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Lilly 2018: Off the roller coaster

Written by: | josh.slatko@medadnews.com | Dated: Tuesday, October 23rd, 2018

 

With new products showing signs of impressive growth, Eli Lilly seems safely past the company’s recent patent trough.

 

lilly-logo

 

Eli Lilly and Co.

Lilly Corporate Center
Indianapolis, IN 46285
Telephone: 317-276-2000
Website: lilly.com

 

Best-Selling Products

Product 2017 Sales 2016 Sales
Humalog

$2,865

$2,769
Cialis

$2,323

$2,472
Alimta

$2,063

$2,283
Trulicity

$2,030

$926
Forteo

$1,749

$1,500
Humulin

$1,335

$1,366
Cyramza

$758

$614
Cymbalta $757 $931
Erbitux

$646

$687
Strattera

$618

$855
Zyprexa

$581

$725
Taltz $559 $113
Trajenta

$538

$437

All sales are in millions of dollars.

 

Financial Performance

  2017 2016
Revenue

$22,871

$21,222

Net income

$(204)

$2,738

Diluted EPS

$(0.19)

$2.58

R&D expense

$5,282

$5,244

  1H 2018 1H 2017
Revenue

$12,055

$11,053
Net income

$958

$897
Diluted EPS

$0.92

$0.85
R&D expense

$2,510

$2,530

All figures are in millions of dollars, except EPS.

 

 

After the loss of patent protection for Zyprexa, Evista, and Cymbalta a few years ago, Lilly executives’ hopes for the future were just that: hopes, nothing more. The company hit a trough in 2014 with revenue down below $20 billion for the first time in seven years. But products like Trulicity, Cyramza, Taltz, and Jardiance were lurking in the pipeline – and last year all of them helped carry Lilly to the company’s best top-line year since 2013, with clear signs of more to come in 2018. The glory days may not entirely be back in Indianapolis – Lilly still has not quite returned to the sales levels of its peak year of 2011 – but company executives can at least sleep at night knowing that the great test is past.

“Lilly’s new products, including Trulicity, Taltz, and Jardiance, continued to drive solid revenue growth in the fourth quarter of 2017, while we maintained flat operating expenses,” says David A. Ricks, Lilly’s chairman and CEO. “Momentum continues for our innovation-based strategy. We recently received approval for Taltz in the U.S. and European Union for active psoriatic arthritis, are encouraged by early use of Verzenio for breast cancer and expect further pipeline progress in 2018 in areas of significant patient need, including cancer, immunologic disorders, diabetes, neurodegeneration and pain.”

Chairman & CEO David A. Ricks: “Lilly’s new products, including Trulicity, Taltz and Jardiance, continued to drive solid revenue growth in the fourth quarter of 2017, while we maintained flat operating expenses.”

Lilly’s top-line revenue was $22.87 billion in 2017, an improvement of 7.8 percent. Net income and earnings per share were in the red – a loss of $204 million and $0.19 respectively – primarily due to a $1.11 billion acquired in-process R&D charge related to the acquisition of CoLucid Pharmaceuticals, $1.67 billion in charges primarily associated with efforts to reduce cost structure, and a $1.91 billion charge related to U.S. tax reform. According to management, without these items the company’s net income would have grown by 21 percent for the year. In the first half of 2018, Lilly’s revenue rose 9.1 percent to $12.06 billion, with net income up 6.8 percent to $958 million and EPS rising seventy cents to $0.92. Lilly executives are projecting that full-year EPS for 2018 will fall between $3.19 and $3.29.

 

Product performance

Remaining atop Lilly’s portfolio in 2017 was the diabetes product Humalog with sales up 3.5 percent to $2.87 billion. According to company leaders, the growth was primarily driven in the United States by higher realized prices due to changes in estimates for rebates and discounts, and outside the United States by increased volume and – to a lesser extent – higher realized prices, partially offset by the unfavorable impact of foreign exchange rates. In the first half of 2018, sales of Humalog rose another 12.6 percent to $1.56 billion, driven by higher realized prices due to changes in estimates to rebates and discounts and changes in payer segment mix, and, to a lesser extent, increased volume. A biosimilar to Humalog, Sanofi’s Admelog, was approved by FDA in December 2017 and launched in April.

Sales of the erectile dysfunction drug Cialis were down 6 percent in 2018 to $2.32 billion, driven by decreased demand partially offset by higher realized prices. Cialis patent protection expired in major European markets in November 2017 and was expected to expire in the U.S. in late September as this magazine was going to press. In first-half 2018, Cialis sales fell another 10.9 percent to $1.03 billion.

Alimta, a treatment for several cancers, generated $2.06 billion in sales for Lilly in 2017, a decline of 9.7 percent. Company leaders say this result was driven by decreased demand due to competitive pressure and loss of exclusivity in several countries. First-half 2018 sales of Alimta edged up by 3.2 percent to $1.06 billion, driven by increased demand and customer buying patterns in the United States and the favorable impact of foreign exchange rates and higher realized prices internationally.

In June, FDA granted approval for a new indication for Alimta in combination with carboplatin and Keytruda for the initial treatment of patients with metastatic nonsquamous non-small cell lung cancer, irrespective of PD-L1 expression status. Under FDA’s accelerated approval regulations, this indication was approved based on tumor response rate and progression-free survival.

Merck won accelerated approval for the combination of Keytruda with Alimta and carboplatin in May 2017. This is the first chemotherapy and immunotherapy combo to earn FDA approval for the first-line treatment of metastatic nonsquamous NSCLC. This indication, now included in the Alimta prescribing information, is based on data from Merck’s KEYNOTE-021 study, Cohort G1.

The type 2 diabetes drug Trulicity enjoyed a solid year in 2017, with sales more than doubling to $2.03 billion, pushed along by increased market share and growth in the glucagon-like peptide-1 (GLP-1) class. In the first half of 2018, Trulicity sales rose another 70.1 percent to $1.46 billion.

Sales of the diabetes product Trulicity more than doubled in 2017 to $2.03 billion.

In February, Lilly announced that Trulicity significantly improved A1C (average blood sugar concentration over two to three months) when added to ongoing treatment with a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, according to results from AWARD-10, a new Phase IIIb clinical study.

At the study’s primary endpoint of 24 weeks, both Trulicity 1.5 milligrams and 0.75 milligrams added to ongoing treatment with an SGLT-2 inhibitor demonstrated statistically superior glycemic control (-1.34 percent, -1.21 percent for Trulicity 1.5 milligrams and 0.75 milligrams, respectively) compared to an SGLT-2 inhibitor with placebo (-0.54 percent). Further, significantly more people in the Trulicity groups reached target A1C levels of less than 7 percent and less than or equal to 6.5 percent. Additional results showed that Trulicity 1.5 milligrams combined with an SGLT-2 inhibitor was associated with greater average weight loss (-3.1 kg) compared to placebo (-2.1 kg). An average weight reduction of -2.6 kg was seen in the Trulicity 0.75 mg group.

In June, Lilly announced that people with type 2 diabetes new to treatment with a GLP-1 receptor agonist had better blood sugar control, were more likely to adhere to treatment, and stayed on treatment longer with once-weekly Trulicity compared to once-daily liraglutide and once-weekly exenatide QW according to real-world data from a restrospective observational study.

The study used U.S. claims data of people with type 2 diabetes newly prescribed Trulicity or either liraglutide or exenatide QW to compare how these treatments performed in a real-world setting. People were matched against key characteristics such as age, gender, location, and baseline A1C to ensure balance in comparing the groups. Trulicity consistently showed advantages across all measures, including A1C reductions, adherence (taking treatment as prescribed) and persistence (staying on treatment).

After six months and one year of treatment, Trulicity provided significantly better glycemic control than liraglutide and better glycemic control than exenatide. Also, after one year patients taking Trulicity were significantly more likely to follow their treatment regimen and less likely to discontinue treatment than with liraglutide or exenatide QW, and patients taking Trulicity had significantly lower rates of discontinuing treatment than those taking liraglutide or exenatide QW.

In July, the U.S. label for Trulicity was updated to show the medicine’s safety and efficacy in people with type 2 diabetes who have moderate to severe chronic kidney disease (CKD). The label now includes data from the AWARD-7 clinical trial, which showed that people treated with Trulicity 1.5 milligrams or 0.75 milligrams in combination with mealtime insulin lispro achieved similar glycemic control with weight loss, compared to those treated with traditional basal-bolus insulin.

The Centers for Disease Control and Prevention estimate that about a third of people with diabetes may develop kidney disease. People with type 2 diabetes and moderate to severe CKD tend to have higher blood sugar levels and more advanced diabetes. Treating this population can be challenging because many diabetes treatments are either contraindicated or require dose adjustments. AWARD-7 was the largest study of its kind for a GLP-1 RA, exclusively enrolling people with type 2 diabetes and late-stage CKD. The positive study results were published online in The Lancet Diabetes & Endocrinology in June.

Forteo, Lilly’s leading osteoporosis product, generated $1.75 billion in sales for the company in 2017, an improvement of 16.6 percent. According to company executives this was driven by higher realized prices and increased volume, primarily due to wholesaler buying patterns. In the first half of 2018, sales of Forteo were down 5.8 percent to $748 million due to decreased demand and lower realized prices.

The diabetes product Humulin was close to static for Lilly in 2017, with sales declining 2.3 percent to $1.34 billion. This was driven primarily by decreased volume and lower realized prices outside the United States. In the first half of 2018, Humulin sales were down 0.5 percent to $672 million.

In June, Lilly announced that Humulin R U-500 administered via an investigational insulin pump (Omnipod U-500 Insulin Management System) provided greater A1C reduction with less daily insulin needed compared to multiple daily injections (MDI) in adults with type 2 diabetes on high dose insulin (201-600 units/day) in the VIVID Phase III study.

At the study’s primary endpoint of 26 weeks, Humulin R U-500 delivered in the investigational pump and through MDI led to A1C reductions from baseline in people with type 2 diabetes (-1.27 percent, -0.85 percent, respectively). Beginning at week eight through the duration of the study, A1C improvement was greater with the pump compared to MDI (-0.42 percent between treatment groups at the primary endpoint). Humulin R U-500 delivered in a pump also led to lower total daily insulin dose compared to MDI (difference of -0.47 units/kg at the primary endpoint).

The oncology drug Cyramza had a solid year in 2017, with sales up 23.5 percent to $758 million, driven in particular by strong volume growth in Japan. In the first half of 2018, Cyramza sales rose another 12.3 percent to $402 million. 

Sales of Cyramza were up by nearly a quarter in 2017; during April 2018, Lilly announced Phase III study results for the drug in urothelial and hepatocellular carcinomas.

In April, Lilly announced additional results from the global, randomized, double-blind, placebo-controlled Phase III RANGE trial evaluating Cyramza in combination with docetaxel in patients with locally advanced or unresectable or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. A positive trend was seen in the secondary endpoint of overall survival which did not reach statistical significance. An improvement in objective response rate was observed.

RANGE is the only Phase III study to demonstrate superior PFS compared to chemotherapy in a post-platinum setting in advanced urothelial carcinoma. Additionally, RANGE is the first Phase III trial to show the benefit of targeting angiogenesis in urothelial carcinoma.

Also in April, Lilly announced top-line results from the Phase III REACH-2 study of Cyramza as a single agent in the second-line treatment of people with hepatocellular carcinoma, also known as liver cancer. The trial met the primary endpoint of overall survival as well as the secondary endpoint of progression-free survival. Cyramza has now demonstrated a survival benefit in four aggressive, difficult-to-treat tumor types in Phase III studies, including as a single agent in gastric cancer and HCC.

With this positive outcome, the REACH-2 study has confirmed the hypothesis generated by the REACH trial results, which showed that a pre-specified subgroup of advanced HCC patients who were AFP-High derived a survival benefit from treatment with Cyramza following first-line treatment with sorafenib. This REACH-2 outcome also builds upon Lilly’s efforts and commitment to providing treatment options for people living with HCC and gastrointestinal cancers. In addition to the Phase III REACH and REACH-2 trials, Lilly is evaluating Cyramza with an immuno-oncology agent in HCC in a Phase 1b study cohort, and is conducting various studies of Cyramza in other gastrointestinal cancers, including gastric, colorectal and biliary tract.

The most impressive grower in Lilly’s portfolio in 2017 was the autoimmune product Taltz, sales of which rose from $113 million to $559 million. In the first half of 2018, Taltz sales rose another 56.1 percent to $367 million. Taltz is approved for the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis.

In February, Lilly announced that Taltz met the primary and all key secondary endpoints in

Taltz sales grew by nearly five times in 2017 to $559 million; during May 2018, FDA approved a label update to include data in psoriasis involving the genital area.

COAST-V, a Phase III study evaluating the safety and efficacy of the drug for the treatment of ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis (axSpA). Taltz demonstrated a statistically significant improvement in the signs and symptoms of AS, as measured by the proportion of patients who achieved Assessment of Spondyloarthritis International Society 40 (ASAS40) response at 16 weeks, when compared to placebo. COAST-V is the first registration trial to use ASAS40 as the primary endpoint, compared to the standard endpoint of ASAS20.

During May, FDA approved a label update for Taltz to include data in psoriasis involving the genital area. Taltz is the first treatment approved by FDA for moderate-to-severe plaque psoriasis that includes such data in its label.

The label update was based on positive results from the first randomized, double-blind, placebo-controlled study in moderate-to-severe psoriasis involving the genital area. Taltz demonstrated a significant improvement compared to placebo at 12 weeks in the severity of psoriasis affecting the genital area, as measured by sPGA of genitalia score; overall psoriasis, as measured by sPGA score; genital itch, as measured by the Genital Psoriasis Symptoms Scale (GPSS) Itch numeric rating scale (NRS); and in the patient-perceived impact of psoriasis involving the genital area on frequency of sexual activity, as measured by Sexual Frequency Questionnaire (SFQ) Item 2 score.

In June, Lilly announced that Taltz met the primary and major secondary endpoints in COAST-W, a Phase III study evaluating the safety and efficacy of Taltz for the treatment of ankylosing spondylitis. This is the first AS study focusing on a difficult-to-treat population of patients who had an inadequate response to one or two tumor necrosis factor (TNF) inhibitors (90 percent of enrolled patients) or intolerance to a TNF inhibitor (10 percent).

Taltz demonstrated a statistically significant improvement in the signs and symptoms of AS, as measured by the proportion of patients who achieved Assessment of Spondyloarthritis International Society 40 (ASAS40) response at 16 weeks, when compared to placebo. COAST-W is part of the clinical development program for Taltz in AS, the first to use ASAS40 across the program as the primary endpoint to define treatment success, rather than the traditionally used endpoint of ASAS20. Based on the positive results from the COAST-V and COAST-W studies, Lilly plans to submit for U.S. regulatory approval in AS later this year.

AS is one type of spondyloarthritis that affects the pelvic joints and spine, and can be characterized by chronic inflammatory back pain, stiffness and impaired function and mobility. Of those affected by AS, approximately 80 percent will experience symptoms before age 30.

In September, Lilly announced the initiation of the IXORA-R head-to-head clinical trial, designed to evaluate superiority between Taltz and Tremfya in adult patients with moderate-to-severe plaque psoriasis. The IXORA-R study will be the first H2H trial between an IL-17 and IL-23 using the Psoriasis Area Severity Index (PASI) 100 score as the primary endpoint.

The IXORA-R study, which is set to be completed by the end of 2019, aims to enroll 960 patients and is a 24-week multicenter, randomized, blinded, parallel-group study comparing the efficacy and safety of Taltz to Tremfya in patients with moderate-to-severe plaque psoriasis. The primary endpoint of the study is the proportion of patients who achieve 100 percent improvement from their baseline as measured by PASI 100 at week 12. Secondary endpoints include: the proportion of patients achieving PASI 75 as early as week 2 and PASI 100 at weeks 4, 8 and 24; and the proportion of patients achieving a Static Physician Global Assessment (sPGA) score of 0 at week 12.

IXORA-R is part of the expansive clinical development program for Taltz in psoriatic disease. In addition to IXORA-R, SPIRIT-H2H is a head-to-head clinical trial comparing Taltz to Humira in adult patients with psoriatic arthritis, which is scheduled to be completed in early 2019.

The Taltz safety profile has been studied in 12 clinical trials in moderate-to-severe plaque psoriasis with a total exposure of more than 15,000 patient-years and four clinical trials in psoriatic arthritis with more than 1,300 patient-years as part of the Taltz clinical trial program.

Trajenta, for type 2 diabetes, generated $538 million in sales for Lilly in 2017, an improvement of 23.1 percent. In the first half of 2018, sales of Trajenta rose another 11 percent to $283 million.

The diabetes product Jardiance did n0t quite reach the $500 million mark in 2017, but sales did more than double from $202 million to $448 million. First-half 2018 sales rose another two-thirds to $298 million. In March, Lilly and Boehringer Ingelheim announced plans to expand their clinical trial program for Jardiance in chronic heart failure with the EMPERIAL clinical trials. These trials will evaluate the effect of Jardiance on exercise ability and heart failure symptoms in people with chronic heart failure independent of whether they have type 2 diabetes. EMPERIAL comprises two Phase III trials that will assess the effect of 12 weeks of treatment with Jardiance on the ability of people with heart failure to perform daily exercise.

The plans for the EMPERIAL trials follow initiation of the EMPEROR studies in March 2017. While the EMPEROR outcome trials focus on long-term morbidity and mortality outcomes in people with heart failure, the EMPERIAL functional studies will investigate possible benefits on exercise capacity and heart failure symptoms. These studies are based on data obtained from the landmark EMPA-REG OUTCOME trial, where the effect of Jardiance on heart failure outcomes was evaluated.

In June, Lilly and Boehringer Ingelheim announced findings from two new analyses of the landmark EMPA-REG OUTCOME trial. Results included a post-hoc analysis demonstrating consistent effects for Jardiance versus placebo on renal outcomes in patients with established cardiovascular (CV) disease and type 2 diabetes, irrespective of control of certain CV risk factors. This new post-hoc analysis of the EMPA-REG OUTCOME trial showed Jardiance consistently reduced the risk of new or worsening kidney disease versus placebo irrespective of control of blood pressure, low-density lipoprotein (LDL) cholesterol or A1C levels, individually or combined. Control of these measures was defined as systolic blood pressure below 140 mmHg, LDL cholesterol under 100 mg/dL and A1C levels below 7.5 percent.

In a separate presentation, the effect of Jardiance versus placebo on CV outcomes was examined in a post-hoc analysis of sub-groups of EMPA-REG OUTCOME defined by CV risk at trial start – low, intermediate, high, and highest risk (per the 10-point TIMI Risk Score for Secondary Prevention). The findings demonstrated consistent reductions in the risk of CV death with Jardiance compared with placebo independent of CV risk group. Similar consistency in the effects of Jardiance among CV risk groups was seen for reduced risk for hospitalization for heart failure and for the combination of hospitalization for heart failure or CV death.

 

Acquisitions and collaborations

Lilly and Livongo Health, a consumer digital health company focused on empowering all people with chronic conditions to live better and healthier lives, announced a strategic collaboration in January. Lilly and Livongo agreed to study real-world evidence and develop new insights to reduce the burden on people living with diabetes. The research collaboration will combine real-world behavioral studies and claims data to advance knowledge about effective interventions in diabetes care. The companies aim to contribute to medical literature in three areas: measuring the impact of remote diabetes self-management education and support on clinical and healthcare cost outcomes; understanding drivers of healthy behaviors; and understanding how people living with diabetes can stay more actively involved in their health. Livongo and Lilly aim to publish the results of their collaborative research studies to further advance diabetes care for people worldwide.

Lilly, the European Foundation for the Study of Diabetes, and the JDRF agreed in March to extend their collaboration for the European Program in Type 1 Diabetes Research through 2020. The program, which began in 2015, encourages research that advances knowledge about type 1 diabetes by providing grants up to €100,000 to nonprofit institutions and groups in Europe. Nineteen research grants including, but not limited to, research in beta cell biology and regeneration, autoimmunity/immunoregulation, novel concepts and biomaterials for beta cell replacement, and novel therapies for improved glycemic control, have been awarded to institutions and groups across Europe since 2015.

With these research grants, the organizations hope to build upon the goals of the program to promote and support high-quality biomedical and clinical type 1 diabetes research, expedite the practical application of scientific advances, and encourage clinical translation of research in Europe. The organizations also hope to increase awareness of type 1 diabetes research in the region.

In April, Lilly and China’s National Center for Cardiovascular Diseases (NCCD) announced plans to collaborate across four strategic initiatives to advance the scientific understanding of type 2 diabetes and related complications, such as cardiovascular disease, and improve care for people living with the condition. In China, the number of people with diabetes has increased from more than 1 percent of the population in 1980 to nearly 11 percent in 2017. The sharp increase in diabetes, including type 2 diabetes, has resulted in increased complications, such as CVD. In addition, rates of pre-diabetes continue to climb across the globe, including in China, where more than 1 in 3 people have pre-diabetes. Less than one-third of people with diabetes receive treatment.

As a response to this national epidemic, company leaders say the collaboration will evaluate the health economic consequences of diabetes in China; develop a simple cardiovascular disease (CVD) risk calculator to improve screening and diabetes management at the primary care level; analyze patient samples to identify new biomarkers for diabetes progression, diabetic kidney diseases (DKD), and CVD; and develop and distribute medical education for health care professionals treating diabetes related CVD in China.

The collaboration will leverage data collected by the Patient-centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project, which is the first large-scale epidemiological screening in China. The PEACE Million Persons Project will provide access to data from more than 1 million people with type 2 diabetes and increased CVD risk.

Also in April, Lilly and Boehringer Ingelheim announced an academic collaboration with the University of Oxford to investigate the effects of Jardiance on the progression of kidney disease and the occurrence of cardiovascular death, in adults with established chronic kidney disease with and without diabetes. EMPA-KIDNEY will be independently conducted, analyzed and reported by the Medical Research Council Population Health Research Unit at the University of Oxford (MRC PHRU), which is based in the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), in partnership with the Duke Clinical Research Institute. Boehringer Ingelheim and Lilly will provide the funding for the study.

The plan to conduct a dedicated outcomes study in adults with chronic kidney disease is based on insights previously obtained from the EMPA-REG OUTCOME trial. This landmark trial investigated the effect of Jardiance, when added to the standard of care, on cardiovascular outcomes in adults with type 2 diabetes and established cardiovascular disease, compared with placebo. About one-third of patients in the EMPA-REG OUTCOME trial also had established chronic kidney disease at baseline. A secondary exploratory endpoint of the study provided promising data relating to the reduction in the relative risk of new onset or worsening kidney disease. EMPA-KIDNEY will help further   understanding of these data.

Also in April, Lilly and Sigilon Therapeutics announced a global collaboration to develop encapsulated cell therapies for the potential treatment of type 1 diabetes. Sigilon is a privately held biopharmaceutical company that is focused on discovering and developing “living therapeutics” with its Afibromer technology product platform.

Encapsulated cell therapy is an emerging area of biopharmaceutical research that aims to take advantage of the therapeutic potential of cells to treat serious diseases without the need for immunosuppression. This approach, company leaders say, holds promise to address chronic conditions, such as type 1 diabetes. In type 1 diabetes, pancreatic beta cells are destroyed by the immune system, leading to hyperglycemia (high blood sugar) and long-term complications if glucose levels are not managed effectively.

In the Lilly-Sigilon collaboration, Sigilon will create proprietary products composed of induced pluripotent stem cells, a type of stem cell derived from adult cells, engineered into differentiated insulin-producing pancreatic beta cells and encapsulated using Sigilon’s Afibromer technology. The goal of these products will be to restore insulin production over sustained periods, without triggering an immune reaction.

Under the terms of the agreement, Lilly will receive an exclusive worldwide license to Sigilon’s Afibromer technology for islet cell encapsulation. Sigilon will receive an upfront payment of $63 million and Lilly will make an undisclosed equity investment in Sigilon. Sigilon is also eligible to receive up to $410 million in development and commercialization milestones, as well as single to double digit tiered royalties on future product sales should the collaboration yield a commercially successful product. Sigilon is responsible for all development activities and costs related to the collaboration until submission of an investigational new drug application. After an IND is submitted, Lilly is responsible for all clinical development and commercialization activities and costs related to the collaboration.

In May, Lilly agreed to acquire ARMO BioSciences Inc. for $50 per share, or about $1.6 billion, in an all-cash transaction. ARMO BioSciences is a late-stage immuno-oncology company that is developing a pipeline of novel, proprietary product candidates designed to activate the immune system of cancer patients to recognize and eradicate tumors. The deal duly closed in June.

This acquisition, company leaders say, bolsters Lilly’s immuno-oncology program through the addition of ARMO’s lead product candidate, pegilodecakin, a PEGylated IL-10 that has demonstrated clinical benefit as a single agent, and in combination with both chemotherapy and checkpoint inhibitor therapy, across several tumor types. Pegilodecakin is being studied in a Phase III clinical trial in pancreatic cancer, as well as earlier-Phase trials in lung and renal cell cancer, melanoma, and other solid tumor types. ARMO also has a number of other immuno-oncology product candidates in various stages of pre-clinical development.

Also in May, Lilly agreed to acquire AurKa Pharma Inc., a company established by TVM Capital Life Science to develop the oncology compound AK-01. The Aurora kinase A inhibitor AK-01 was originally discovered at Lilly. The compound is a potential first-in-class asset that AurKa Pharma is studying in Phase I clinical trials in multiple types of solid tumors.

Aurora kinases are believed to play a crucial role in cellular division by controlling chromosomal segregation. Defects in segregation can cause genetic instability, a condition highly associated with the formation of tumors. Aurora kinases, consisting of Aurora A, Aurora B and Aurora C, are key mitotic regulators required for genome stability and are frequently overexpressed in cancerous tumors. AurKa Pharma’s asset, AK-01, has been shown to be highly selective for Aurora A, with potential clinical benefit observed in Phase I trials. Future studies will seek to determine if the selectivity profile of AK-01 can improve efficacy while limiting toxicity risks to a manageable level.

After a review of clinical pipeline priorities in 2016, Lilly sold the compound to TVM Capital Life Science, which then established AurKa as part of the TVM Life Science Ventures VII fund. The fund is a novel investment model that seeks to develop early-stage pharmaceutical assets in a capital-efficient manner.

During July, Lilly announced a three-year extension of its cancer research collaboration with Dana-Farber Cancer Institute. Since 2015, scientists from Lilly and Dana-Farber have been working together on pre-clinical and clinical studies, molecular analyses of patient samples and the design and conduct of clinical trials to help advance cancer care.

During the first three years of the collaboration, Lilly has been allowed access to expertise within Dana-Farber to further develop multiple pre-clinical and clinical compounds in Lilly’s product pipeline, including new indications, novel combinations and biomarker strategies. This collaboration, company leadership says, has fostered fresh ideas, strong communication and important feedback in pre-clinical and clinical study design, process and execution.

Under the agreement, Dana-Farber researchers were, and will continue to be, granted permission to conduct independent pre-clinical and clinical studies on select Lilly compounds. All compounds evaluated through this collaboration will continue to be fully owned by Lilly. Financial terms of the agreement were not disclosed.
In September, Lilly and the Indiana Biosciences Research Institute (IBRI), in collaboration with Indiana University School of Medicine, created the Lilly Diabetes Center of Excellence (LDCE), which aims to establish a nexus of strategically aligned basic diabetes research operations in Indianapolis.

The LDCE will recruit high-potential and established principal investigators (PIs) who aim to pursue cutting-edge research in diabetes, diabetic complications, and related metabolic disorders. The PIs will receive five-year sponsored appointments at the IBRI, subsidized by Lilly, and faculty appointments at IU School of Medicine. Each appointed PI will pursue their area of research with full academic freedom. Lilly will provide opportunities for close collaborations, including access to drug discovery tools and expertise, to allow faculty to rapidly explore the translational potential of their research. The LDCE will also serve as a bridge between academia and industry by providing opportunities for interaction, training, and mentoring across the IBRI, Lilly, and IU School of Medicine.

“Building on Lilly’s nearly 100 years of heritage of diabetes research, we seek to spearhead innovative research right here at home in Indiana,” says Ruth Gimeno, Ph.D., VP of diabetes and complications at Lilly. “Lilly is excited to join forces with the IBRI and IU School of Medicine on this important initiative to advance diabetes research for the millions who are suffering from this chronic disease.”

 

In the pipeline

FDA approved Verzenio (abemaciclib) during February in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. This FDA approval marked the third indication for Verzenio within five months. In September 2017, Verzenio became the first cyclin-dependent kinase (CDK)4 and 6 inhibitor approved in combination and as a single agent in metastatic breast cancer. Specifically, Verzenio was approved for use in combination with fulvestrant for the treatment of women with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy, and as monotherapy for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

The latest approval of Verzenio as initial therapy in combination with an AI was based on the efficacy and safety demonstrated in the pivotal MONARCH clinical trial. MONARCH 3 is a Phase III, randomized, double-blind, placebo-controlled study evaluating Verzenio in combination with an AI as initial endocrine-based therapy that enrolled 493 postmenopausal women with HR+, HER2- advanced breast cancer who had no prior systemic treatment for advanced disease.

In MONARCH 3, Verzenio dosed orally at 150 milligrams twice daily on a continuous schedule with an AI demonstrated a greater than 28-month median progression-free survival in patients who received initial endocrine-based therapy for metastatic disease (28.2 months versus 14.8 months with placebo plus an AI). In patients with measurable disease who received Verzenio plus an AI, an objective response rate of 55.4 percent was achieved, with 52.1 percent of patients having achieved a partial response and 3.4 percent having achieved a complete response.
In comparison, in the placebo-plus-AI group of patients with measurable disease, ORR was 40.2 percent, with all women being partial responders. Median duration of response was 27.4 months with Verzenio plus an AI versus 17.5 months with placebo plus an AI.

During June, Lilly announced results from a post-hoc analysis that demonstrated efficacy of Emgality (galcanezumab-gnlm) in patients with episodic and chronic migraine who had previously failed preventive treatment with Botox. In the subgroup analysis, patients treated with both doses of Emgality who previously failed preventive treatment with Botox experienced a statistically significantly greater reduction in the average number of monthly migraine headache days, and a statistically significantly greater percent (at least a 50 percent) reduction in the number of migraine headache days, compared to patients treated with placebo. Emgality is a once-monthly, self-administered calcitonin gene-related peptide antibody currently under review by FDA for the prevention of migraine in adults. A decision was expected by the end of September 2018.

Also in June, Lilly announced that its ultra rapid lispro (URLi) led to improved and sustained blood sugar control after meals in people with type 1 and type 2 diabetes, according to results from three Phase Ib studies evaluating URLi compared to Humalog. Two of the studies evaluated URLi administered through multiple daily injections in people with type 1 and type 2 diabetes to understand the differences in the pharmacokinetics (the amount of insulin in the blood) and pharmacodynamics (how insulin works to control blood glucose levels) between URLi and Humalog. The third study evaluated URLi delivered through an insulin pump in people with type 1 diabetes. Across all three studies, URLi was absorbed faster than Humalog, which led to improved post-meal blood sugar control that was sustained over time. URLi is undergoing Phase III studies in people with type 1 and type 2 diabetes. These trials are expected to complete during 2018.

Humalog sales continued to rise in the first half of 2018 but the product is now competing with a biosimilar, launched this past April.

Additionally in June, Lilly and partner developer AstraZeneca discontinued the global Phase III trials of lanabecestat, an oral beta secretase cleaving enzyme (BACE) inhibitor for treating Alzheimer’s disease. The decision was based on recommendations by an independent data monitoring committee which concluded that the AMARANTH trial, in early Alzheimer’s disease, and the DAYBREAK-ALZ trial, in mild Alzheimer’s disease dementia, were not likely to meet their primary endpoints upon completion and therefore should be stopped for futility.

As a result of this decision, the related AMARANTH extension trial will also be discontinued. The IDMC recommendation to stop the studies was not based on safety concerns.

The Lilly and AstraZeneca BACE Alliance for lanabecestat remains in place, and the companies are working with the clinical trial sites involved to implement the discontinuations.

Also in June, FDA approved the 2-milligram dose of Olumiant (baricitinib), a once-daily oral medication for the treatment of adults with moderately-to-severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) inhibitor therapies.

The Olumiant clinical trial program included RA-BEACON, a randomized, double-blind placebo-controlled study in which patients were randomly assigned to receive Olumiant 2 milligram, baricitinib 4 milligram, or placebo, in addition to conventional DMARDs that they were currently using. This study included 527 patients who had an inadequate response or intolerance to one or more TNF inhibitor therapies. Patients could have had prior therapy with other bDMARDs.

The study results showed that significantly higher ACR20 response rates and improvement in all individual ACR20 component scores were observed at Week 12 with Olumiant. The study found that patients treated with Olumiant had significantly higher rates of ACR20 response versus placebo-treated patients at Week 12 (49 percent of Olumiant-treated patients versus 27 percent of placebo-treated patients). Olumiant also demonstrated early symptom relief, with ACR20 responses seen as early as Week 1. Patients treated with Olumiant reported significant improvements in physical function based on the Health Assessment Questionnaire Disability Index (HAQ-DI) (recording an average score of 1.71 before treatment and 1.31 at Week 12) compared to placebo-treated patients (who recorded an average score of 1.78 before treatment and 1.59 at Week 12).

In July, Lilly and partner developer Incyte Corp. announced that results of a global systemic lupus erythematosus (SLE) Phase II study for Olumiant were published by The Lancet. The study, the first completed Phase II study of a JAK inhibitor in SLE, showed that a statistically significant proportion of patients treated with 4 milligrams of baricitinib achieved resolution of their SLE-related arthritis or rash compared to placebo at week 24, the primary endpoint for the trial.

In the study, 314 patients were randomized 1:1:1 to receive placebo, baricitinib 2 milligrams, or baricitinib 4 milligrams. Patients treated with 4 milligrams of baricitinib experienced improvements compared to placebo on several pre-specified secondary endpoints. Compared to placebo, a statistically significant greater proportion of patients treated with 4 milligrams of baricitinib experienced lower overall disease activity at week 24 as measured by the SLE Responder Index 4 (SRI-4).

A statistically significant greater proportion of patients treated with 4 milligrams of baricitinib achieved a state of low disease activity, as measured by the Lupus Low Disease Activity State, and experienced improvements in pain from baseline, two exploratory endpoints of the study. Lilly plans to initiate Phase III trials to evaluate the safety and efficacy of baricitinib for the treatment of SLE in the second half of 2018.

Also in July, Lilly and partner developer Pfizer Inc. announced that a 16-week Phase III study in patients with osteoarthritis (OA) pain evaluating subcutaneous administration of tanezumab, an investigational humanized monoclonal antibody, met all three co-primary endpoints. The study demonstrated that patients who received two doses of tanezumab separated by eight weeks experienced a statistically significant improvement in pain, physical function and the patients’ overall assessment of their OA, compared to those receiving placebo. Tanezumab is part of an investigational class of pain medications known as nerve growth factor (NGF) inhibitors and in addition to OA pain, is being evaluated for chronic low back pain (CLBP) and cancer pain (due to bone metastases). FDA granted Fast Track status to tanezumab for the treatment of OA pain and CLBP in June 2017.

In September, Lilly and the company’s wholly owned subsidiary Avid Radiopharmaceuticals Inc. announced that a Phase III study of flortaucipir F 18, a Positron Emission Tomography (PET) imaging agent, met its two primary endpoints, defined as predicting brain tau pathology and predicting Alzheimer’s disease diagnosis.

The study, referred to as A16, enrolled a total of 156 end-of-life patients with dementia, mild cognitive impairment, or normal cognition who underwent flortaucipir PET imaging. Subsequently, 67 of these patients were evaluated post-mortem. The study met pre-specified endpoints with flortaucipir demonstrating statistically significant sensitivity and specificity for detecting tau pathology of Braak Stage V/VI, a pathological staging scale for tau neurofibrillary tangles.

Flortaucipir showed statistically significant sensitivity and specificity for detecting a high level of total Alzheimer’s disease neuropathologic change (combining both tau and amyloid plaque densities), using the National Institute on Aging and Alzheimer’s Association (NIA-AA) neuropathology criteria.

 

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