Lilly: Nowhere But Up
Lilly Corporate Center
Indianapolis, IN 46285
Telephone: 317-276-2000
Website: lilly.com
Best-Selling Products
| Product | 2014 Sales | 2013 Sales |
|---|---|---|
| Alimta |
$2,792 |
$2,703 |
| Humalog |
$2,785 |
$2,611 |
| Cialis |
$2,291 |
$2,159 |
| Cymbalta |
$1,615 |
$5,084 |
| Humulin |
$1,400 |
$1,316 |
| Forteo |
$1,322 |
$1,245 |
| Zyprexa |
$1,037 |
$1,195 |
| Strattera |
$738 |
$709 |
| Effient |
$522 |
$509 |
All sales are in millions of dollars.
Financial Performance
| 2014 | 2013 | |
|---|---|---|
| Revenue |
$19,616 |
$23,113 |
| Net income |
$2,391 |
$4,685 |
| Diluted EPS |
$2.23 |
$4.32 |
| R&D expense |
$4,734 |
$5,531 |
| 1H15 | 1H14 | |
|---|---|---|
| Revenue |
$9,623 |
$9,619 |
| Net income |
$1,130 |
$1,461 |
| Diluted EPS |
$1.06 |
$1.36 |
| R&D expense |
$2,209 |
$2,305 |
In millions of dollars, except EPS
The leaders at Eli Lilly saw the storm coming back in 2009. In the five-year period ahead, the company was due to lose a third of its revenue to expiring patents, with the trough to come in — you guessed it — 2014. And so they planned, and managed expectations, accordingly.
So far, so good. The company aimed for $20 billion-plus in revenue and $3 billion-plus in net income every year through 2013 — check. Management targeted having at least 10 compounds in Phase III testing by the end of 2011 — check, with 13 by the end of 2013, plus four new approvals in 2014 and other new compounds pending approval. And Lilly aimed to drive underlying growth in key areas such as animal health, Japan, and emerging markets — check, check, and check. Even more impressive, investors have been trusting the plan even as the company’s revenue has dropped. When Lilly announced its lean-times strategy back at the end of 2009, the company’s stock was at about $35 per share. As of this writing, it’s just north of $84.
“As we stand today, following our toughest year, this much is clear: We are emerging … as an independent company charting our own destiny, launching new products, and competing more effectively, and in possession of one of the strongest pipelines in our history,” says Lilly CEO, chairman, and president John C. Lechleiter, Ph.D. “New Lilly medicines are helping more and more patients suffering from the ravages of cancer and diabetes — and we’ll be touching even more in the months and years ahead.”
Lilly’s top-line revenue for 2014 totaled $19.62 billion, down 15.1 percent compared with the previous year, mostly due to the patent expiration of Cymbalta. Net income for the year fell by nearly half to $2.39 billion, and diluted earnings per share dropped by $2.09 from the 2013 total to $2.23. R&D expense for the year was down 14.4 percent to $4.73 billion. As company leaders had hoped, it appears that the numbers are beginning to stabilize this year; in the first half of 2015, total revenue was nearly static at $9.62 billion, though net income dropped 22.7 percent to $1.13 billion and adjusted EPS shed 30 cents to $1.06. R&D expense during the first half was down 4.2 percent to $2.21 billion. Company leaders are expecting earnings per share for full-year 2015 to fall between $2.20 and $2.30.
Acquisitions and partnerships
During September 2014, Eli Lilly and AstraZeneca announced an agreement to jointly develop and commercialize AZD3293, an oral beta secretase cleaving enzyme (BACE) inhibitor in development as a potential treatment for Alzheimer’s disease.
The progression of Alzheimer’s disease is characterized by the accumulation of amyloid plaque in the brain. BACE is an enzyme associated with the development of beta-amyloid. Inhibiting BACE is expected to prevent the formation of amyloid plaque and eventually slow the progression of the disease.
AZD3293 is an oral potent small molecule inhibitor of BACE that has been shown in Phase I studies to reduce levels of beta-amyloid in the cerebro-spinal fluid of Alzheimer’s patients and healthy volunteers. AstraZeneca announced earlier in 2014 its plan to move AZD3293 into registration trials.
AstraZeneca and Lilly aimed to progress AZD3293 rapidly into a Phase II/III clinical trial in patients with early Alzheimer’s disease – the first patient was enrolled in such a trial three months after the co-development agreement was announced. Lilly will lead clinical development, working with researchers from AstraZeneca’s Innovative Medicines Unit for neuroscience, while AstraZeneca is responsible for manufacturing. The companies will take joint responsibility for commercialization of AZD3293. The companies will share all future costs equally for the development and commercialization of AZD3293, as well as net global revenues postlaunch.
In October 2014, Boehringer Ingelheim and Lilly announced changes to the operational and financial structure of their diabetes alliance in certain countries. Under the revised agreement, 17 countries representing more than 90 percent of the alliance’s anticipated market opportunity will continue their c0-promotion work. In all other countries, the companies will exclusively commercialize the respective molecules they brought to the alliance. The changes were to be implemented starting Jan. 1, 2015. The Lilly/BI alliance dates to January 2011 and is responsible for five marketed products (Trajenta, Jardiance, Jentadueto, Glyxambi, and Synjardy) as well as an insulin glargine product that has been approved in Europe and tentatively approved in the United States.
The scope of the alliance will remain unchanged in the following 17 countries: United States, Germany, Italy, Spain, France, United Kingdom, Republic of Ireland, Portugal, Canada, Japan, China, Australia, New Zealand, South Korea, Taiwan, Brazil, and Mexico. Under a revised agreement, Boehringer Ingelheim and Lilly will exclusively commercialize the respective molecules they brought to the alliance in all other countries under revised financial terms that will include an upfront payment and ongoing payments paid to Lilly in lieu of commission payments in those markets.
Also in October 2014, Lilly and Zymeworks Inc. announced the expansion of their existing licensing and collaboration agreement. Originally announced in January 2014, the global strategic collaboration is focused on the development of an undisclosed number of novel bi-specific antibody therapeutics using Zymeworks’ proprietary Azymetric platform. Lilly is opting to expand the collaboration by up to $375 million in milestones and other payments, plus tiered sales royalties based on country-by-country intellectual property, and sales to include development of several immuno-modulatory bi-specific antibodies against multiple targets. Zymeworks received an initial upfront payment in the form of an equity investment. The majority of financial terms consist of potential milestone payments contingent on the achievement of certain development and commercial milestone events predominantly focused on the United States, Japan, and global sales. Bi-specific antibodies have the potential to provide improved outcomes for patients by simultaneously targeting two proteins resulting in additive or synergistic responses.
In December, Lilly and Adocia announced a worldwide licensing collaboration focused on developing an ultra-rapid insulin, known as BioChaperone Lispro, for treatment in people with type 1 and type 2 diabetes. BioChaperone Lispro relies on Adocia’s proprietary BioChaperone technology and is currently in Phase Ib studies.
Lilly and Adocia will develop BioChaperone Lispro with the goal of optimizing glucose levels during and after meals. Potential benefits of BioChaperone Lispro include greater flexibility in the timing of insulin injections, lower variability of post-meal blood glucose elevations, lower rates of hypoglycemia, and better overall glucose control.
Also in December, Lilly announced a five-year research partnership with the University of Surrey to study health outcomes, focusing on the effects of treatment in people with type 2 diabetes, which affects about 95 percent of those with the disease. Using real-world evidence (routine data gathered from patients undergoing diabetes treatments), Lilly and the University of Surrey are focused on developing answers to commonly asked clinical questions about the continuum of diabetes care, such as the role and timing of injectable therapy, factors impacting adherence to prescribed medicines, and the pattern and rationale of therapy following diagnosis.
Initially the Lilly-Surrey collaboration will focus on several key questions. These will include why some people follow their diabetes treatment plan while others do not, what role healthcare providers play in improving adherence rates, and what the barriers and the long-term effects are for those who do not adhere to their treatment. Other questions will include how healthcare providers can gain a better understanding of the patient’s journey, what the key questions are that they and the patient can ask each other, and if real-world perspectives increase understanding of why some patients accept transition from orals to injectables to insulin, while others are less enthusiastic.
In January, Lilly and Bristol-Myers Squibb Co. announced a clinical trial collaboration to evaluate the safety, tolerability, and preliminary efficacy of BMS’ immunotherapy Opdivo in combination with Lilly’s galunisertib. The Phase I/II trial is evaluating 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.
Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells. Galunisertib is a TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system, and increases the ability of tumors to spread in the body. This collaboration will address the hypothesis that co-inhibition of PD-1 and TGF beta negative signals may lead to enhanced anti-tumor immune responses than inhibition of either pathway alone. The study is being conducted by Lilly.
That same month, Lilly and Merck & Co. announced an oncology clinical trial collaboration to evaluate the safety, tolerability and efficacy of Keytruda, Merck’s anti-PD-1 therapy, in combination with Lilly compounds in multiple clinical trials. Merck will conduct a Phase II study examining the combination of Keytruda with pemetrexed in first-line non-squamous, non-small cell lung cancer. Lilly will conduct a multiple-arm Phase I/II study examining the combination of Cyramza with Keytruda in multiple tumors. This study was anticipated to begin in 2015. Additionally, Lilly will conduct a Phase I/II study examining the combination of necitumumab with Keytruda in NSCLC. This study was anticipated to begin in 2015.
Also in January, Lilly completed the acquisition of Novartis Animal Health, which company leaders say will further position Lilly’s Elanco as a global leader in the animal health industry. As part of regulatory approval for the acquisition, certain animal health assets in the United States relating to the Sentinel canine parasiticide franchise will be divested to Virbac. The combined organization will increase Elanco’s product portfolio, and expand its global commercial presence. The acquisition also augments Elanco’s manufacturing and R&D capabilities with a total of 17 manufacturing sites and 14 R&D locations in the newly combined organization. Further, company leaders say Elanco will have a more balanced and diversified business with revenue more evenly split between food animal and companion animal, as well as stronger geographic representation.
Under the terms of the agreement, Lilly acquired the Novartis Animal Health business in an all-cash transaction for about $5.4 billion, including anticipated tax benefits. Lilly funded this acquisition with about $3.4 billion of cash-on-hand and $2 billion in debt.
In March, Lilly and Innovent Biologics Inc. began what company leaders call one of the largest biotech drug development collaborations in China to date between a multinational and domestic company. Under terms of the agreement, Lilly and Innovent will collaborate to support the development and potential commercialization of at least three cancer treatments over the next decade.
Innovent will lead the development and manufacturing for the China market, while Lilly will be responsible for commercialization of the three potential medicines. Innovent also has co-promotion rights. Lilly will contribute its cMet monoclonal antibody gene for possible treatment of non-small cell lung cancer. Separate from this collaboration, Lilly will continue the development of its cMet monoclonal antibody program outside of China. Innovent will contribute its monoclonal antibody targeting protein CD20 for investigation in hematologic malignancies. Innovent has received investigational new drug approval in China to begin Phase I development of this potential therapy. Innovent will contribute a preclinical immuno-oncology molecule for development in China. Lilly will be responsible for development, manufacturing and commercialization of this molecule outside of China, and will receive rights to develop and commercialize up to three preclinical bispecific immuno-oncology molecules outside of China.
Also in March, Lilly and Hanmi Pharmaceutical Co. entered into an exclusive license and collaboration agreement for the development and commercialization of Hanmi’s oral Bruton’s tyrosine kinase (BTK) inhibitor HM71224 for the treatment of autoimmune and other diseases. This small molecule is ready to enter Phase II and the parties plan to investigate the molecule for the potential treatment of rheumatoid arthritis, lupus, lupus nephritis, Sjögren’s syndrome, and other related conditions.
Under the terms of the agreement, Lilly will receive worldwide rights to the molecule excluding China, Hong Kong, Taiwan, and Korea. Lilly will take development, regulatory, manufacturing, and commercial leadership for the molecule in the Lilly territories.
In May, Lilly and AstraZeneca entered into a clinical trial collaboration to evaluate the safety and preliminary efficacy of AstraZeneca’s investigational anti-PDL1 immune checkpoint inhibitor, MEDI4736, in combination with Cyramza, Lilly’s VEGF Receptor 2 antiangiogenic cancer medicine. The planned study will assess the combination as a treatment for patients with advanced solid tumors.
The Phase I study is expected to establish the safety and a recommended dosing regimen – with the potential to open expansion cohorts in various tumors of interest – for the combination of MEDI4736 and Cyramza. Under the terms of the agreement, the trial will be sponsored by Lilly.
MEDI4736 is a monoclonal antibody developed by MedImmune, AstraZeneca’s global biologics research and development arm, directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. Cyramza is a vascular endothelial growth factor Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGFA, VEGFC, and VEGFD. Preclinical data indicate that combining VEGFR inhibitors with immune checkpoint blockades has the potential to enhance anti-tumor activity.
During that same month, Lilly and BioNTech AG entered into a research collaboration to discover novel cancer immunotherapies. The companies will seek to use the power of the body’s own immune system to attack cancer cells and create possible new treatment options for cancer patients. Lilly and BioNTech will collaborate to identify and validate novel tumor targets and their corresponding T cell receptors (TCRs) in one or more types of cancer. These tumor targets and TCRs may then be engineered and developed into potent and selective cancer therapies.
Also in May, Lilly and Sanford-Burnham Medical Research Institute announced that they will collaborate to discover and develop immunological therapies. Lilly and Sanford-Burnham, a nonprofit medical research institute, will investigate potential therapeutics using biotechnology approaches in targeting multiple immune checkpoint modulators for the treatment of immunological diseases such as lupus, Sjögren’s Syndrome, inflammatory bowel disease, and other autoimmune disorders.
Lilly has established its presence in immunology in recent years through its own R&D and collaborations, with seven molecules currently in the pipeline for conditions such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel disease. Sanford-Burnham’s work in this area focuses on cell communication pathways that control the development of lymphocytes, innate and adaptive immune responses, and inflammation. Their work has led to the discovery of molecular targets for the development of treatments for immunological and inflammatory diseases as well as cancer.
In June, Lilly and Dana-Farber Cancer Institute announced a multiyear collaboration to research new medicines under development to fight cancer. Per the agreement, over the course of three years Dana-Farber will provide research and development expertise for a number of early-stage Lilly oncology compounds. Dana-Farber researchers and Lilly scientists will work collaboratively on preclinical and clinical studies, molecular studies of patient samples, and the design and conduct of clinical trials, which may result in important advances in the science of cancer care. The agreement also allows Dana-Farber scientists to conduct independent studies on select Lilly compounds. Following research conducted at Dana-Farber, the evaluated compounds will still be fully owned by Lilly.
That same month, Lilly and Immunocore Ltd. entered into an immunotherapy-based clinical trial collaboration to explore the utility of Immunocore’s lead T cell receptor-based investigational therapeutic, IMCgp100, in combination with Lilly’s galunisertib and merestinib, for the treatment of melanoma. The goal of the collaboration is to identify combination regimens that provide synergies in efficacy and durability in patients with metastatic cutaneous and uveal melanomas. Immunocore and Lilly had previously entered into a co-discovery and co-development collaboration, announced in July 2014, to research and potentially develop other novel T cell-based cancer therapies built on Immunocore’s ImmTAC platform.
Under the terms of the agreement, Immunocore and Lilly will conduct a Phase Ib/II clinical study evaluating the safety and preliminary efficacy of IMCgp100 in combination with galunisertib in metastatic cutaneous melanoma. A second Phase Ib/II study will be conducted combining IMCgp100 with merestinib in metastatic uveal melanoma. Lilly will act as trial sponsor. These studies are anticipated to begin in 2016.
IMCgp100 and galunisertib are members of a new class of cancer treatments known as immunotherapies, which are designed to enhance the body’s own immune system in fighting cancer and whose mechanisms of action have the potential to be complementary. IMCgp100 is Immunocore’s most advanced Immune mobilizing mTCR Against Cancer molecule (ImmTAC), which are a novel class of bi-specific biologic drugs based on T cell receptors with ultra-high affinity for intracellular and extracellular cancer targets. Lilly’s galunisertib is a small molecule inhibitor of TGF beta R1 kinase that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system, and increases the ability of tumors to spread. Merestinib is Lilly’s small molecule multikinase inhibitor that in vitro selectively blocks signaling of MET, MST1R (RON), AXL, and MKNK1/2, pathways that potentially play a role in metastatic uveal melanoma.
Also in June, Lilly and Sarah Cannon Research Institute (SCRI) announced a strategic partnership to co‑develop an investigational oncology compound, LY3023414, a PI3K/mTOR dual inhibitor. Under the agreement, SCRI will collaborate with Lilly to provide clinical development expertise and program design, as well as medical oversight and trial management. Patient enrollment for the initial Phase II clinical trial is underway. The partnership supports the development of this novel targeted cancer therapy, including flexible and efficient program design and implementation, as well as more rapid patient enrollment to clinical trials by accessing SCRI’s large network of patients.
Product performance
The oncology drug Alimta took over first place at the top of Lilly’s product portfolio in 2014, though by a narrow margin. Alimta, with two indications in NSCLC and another in mesothelioma, generated $2.79 billion in sales for the year, an improvement of 3.3 percent, which company executives credited to increased volume. In the first half of 2015, Alimta sales totaled $1.24 billion, a decrease of 7.9 percent, which Lilly leaders blamed on unfavorable foreign exchange.
Also generating $2.79 billion in sales for 2014 was Lilly’s leading diabetes product Humalog, an improvement of 6.7 percent versus the prior calendar term. In the first half of 2015, Humalog sales dropped 0.9 percent to $1.34 billion.
In May 2015, FDA approved Humalog 200 units/mL KwikPen, a prefilled pen containing a concentrated formulation of Humalog to improve glycemic control in people with type 1 and type 2 diabetes. Humalog U200 KwikPen marks the first FDA approval of a concentrated mealtime insulin analog. The new KwikPen was launched in August.
Humalog U200 KwikPen holds twice as many units of insulin (600 units vs. 300 units) as the U100 formulation in the same three-milliliter cartridge. This offers patients a pen that lasts longer between pen changes, allowing for fewer changes every month. Humalog U200 KwikPen delivers the same dose in half the volume of Humalog U100 KwikPen with no dose conversions required, and can be dialed in one-unit increments to a maximum of 60 units per injection.
Next up was the ED/BPH drug Cialis, which generated $2.29 billion in sales for the year, a 6.1 percent improvement, which company leaders credited to higher prices. In the first half of 2015, Cialis sales edged up by 0.5 percent to $1.11 billion.
After losing patent protection at the end of 2013, sales of the anti-depressant Cymbalta fell off by 68.2 percent in 2014 to $1.61 billion. Sales were down another 36.2 percent in the first half of 2015, to $561 million.
Fifth among all Lilly drugs in 2014 was the diabetes product Humulin, which generated $1.4 billion in sales, an improvement of 6.4 percent. Sales of Humulin in the first half of 2015 totalled $632 million, a drop of 5.5 percent.
Sales of the osteoporosis product Forteo rose 6.2 percent in 2014 to $1.32 billion. In the first half of 2015, Forteo sales were up 2.1 percent to $621 million.
The schizophrenia drug Zyprexa remained a blockbuster for Lilly in 2014, though not by much. Zyprexa sales for the year totaled $1.04 billion, down 13.2 percent from the previous year. Zyprexa lost patent protection in the United States back in 2011; it will be losing protection in Japan, from whence nearly half of its remaining sales derive, at the end of 2015. In the first half of 2015, Zyprexa sales dropped another 10.2 percent to $473 million.
The ADHD product Strattera brought in $739 million in sales for Lilly in 2014, an improvement of 4.1 percent over the previous year. Strattera sales rose another 3.9 percent in the first half of 2015, to $366 million.
The cardiovascular drug Effient generated $522 million in sales for Lilly in 2014, up 2.6 percent. In the first half of 2015, Effient sales were down 0.9 percent to $251 million.
Recent product approvals and pipeline updates
Since its initial U.S. approval in April 2014, Lilly’s oncology drug Cyramza has received three additional approvals from FDA. In November, the agency approved Cyramza in combination with paclitaxel (a type of chemotherapy) as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. The following month, Cyramza was approved in combination with docetaxel, for the treatment of patients with metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. And in April, the drug was approved in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) chemotherapy for the treatment of patients with metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
In August 2014, FDA approved Jardiance (empagliflozin) tablets as an adjunct to diet and exercise to improve glycemic control, or blood glucose levels, in adults with type 2 diabetes (T2D). Jardiance, a once-daily 10 milligram or 25 milligram tablet, is a sodium glucose cotransporter-2 (SGLT2) inhibitor. Jardiance, a product of the Lilly/Boehringer Ingelheim diabetes partnership, works by blocking the reabsorption of glucose in the kidney, increasing glucose excretion and lowering blood glucose levels in adults with T2D who have elevated blood glucose levels. The new product was launched that same month.
The FDA marketing approval of Jardiance was based on results from a large clinical program comprising more than 10 multinational clinical trials and more than 13,000 adults with T2D. Phase III studies showed Jardiance significantly reduced hemoglobin A1C (a measure of average blood glucose over the past two to three months) and fasting blood sugar after 24 weeks as a standalone treatment or in combination with a range of background treatments, including metformin, sulfonylureas, insulin, and pioglitazone.
Also in August 2014, FDA granted tentative approval for Basaglar (insulin glargine injection), which is indicated to improve glycemic control in adults with type 2 diabetes and in combination with mealtime insulin in adults and pediatric patients with type 1 diabetes. Basaglar is Lilly and Boehringer Ingelheim’s basal insulin, which is intended to provide long-lasting blood sugar control in between meals and during the night. Basaglar has the same amino acid sequence as the currently marketed insulin glargine product and was tentatively approved for use with the pre-filled dosing device KwikPen.
With a tentative approval, FDA has determined that Basaglar meets all of the regulatory requirements for approval, but it is subject to an automatic stay of up to 30 months as a result of litigation filed by Sanofi, claiming patent infringement. Under the Drug Price Competition and Patent Term Restoration Act, FDA cannot give final approval until the end of the 30-month period in mid-2016, unless the court finds in favor of Lilly earlier.
The tentative approval is based, in part, on results from Lilly and Boehringer Ingelheim’s extensive clinical development program for the alliance’s insulin glargine product. The submission included results from pharmacokinetic and pharmacodynamics studies, as well as Phase III studies in people with type 1 and type 2 diabetes. The Basaglar new drug application was filed through the FDA’s 505(b)(2) regulatory pathway, which allows the agency to consider the efficacy and safety of the existing insulin glargine product. The product was approved by European regulators in September 2014.
In September 2014, FDA approved Trulicity (dulaglutide) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Lilly’s new GLP-1 receptor agonist was launched to U.S. pharmacies two months later.
FDA’s approval of Trulicity was based on a number of studies of the drug used alone or in combination with commonly prescribed diabetes medications, including metformin, pioglitazone, glimepiride, and insulin lispro. These studies included five large Phase III clinical trials from the Assessment of Weekly AdministRation of LY2189265 in Diabetes (AWARD) clinical development program. The efficacy of Trulicity was compared to four commonly used type 2 diabetes medicines: metformin, Januvia, Byetta, and Lantus.
In October 2014, Lilly discontinued development of tabalumab — being studied for the treatment of systemic lupus erythematosus (SLE, commonly known as lupus) due to insufficient efficacy in two pivotal Phase III trials. In the ILLUMINATE 1 study, tabalumab did not achieve the primary endpoint, at either dose studied, of statistically significant improvement on SRI5 (SLE Responder Index-5, a measurement of lupus disease activity and response), compared to standard of care therapy. In ILLUMINATE 2, the higher dose of tabalumab met this endpoint, the first time a lupus study has achieved this efficacy measure as a primary endpoint in a Phase III trial. Collectively, the data from these studies did not meet expectations for efficacy in the context of existing treatments. Given the overall efficacy results from these two pivotal Phase III studies, Lilly will not move forward with submissions to global regulators.
In February, FDA approved Glyxambi tablets as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when both empagliflozin (Jardiance) and linagliptin (Tradjenta) are appropriate treatments. The new product was launched in March.
Glyxambi, a single-pill combination of Jardiance and Tradjenta, is the first and only diabetes treatment in the United States to combine the dual mechanisms of action of a sodium glucose cotransporter-2 (SGLT2) inhibitor and a dipeptidyl peptidase-4 (DPP4) inhibitor in a once-daily tablet taken in the morning. SGLT2 inhibitors remove glucose through the urine by blocking blood glucose reabsorption in the kidney. DPP4 inhibitors work by increasing hormones that stimulate the pancreas to produce more insulin and stimulate the liver to produce less glucose.
The FDA approval was based on a Phase III clinical trial that evaluated the efficacy and safety of Glyxambi compared with the individual components of empagliflozin or linagliptin in adults with T2D who were also taking high-dose metformin. The study, which randomized 686 adults with T2D and hemoglobin A1C between 7.0 and 10.5 percent, examined the change from baseline in A1C at 24 weeks. In the study, as an add-on to metformin, Glyxambi showed statistically significant reductions in A1C compared with empagliflozin and linagliptin alone at 24 weeks. The percentage of patients achieving an A1C less than 7 percent with Glyxambi 10/5 milligrams or 25/5 milligrams was 58 percent and 62 percent, respectively, compared with 28 percent, 33 percent and 36 percent for empagliflozin 10 milligrams, empagliflozin 25 milligrams, and linagliptin 5 milligrams, respectively.
Also in February, Lilly and partner developer Incyte Corp. announced that the investigational medicine baricitinib had demonstrated a statistically significant improvement compared to placebo in a second consecutive Phase III trial in rheumatoid arthritis. The RA-BUILD study included patients with moderately-to-severely active rheumatoid arthritis who had an inadequate response to, or were intolerant of, at least one conventional disease-modifying antirheumatic drug (cDMARD). The study met its primary endpoint of an improved ACR20 response rate compared to placebo after 12 weeks of treatment.
Part of an extensive Phase III program testing baricitinib in more than 3,000 patients at different stages along the RA treatment continuum, the RA-BUILD study enrolled 684 patients with rheumatoid arthritis who previously had an inadequate response to, or were intolerant of, at least one cDMARD and had not received a biologic disease-modifying antirheumatic drug (bDMARD). Patients received either one of two doses of once-daily baricitinib or placebo, in addition to their background therapy.
In March, Lilly and partner developer Pfizer Inc. announced that they are preparing to resume the Phase III clinical program for tanezumab. This announcement followed a decision by FDA to lift the partial clinical hold on the tanezumab development program after a review of a robust body of nonclinical data characterizing the sympathetic nervous system response to tanezumab. The data were submitted to FDA in February 2015. Tanezumab is a humanized monoclonal antibody that selectively targets nerve growth factor (NGF), a regulator of pain processing and sensitivity. NGF levels increase as a result of injury or inflammation and in chronic pain states. Tanezumab selectively binds to NGF, thereby inhibiting this protein from activating pain-signaling neurons.
In the prior clinical studies of more than 11,000 patients, tanezumab demonstrated clinically meaningful efficacy versus placebo and other select commonly used pain medicines. A partial clinical hold has been in place for tanezumab and all other anti-nerve growth factor antibodies since December 2012 due to adverse changes in the sympathetic nervous system of mature animals. Studies in terminal cancer pain were allowed to proceed.
In June, Lilly announced that LY2951742, its investigational medicine for the prevention of migraine, met the primary endpoint in a Phase IIb study in episodic migraine. The randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of four different doses of LY2951742 given in a once-monthly, subcutaneous injection in more than 400 patients with episodic migraine (people who experience between four and 14 migraine headache days per month). The primary objective was to assess whether at least one dose of LY2951742 was superior to placebo in the prevention of migraine headache. LY2951742 demonstrated a statistically significant reduction in migraine headache days and a safety and tolerability profile confirming the previous results seen in a Phase IIa study.
In addition to the migraine program, Lilly has initiated two Phase III trials with LY2951742 in patients suffering from cluster headache. Based on the unmet medical need and significance of this disorder for patients, Lilly has been granted fast track designation by FDA for cluster headache.
Also in June, detailed results of two pivotal Phase III studies for ixekizumab were published by The Lancet. The UNCOVER-2 and UNCOVER-3 clinical studies of more than 2,500 patients found ixekizumab to be statistically superior to etanercept and placebo on all measures of skin clearance. Patients treated with ixekizumab demonstrated significant and meaningful improvements in health-related quality-of-life measures. Ixekizumab is Lilly’s investigational medicine for the treatment of moderate-to-severe plaque psoriasis.
In each study, co-primary efficacy objectives assessed whether ixekizumab administered once every two weeks or once every four weeks was superior to etanercept and placebo after 12 weeks, as measured by a Psoriasis Area and Severity Index reduction of at least 75 percent (PASI 75) and a Static Physician Global Assessment score of clear or minimal (sPGA 0/1). A PASI 75 score signals at least a 75 percent reduction in a patient’s psoriasis from their baseline assessment. The sPGA is the physician’s assessment of severity of a patient’s psoriasis lesions overall at a specific point in time.
Patients treated with ixekizumab also achieved higher rates of skin clearance as measured by PASI 90 and PASI 100 compared with etanercept and placebo. PASI 90 reflects at least a 90 percent reduction in psoriasis symptoms, while PASI 100 is the highest possible reduction, representing complete skin clearance. Patients treated with ixekizumab were five to seven times more likely to achieve a PASI 100 score than with etanercept.
In Phase III trial data released in June, Lilly’s basal insulin peglispro (BIL) demonstrated statistically significantly lower hemoglobin A1c (HbA1c) compared to insulin glargine at 26 and 52 weeks in people with type 1 diabetes. People with type 1 diabetes in these trials were also taking mealtime insulin. Lilly executives anticipate submitting BIL for regulatory approval after 2016.
BIL has a hepato-preferential activity profile derived from its reduced effect in peripheral tissue, making it more similar to endogenous insulin compared to other exogenous insulins with a conventional activity profile.
In IMAGINE-1 and IMAGINE-3, BIL demonstrated superiority in HbA1c compared to insulin glargine. Significantly more patients taking BIL met the ADA’s recommended HbA1c target of less than 7 percent and experienced lower rates of nocturnal hypoglycemia compared to those taking insulin glargine. In both trials — in which patients were taking both mealtime and basal insulin — there was a statistically significant increase in the rate of total hypoglycemia for patients taking BIL compared with those taking insulin glargine due to a higher rate of daytime hypoglycemic events.
In both trials, patients treated with BIL experienced mean weight loss compared to weight gain in patients who took insulin glargine. Also in both trials, patients taking BIL had an increase in triglycerides compared to insulin glargine. In IMAGINE-3, patients taking BIL had an increase in LDL cholesterol, a decrease in HDL cholesterol and increases in systolic and diastolic blood pressure compared to insulin glargine. The rate of major adverse cardiac events MACE+ (cardiovascular death, nonfatal stroke, nonfatal MI, and hospitalization due to unstable angina) was lower for patients taking BIL compared with those taking insulin glargine in IMAGINE-3. There were no MACE+ events in IMAGINE-1.
Additionally, in both studies, patients taking BIL had an increase in the liver enzyme ALT (alanine aminotransferase). Four weeks after BIL was discontinued these levels decreased toward baseline. Liver fat was measured by MRI in a subset of patients in both studies and was higher in patients treated with BIL compared to insulin glargine.
That same month, Lilly accepted the recommendation of the ACCELERATE study data monitoring committee to continue the Phase III trial of the investigational medicine evacetrapib, based on data from an interim futility analysis. The last patient visit in ACCELERATE — which is evaluating evacetrapib in approximately 12,000 patients with high-risk atherosclerotic cardiovascular disease — is expected in July 2016. Evacetrapib is a potent and selective inhibitor of cholesteryl ester transfer protein, and in clinical studies has demonstrated effects on high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and cholesterol efflux.
During July, FDA’s Oncologic Drugs Advisory Committee met to discuss the data supporting Lilly’s necitumumab in combination with gemcitabine and cisplatin for use in first-line treatment of patients with advanced squamous non-small cell lung cancer. Necitumumab is a recombinant human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human epidermal growth factor receptor 1 (EGFR). Activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis or cell death. Necitumumab in combination with gemcitabine and cisplatin is the first regimen to show a significant improvement in overall survival over chemotherapy alone, specifically in the first-line setting. FDA is expected to make a decision on Lilly’s biologics license application for necitumumab later this year.
Also in July, Lilly announced results suggesting the treatment effect of solanezumab was preserved within a pre-specified amount in patients with mild Alzheimer’s disease who received solanezumab earlier in the disease compared to patients who began treatment at a later point. These results were from a pre-specified secondary analysis of the Phase III EXPEDITION, EXPEDITION2, and EXPEDITION-EXT studies. The results support the use of the “delayed-start” method for assessing the potential effects of a treatment on the underlying disease progression of Alzheimer’s disease.
Treatment differences in cognition and function between early-start and delayed-start groups at the end of the placebo-controlled period (80 weeks since randomization) were preserved at the primary time point of 108 weeks (28 weeks after the start of EXPEDITION-EXT) within a predefined margin. This difference at 108 weeks remained statistically significant. Also, treatment differences in cognition and function between early-start and delayed-start groups at the end of the placebo-controlled period (80 weeks since randomization) were also preserved at an additional time point of 132 weeks (52 weeks after the start of EXPEDITION-EXT) within a pre-defined margin. This difference at 132 weeks was statistically significant.
In August, FDA approved Synjardy tablets, from Boehringer Ingelheim and Lilly, for the treatment of adults with type 2 diabetes (T2D). Synjardy is the third product containing empagliflozin to be approved by FDA, following Jardiance (empagliflozin) and Glyxambi (empagliflozin/linagliptin).
Synjardy is a combination of empagliflozin and metformin — two medicines with complementary mechanisms of action — to help control blood glucose in people with T2D. Empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, removes excess glucose through the urine by blocking glucose reabsorption in the kidney. Metformin, a commonly prescribed initial treatment for T2D, lowers glucose production by the liver and its absorption in the intestine. Synjardy was also approved by European regulators in May.
