstructive pulmonary disease. The results from the EXPEDITION (including FLIGHT 1, 2 and 3 studies) and GEM clinical programs met their primary and secondary endpoints for each product.
The FLIGHT 1 and 2 trials met their primary objectives with twice-daily QVA149 showing statistically significant and clinically meaningful improvements in lung function (FEV1 AUC0-12) at Week 12, compared to indacaterol and glycopyrronium bromide in moderate-to-severe COPD patients. In the GEM 1 and 2 studies, twice-daily NVA237 showed significant and clinically meaningful improvements in lung function (FEV1 AUC0-12h) at Week 12 in moderate-to-severe COPD patients versus placebo, meeting its primary objective.
Twice-daily QVA149 27.5/12.5 mcg, as used in the EXPEDITION program, is being filed for U.S. approval only. Outside of the United States, QVA149 has been developed and marketed as Ultibro Breezhaler 110/50 mcg, which is a once-per-day maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. Once-daily Ultibro Breezhaler is approved for marketing in more than 50 countries, including in the EU and Latin America, Japan, Canada, Switzerland and Australia.
Twice-daily NVA237 (12.5 mcg, as used in the GEM trials) is also being filed for U.S. registration only. Outside of the United States, NVA237 has been developed/marketed as Seebri Breezhaler 50 mcg, which is a once-daily medication indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. The medicine is approved for use in 70-plus countries, including within the EU and Latin America, Japan, Canada, Switzerland and Australia.
Sonidegib (product code LDE225) in advanced basal cell carcinoma is awaiting U.S. and EU regulatory clearance. The sonidegib regulatory application was filed with FDA during third-quarter 2014 and with EU regulators in second-quarter 2014. The oral, investigational, selective smoothened inhibitor is being studied in various cancers. Smoothened (SMO) is a molecule that regulates the hedgehog (Hh) signaling pathway, which plays a crucial role in stem cell maintenance and tissue repair, as well as in advanced basal cell carcinoma. LDE225 is undergoing clinical development for diseases that include myelofibrosis, leukemia and solid tumors.
Sandoz, a Novartis company, announced in January 2015 that FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended approval of its investigational biosimilar filgrastim. The committee additionally recommended approval of the biosimilar for use in all indications included in label of the reference product, Amgen’s blockbuster medicine Neupogen. The biosimilar application for filgrastim was submitted under the biosimilar pathway created in the Biologics Price Competition and Innovation Act of 2009. Sandoz is the first company to announce a biologic filing via this pathway.
Novartis struck deals during January 2015 with IntelliaTherapeutics for the discovery and development of new medicines using CRISPR genome editing technology and Caribou Biosciences for the development of drug-discovery tools. Intellia and Caribou are two of the leading biotech companies developing this novel technology.
CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is an approach that enables scientists to easily and precisely edit the genes of targeted cells. According to Novartis, in a short amount of time it has proven to be a powerful tool for creating very specific models of disease for use in drug discovery and has great potential as a therapeutic modality for treating disease at the genetic level by deleting, repairing or replacing the genes that cause disease.
The alliance with Intellia unites the resources, research expertise as well as cell and gene therapy leadership at the Novartis Institutes for BioMedical Research with Intellia’s rapidly growing CRISPR expertise and organization. R&D activities will concentrate on using CRISPR ex vivo for engineering chimeric antigen receptor T-cells (CARTs) and hematopoietic stem cells (HSCs). The collaboration and licensing deal is focused on using Caribou’s foundational CRISPR platform and intellectual property as a drug-discovery research tool.
Regarding Intellia, Novartis is receiving exclusive rights to develop all collaboration programs concentrated on engineered CARTs and the right to develop an undisclosed amount of targets for ex vivo editing of HSCs. Novartis gains non-exclusive rights for limited in vivo therapeutic applications of CRISPR systems as well. Novartis is increasing its equity investment in Intellia, making an up-front payment and will provide technology access fees and funding for R&D programs during the five-year period of the collaboration. Intellia is eligible to receive downstream success-based milestones and royalties. Under the terms of the agreement, Novartis is receiving non-exclusive rights to Caribou’s CRISPR platform for research performed during the collaboration and is providing funding for the one-year research program. Novartis is additionally making an equity investment in the company.
In other January 2015 deals, Novartis Pharmaceuticals announced plans to establish a joint investment company with Qualcomm Ventures, the investment arm of Qualcomm Inc. The new venture will target early-stage companies offering technologies, products or services that “go beyond the pill” to benefit physicians and patients. The plan joins together the knowledge of Novartis’ innovation in the R&D and manufacturing of innovative medicines with Qualcomm’s expertise in digital and mobile technologies.
Once the leading force in the pharmaceutical industry, in recent years Pfizer has been viewed less favorably by industry insiders, particularly during the post-Lipitorera. But with a reported $33 billion in cash on the balance sheet as of January 2015, a rapidly growing vaccines business, and a burgeoning pipeline that includes promising oncology medicines, Pfizer is still able to rev up the engine on the fast track amongst the world’s leading healthcare players. As of early November 2014, Pfizer’s R&D programs included 64 new molecular entities, 17 additional indications, and five biosimilars.
That is not to suggest that the New York-based biopharma company has another Lipitor in its pipeline, because how many companies do? The cholesterol-lowering therapy is by far the bestselling prescription drug of all-time, with peak sales of more than $13 billion in 2006. But Pfizer does possess in its clinical-development arsenal some drug compounds for a variety of medical conditions that are expected to generate annual sales exceeding $1 billion.
The company’s promising new product candidates include the cholesterol-reducing agent bococizumab. The large-molecule antibody is being developed as a twice-monthly injection that has demonstrated the ability to lower cholesterol by about 60 percent.
As a statin, Lipitor targets a liver enzyme to inhibit the production of LDL cholesterol, but can stimulate the production of the PCSK9 enzyme as well. PCSK9 binds to a liver’s LDL receptors, throttling the liver’s ability to diminish LDL (‘bad’) cholesterol levels. That has led to the development of a new class of statin drugs known as PCSK9 inhibitors, including bococizumab. The injected drugs are being developed for patients who can not tolerate statins or whose cholesterol cannot be controlled with the older medicines.
Pfizer’s SPIRE-LDL clinical study for bococizumab, which is expected to be the foundation of an eventual BLA submission, is on track to be finished in June 2016. With possible FDA approval in late 2016 or early 2017, bococizumab has potential as a best-in-class therapy and yearly billion-dollar-sales generator. However, bococizumab is expected to face stiff competition from two other monoclonal antibodies/PCSK9 inhibitors – Amgen’s evolocumab and Sanofi/ Regeneron’s alirocumab – which are ahead of the Pfizer compound in terms of clinical development.
Pfizer is developing bococizumab in conjunction withHalozyme Therapeutics and its Enhanze technology. The proprietary delivery platform uses Halozyme’s first approved enzyme, recombinant human hyaluronidase – rHuPH20. This enzyme temporarily degrades hyaluronan, a structural component of the subcutaneous space located just under the outside surface of the human skin. This temporary degradation creates an opportunistic window for the improved subcutaneous delivery of injectable biologics including monoclonal antibodies and other large therapeutic molecules, as well as small molecules and fluids.
News headlines abounded in January 2015 about other drug compounds being developed by Pfizer that target the PCSK9 protein in the form of a pill and vaccine. Pfizer intends to launch a human clinical study during 2015 of the experimental small-molecule pill, which is designed to target the PCSK9 protein. Animal trials of the experimental pill have reportedly shown a substantial reduction in cholesterol.
Pfizer’s developmental PCSK9 vaccine, which is designed to induce the body to produce its own PCSK9 antibodies, is expected to begin human testing in 2016. If successful, the vaccine could eventually be made into a yearly injection.
Ibrance (albociclib) is another anticipated future blockbuster product for Pfizer. The investigational oral targeted agent selectively inhibits cyclin-dependent kinases (CDKs) 4 and 6 to regain cell cycle control and block tumor cell proliferation. Loss of cell cycle control is a hallmark of cancer and CDK 4/6 are overactivated in numerous cancers, resulting in a loss of proliferative control. CDK 4/6 are important regulators of the cell cycle that trigger cellular progression from growth phase (G1) into phases associated with DNA replication (S). CDK 4/6, whose increased activity is frequent in estrogen receptor-positive (ER+) breast cancer (BC), are principal downstream targets of ER signaling in ER+ BC.6 Preclinical data suggest that dual inhibition of CDK 4/6 and ER signaling is synergistic, and it has been demonstrated to halt growth of ER+ BC cell lines in the G1 phase.
Breakthrough Therapy designation from U.S. regulators during April 2013 for the first-line systemic treatment of women with advanced or metastatic ER+, HER2-breast cancer. In October 2014, Pfizer announced FDA’s acceptance of palbociclib’s New Drug Application with Priority Review in combination with letrozole (marketed as Femara) as a first-line treatment for postmenopausal women with ER+, human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who have not received previous systemic treatment for their advanced disease.
In January 2015, Pfizer revealed that FDA’s Oncologic Drugs Advisory Committee had no plans to review the drug, implying that U.S. approval is highly likely. The Prescription Drug User Fee Act (PDUFA) goal date for an FDA decision is April 13, 2015.
Industry analysts have projected that Ibrance could generate $4 billion in sales within five years of marketing clearance and a peak-year total topping $6 billion.
Pfizer is benefitting from the market success ofPrevnar 13 for children to protect against bacterial infections including bacterial meningitis. The blockbuster vaccine is also approved for use in adults 50 years of age and older as well as for use in older children and adolescents aged 6 to 17 years. Pfizer received a positive recommendation from the Centers for Disease Control in August 2014 for administering Prevnar 13 to adults 65 years and older, which would open a whole new market for the vaccine.
In addition to potentially approved new indications for the Prevnar family, Pfizer vaccine pipeline developments include FDA’s accelerated approval ofTrumenba in August 2014. Trumenba is the first approved vaccine in the United States for the prevention of meningococcal meningitis B. The vaccine is intended for active immunization to prevent invasive disease caused by Neisseria meningitidis serogroup B in individuals 10 years through 25 years old.
To improve its vaccine pipeline, Pfizer used some of its bountiful cash flow during January 2015 to acquire a controlling interest in Redvax GmbH. Redvax is a spin-off from Redbiotec AG, a privately held Swiss biopharmaceutical company based in Zurich-Schlieren. This deal provides Pfizer with access to a preclinical human cytomegalovirus
(CMV) vaccine candidate, as well as intellectual property and a technology platform related to a second, undisclosed vaccine program. The CMV vaccine program will complement Pfizer’s robust research portfolio of high-quality and life-saving investigational vaccines and place it among the leaders in CMV R&D. CMV is a herpes virus that infects 50-90% of the adult population, with a majority remaining asymptomatic.
Pfizer and Merck KGaA struck a pact during November 2014 that includes the joint development and commercialization of MSB0010718C. The investigational anti-PD-L1 antibody has been under development by Merck KGaA as a potential treatment for various types of cancer. Pfizer and Merck KGaA are exploring the therapeutic potential of this novel anti-PD-L1 antibody as a single agent as well as in various combinations with the companies’ broad portfolio of approved and investigational oncology therapies.
MSB0010718C is designed to galvanize an immune system attack on tumors by blocking a pathway called PD-1, which, left unchecked, enables cancer cells to pass undetected by the body’s natural defenses. Pfizer is paying Merck KGaA $850 million in advance and up to $2 billion more in regulatory and commercial milestone payments to collaborate on potentially 20 new cancer immunotherapies. The entire class of PD-1 and PD-L1 inhibitors is predicted to generate over $35 billion in peak annual sales.
In January 2015, it was reported that Pfizer and Merck KGaA would not pursue melanoma – regarded as the industry first immuno-oncology target – and instead focus on cancers of the kidney, bladder and lung. “That’s our aim, to be a company that can take part in a share of the first wave, and be among the two or three leaders in the second wave,” Pfizer R&D chief Mikael Dolsten told Bloomberg, also mentioning that the two companies could launch up to six pivotal trials in 2015.
Top-line results were presented by Pfizer during December 2014 from a double-blind Phase III trial evaluating its pregabalin CR formulation in adult patients with postherpetic neuralgia. Pregabalin is the main chemical in Pfizer’s blockbuster medicine Lyrica. Pregabalin CR resulted in a statistically significant positive effect versus placebo in the primary endpoint, time to loss of therapeutic response (LTR) in pain reduction. This study was the final of three Phase III clinical trials of the pregabalin CR formulation conducted to ascertain the potential use of pregabalin as a once-a-day therapy.
Pfizer announced during December 2014 the strategic decision to expand the company’s rare disease R&D activities via the establishment of a gene therapy platform to investigate potential treatments for patients. Pfizer reached a deal with Spark Therapeutics to develop SPK-FIX, a program incorporating a bio-engineered AAV vector for the potential treatment of hemophilia B that is expected to enter Phase I/II clinical studies during first-half 2015. Spark maintains responsibility for clinical development through Phase I/II studies. Pfizer will assume responsibility for pivotal trials, any regulatory approvals and potential worldwide commercialization of the product.
According to EvaluatePharma’s “World Preview 2014, Outlook To 2020” report, the Swiss healthcare giant Roche accounted for three out of the top 20 most valuable R&D projects as of June 2014: RG7446($15.64 billion), lampalizumab ($4.52 billion), andocrelizumab ($2.78 billion). If the three new molecules stayed on their projected clinical development and regulatory approval track, they would produce nearly $5 billion in combined sales during 2020 per the report’s forecasts.
RG7446 (also known as MPDL3280A) is an engineered monoclonal antibody that targets the ligand PD-L1 (programmed death ligand 1) aiming to prevent cancer immune evasion. The anti-PDL1 antibody is designed to make cancer cells more vulnerable to the body’s own immune system by interfering with the PD-L1 protein. Management from Roche company Genentech said they chose to target the PD-L1 protein on tumor cells because this approach has the potential to maximize durable response and allows for the most direct connection to PD-L1 for the purposes of biomarker identification and diagnostic testing. Additionally, they modified the binding region of their antibody to eliminate a process known as antibody-dependent cell-mediated cytotoxicity, or ADCC. This modification could enable enhanced efficacy and safety.
The investigational medicine is being studied for an abundant amount of indications, per Roche’s pipeline posted in October 2014. The indications include solid tumors, alone and in combination with each of Avastin,Tarceva, Zelboraf, and cobimetinib; metastatic urothelial bladder cancer; metastatic non-small cell lung cancer; renal cell cancer in combination with Avastin; and second-line non-small cell lung cancer.
Lampalizumab (anti-Factor D Fab) is a humanized monoclonal antibody fragment that targets complement factor D. The drug compound is designed to inhibit complement activation and chronic inflammation in tissues. Complement factor D belongs to the trypsin family of peptidases and is a component of the alternative complement pathway.
Managed by Genentech Research and Early Development, lampalizumab (product code RG7417) is being developed for geographic atrophy associated with age-related macular degeneration, a progressive condition that can lead to blindness. Roche announced initiation of Phase III trials for lampalizumab as the first potential treatment for geographic atrophy (GA) in September 2014. GA is a severe and advanced form of AMD affecting over 5 million people globally.
Lampalizumab is the first ophthalmic medicine in clinical development that specifically targets Complement factor
D. Complement factor D is a rate-limiting enzyme involved in the activation of the alternative complement pathway (ACP), which is a component of the immune system. Genetic polymorphisms and hyperactivity of the ACP have been implicated in the development of AMD, including GA.
The humanized monoclonal antibody ocrelizumab selectively targets the CD20-positive B-cells implicated in the inflammatory and neurodegenerative processes of multiple sclerosis, to effectively impact disease progression while maintaining immunosurveillance. The investigational medicine is undergoing Phase III trials for primary progressive multiple sclerosis and relapsing multiple sclerosis, with expected regulatory filings occurring in 2015.
Ocrelizumab was formerly developed by Roche and Biogen Idec as a promising treatment for rheumatoid arthritis. In March 2010, the companies announced the suspension of their RA program following the recommendation of the independent Ocrelizumab RA & Lupus Data and Safety Monitoring Board (DSMB) based on their assessment of studies in rheumatoid arthritis and lupus.
During a five-day span in January 2015, Roche announced three transactions expected to help the group’s overall R&D platform moving forward. The three deals broadly encompass the areas of oncology molecular information, bacterial resistance to antibiotics, and neuromuscular disease.
Roche and Foundation Medicine Inc. announced a broad strategic collaboration to further advance FMI’s market-leading position in molecular info and genomic analysis while providing Roche a unique opportunity to optimize the identification and development of novel treatment options for cancer patients. The emerging area of molecular information and genomic analysis will play an increasingly significant role for future medicines and diagnostic solutions, particularly for cancer patients. FMI supports physicians by providing comprehensive molecular info to characterize a tumor that is being matched with approved targeted therapy options and novel treatments being developed. Understanding the comprehensive genomic profile of a cancer patient’s disease will allow for better personalized healthcare solutions to optimize patient treatment outcomes.
Roche is committing to R&D funding of potentially more than $150 million for at least five years and will contribute its expertise and breadth in oncology. FMI will continue to operate independently and contribute its experience in developing comprehensive genomic profiling tests for oncology. The initial focus of the R&D collaboration is the development of genomic profile tests for cancer immunotherapies and for continuous blood-based monitoring.
Roche will be able to use FMI’s proprietary molecular information platform to standardize clinical study testing. This aspect of the relationship is designed to allow for comparability of clinical trial results for R&D purposes, and ultimately in the clinic.
The R&D collaboration and FMI’s current and future tests are anticipated to deliver insights to support development of combination therapies, novel targets, more accurate patient population identification and inclusion in clinical trials, and next-generation companion diagnostics. The plan is to improve decision making and support optimization of patient care as oncology management becomes more complex.
One day after announcing the FMI collaboration, Roche revealed it was teaming up with Meiji Seika Pharma and Fedora to tackle increasing bacterial resistance to antibiotics. The three parties entered into a license pact for the development and commercialization of OP0595, a beta-lactamase inhibitor in Phase I development. Roche obtained global rights from both companies for development and commercialization with the exception of Japan, where Meiji retains sole commercialization rights. Beta-lactamase inhibitors restore or potentiate beta-lactam antibiotic activity. The combination of OP0595 with a betalactam antibiotic targets severe infections resulting from Enterobacteriaceae, including multi-drug-resistant strains.
Meiji and Fedora gain up-front plus development, regulatory and sales event milestone payments amounting potentially up to $750 million. Meiji and Fedora are entitled to receive tiered royalties on sales of products originating from this transaction.
The third aforementioned deal involved the acquisition of Trophos, a privately held biotech company based in Marseille, France. Trophos’ proprietary screening platform generated olesoxime (product code TRO19622), which is being developed for Spinal Muscular Atrophy. SMA is a rare and debilitating genetic neuromuscular disease most commonly diagnosed in children. Pivotal Phase II results with olesoxime in SMA demonstrated a beneficial effect on the maintenance of neuromuscular function in individuals with Type II and non-ambulatory Type III SMA, as well as a reduction in medical complications associated with the disease.
Trophos’ shareholders receive an upfront cash payment of EUR 120 million, and other contingent payments of up to EUR 350 million based on achievement of certain predetermined milestones.
The investigational medicine olesoxime is designed to protect the health of motor nerve cells. Results of a pivotal Phase II trial of olesoxime in Type II and non-ambulatory Type III SMA patients from the ages of 3 years to 25 years were first presented in April 2014 at the 66th American Academy of Neurology. Trophos’ development program was supported by the French Muscular Dystrophy Association. Olesoxime has been granted Orphan Medicinal Product designation for treating SMA by the European Medicines Agency and Orphan Drug Designation by FDA.
Roche announced in October 2014 investments of 3 billion Swiss francs in modern research infrastructure, attractive workplaces and sustainable site development in its Basel, Switzerland site. For a 10-year period, Roche will invest in the construction of a new R&D center for about 1,900 employees, in a state-of-the-art office building for up to 1,700 employees, in upgrading infrastructure, and in renovating the historic office building designed by Otto R. Salvisberg.
Roche’s acquisition of InterMune was finalized in September 2014, adding a new medicine for idiopathic pulmonary fibrosis: Esbriet, which was FDAapproved in October 2014. IPF is a progressive disease that results in scarring of the lungs and has a survival rate of two to three years from diagnosis. Roche successfully issued bonds to the value of $5.75 billion to finance the acquisition.
Brisbane, Calif.-based biotechnology company InterMune has focused on the R&D and commercialization of innovative therapies in pulmonology and fibrotic diseases. The acquisition enables Roche to broaden and strengthen its respiratory portfolio on a worldwide scale. In addition to pirfenidone, InterMune research programs have explored new targets and pathways that may ultimately result in improved treatment options for people with IPF as well as other fibrotic diseases.
Roche generates more sales from biotech medicines than any other company in the world, and the group continues to study its blockbuster portfolio for potential new indications and formulations. At the European Society for Medical Oncology (ESMO) annual congress in September 2014, Roche presented final overall survival data from the Phase III CLEOPATRA trial ofPerjeta in HER2-positive metastatic breast cancer. The results demonstrated that in combination withHerceptin and chemotherapy, Perjeta extended overall survival by 15.7 months, compared with Herceptin and chemotherapy alone. Results of the Phase III coBRIM study, testing the combination of Zelboraf and the Roche investigational MEK inhibitor cobimetinib, in patients with malignant melanoma, demonstrated that treatment with the combination halved the risk of the disease worsening.
Other highlights at ESMO included encouraging data from early phase trials of MPDL3280A in bladder cancer, a disease for which the drug has received FDA Breakthrough Therapy Designation. Positive early data were revealed for anti-PDL1 in combination with Avastin in renal cell carcinoma and other solid tumors. Cancer immunotherapy is a new approach that intends to allow the body’s immune system to fight cancer.
Other positive pipeline news came in two Phase III studies (IMELDA and TANIA) for Avastin in treating HER2-negative breast cancer – the most common form of breast cancer – demonstrating significant improvements in progression-free survival. In Japan,Alecensa (alectinib) was approved for treating ALK-positive non-small cell lung cancer in July 2014, based on the results of a Japanese study. FDA has granted Breakthrough Therapy Designation for alectinib and worldwide studies are under way.
Extensive pharmaceutical business and marketing intelligence. If you would like to purchase a back issue, please contact our customer service department at MDAD@kmpsgroup.com, or call 800-869-6882.
February 2015 Focus: Agenda 2015, Top 10 Pipelines, SFE