Nearly two months after Eli Lilly secured an expanded approval indication for its cancer drug Verzenio, the company unveiled final data from the MONARCH 3 trial that won the latest nod from the U.S. Food and Drug Administration for the treatment of some breast cancer patients (Press release, BioSpace, APR 18, 2018, View Source [SID1234525503]).

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During a presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Chicago this weekend Lilly revealed that Verzenio (abemaciclib), a cyclin-dependent kinase inhibitor, provided even longer progression-free survival than originally believed. Last fall Eli Lilly released interim-data from the MONARCH 3 trial that showed PFS was estimated at 14 months. Now though data shows Verzenio in combination with an aromatase inhibitor (AI) provides progression-free survival of 28 months.

"That’s a significant prolongation in progression-free survival that is important for the lives of patients," Levi Garraway, senior vice president of global development and medical affairs at Eli Lilly told BioSpace in an exclusive interview. "We’ve been happy with the news that this gives women with breast cancer one more option."

In February the FDA gave approval for the treatment of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. That approval marked the third time the FDA gave the drug the green light since its first regulatory win in September 2017.

By adding abemaciclib to endocrine therapy as part of a treatment regimen, Eli Lilly said the program demonstrated improved progression-free survival in patients with HR+/HER2-negative breast cancer. In patients with measurable disease, the objective response rate was 55.4 percent in the abemaciclib arm and 40.2 percent in the placebo arm, according to data.

Within the MONARCH 2 and MONARCH 3 clinical trial subgroup populations, researchers at Eli Lilly identified certain clinical characteristics of the disease that typically confer a less favorable prognosis. Eli Lilly believes this information may help clinicians optimize treatment decisions, including the use of CDK4 & 6 inhibitors, and potentially provide the groundwork for more individualized therapy.

During the conference Garraway said he engaged with several doctors about the use of cyclin-dependent kinases inhibitors in the treatment of breast cancer. He said the response they have seen from prescribers is positive, which indicates there is a path for cyclin-dependent kinases inhibitors.

"These doctors, they’ve been seeing some positive moves and are gaining confidence in its (Verzenio) use," Garraway said.

With the success that Eli Lilly has had with Verzenio, the company now aims to determine if it can be used as a treatment in other types of breast cancer, as well as other cancer indications. Currently, the company has Verzenio in a study in the high-risk adjuvant breast cancer setting, as well as an ongoing Phase II study in Her2+ breast cancer. Garraway said data from the mid-stage trial is expected by the end of the year. While Garraway did not provide many details on the Phase II study, He said it was designed so that if the data readout is strong enough there is a chance Eli Lilly could seek regulatory approval on that data alone. But, he quickly noted that it depends on whether or not there is a large enough of an effect from the treatment for the company to go into regulatory discussions as opposed to a Phase III study.

"There’s a biological rationale for the testing and we’re looking forward to seeing the results later this year," Garraway said.

For potential uses outside of breast cancer Garraway would not disclose what areas the company is exploring with Verzenio, he said the company has identified some areas "that are worth the investment."

Not related to Eli Lilly’s presentations at AACR (Free AACR Whitepaper), this morning the company announced a partnership with Boehringer Ingelheim and 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. The primary outcome of the study is to assess the effect of Jardiance on time to clinically relevant kidney disease progression or cardiovascular death.

On April 18, 2018 Abbott reported financial results for the first quarter ending March 31, 2018. Key takeaways from this morning’s earnings call include (Press release, BioSpace, APR 18, 2018, View Source [SID1234525502]):

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First-quarter reported sales growth of 16.7 percent
First-quarter organic sales growth of 6.9 percent
First-quarter adjusted earnings per share from continuing operations of 59 cents, at the upper end of the previous guidance range
Several recently launched products contributing to strong growth
"We’re off to a strong start to the year as we forecasted," said Miles D. White, chairman and chief executive officer. "We’re particularly pleased with the continued strong growth in medical devices and improving performance in our nutrition business."

The company’s adjusted income rose to 59 cents per share on $7.39 billion in sales for its first quarter, beating Zacks Investment Research estimates of 58 cents on $7.26 billion in sales. Last year at this time, Abbott shares were trading at 48 cents with $6.34 billion in sales.

An infographic from the company highlights an increase of 6.9 percent in worldwide organic sales led by successes in nutrition, diagnostics, established pharmaceuticals and medical devices.

"Back in January I commented that we were entering the year with strong momentum which has continued as we forecasted," White added during the earnings call. "The strong growth we are achieving is a direct result of the steps we have taken to position the company in the most attractive areas of health care as well as the outstanding productivity of our new product pipeline."

Despite the company’s upbeat attitude about its Q1 earnings, shares dipped 3.5 percent early Wednesday on pharmaceutical sales that lagged behind Wall Street’s expectations by nearly 4 percent.

Revenue from established pharmaceuticals fell short by $56 million, RBC Capital Markets wrote in a note to clients. Also, Evercore noted the $1.04 billion in sales for that unit missed the consensus by 3.6 percent.

Medical device sales had the best organic growth in Q1, rising 9.4 percent to $2.74 billion. That beat the consensus for $2.67 billion, Evercore noted. Diagnostics also performed well, rising 5.5 percent organically to $1.84 billion in sales to top the consensus by $69 million.

"For the full year 2018, we continue to forecast organic sales growth of 6 percent to 7 percent," said Chief Financial Officer Brian Yoor. "In addition, we continue to expect rapid diagnostics to contribute sales of a little more than $2 billion."

With a forecasted adjusted gross margin ratio of around 59 percent of sales, Yoor said that research and development investments will be adjusted to around 7.5 percent of sales, and selling, general and administrative expenses adjusted above 30.5 percent of sales."

Worldwide, nutrition sales were $1.76 billion, up 4.7 percent organically and topping guidance for low single-digit growth. Both adult and pediatric segments performed well, growing a respective 4.3 percent and 5.1 percent on an organic basis.

But, White cautioned, nutrition is a highly competitive business in a branded space. "I give our U.S. team a lot of credit for how well they’ve done in the pediatric and adult (nutrition) space. It’s extremely competitive and it’s competitive in both pediatric and adult. And we will see from time-to-time a competitor tries false advertising or other things to take momentary share. But I think overall, we’ve not only sustained our position, but steadily grown it, from a share standpoint."

For the year, Abbott reaffirmed its adjusted profit target of $2.80 to $2.90 a share. Analysts modeled adjusted earnings of $2.87 per share and $30.91 billion in sales. Abbott also sees second-quarter adjusted income coming in at 70 to 72 cents per share.

On April 18, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, "Astellas" ) and Kite, a Gilead Company (Nasdaq: GILD, President and CEO: John Milligan, "Kite"), reported that an agreement has been completed for the transfer of certain Agensys research facilities in Santa Monica, California, USA, to Kite (Press release, Astellas Pharma US, APR 18, 2018, View Source [SID1234525501]). The asset transfer was completed on April 12, 2018. Additional financial information or further deal terms are not being disclosed.

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Astellas is a pharmaceutical company dedicated to improving the health of people around the world. (PRNewsFoto/Astellas Pharma Inc.)

The facilities transfer is part of the wind-down process of the Agensys research operations, as announced by Astellas on July 27, 2017. Additional wind-down activities were completed in the first quarter of calendar year 2018, following the Company’s decision to further refine its oncology strategy by expanding its investment in the research of new technologies and modalities and reducing its focus on Antibody-Drug Conjugate (ADC) research, which was the core focus of work conducted at Agensys. Astellas will continue certain clinical trials and collaborations on some ADC programs that have been in progress at Agensys, including its collaboration with Seattle Genetics, Inc.

On April 18, 2018 Trillium Therapeutics Inc. (Nasdaq/TSX: TRIL), a clinical-stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported that preclinical data from its TTI-622 (SIRPa-IgG4 Fc) immune checkpoint inhibitor program were presented at the 109th Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Trillium Therapeutics, APR 18, 2018, View Source [SID1234525500]).

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TTI-622 (SIRPa-IgG4 Fc) is the second SIRPaFc decoy receptor that Trillium is advancing into the clinic. It consists of the CD47-binding domain of human SIRPa linked to an IgG4 Fc region and is being developed primarily for combination therapy.

The data presented at AACR (Free AACR Whitepaper) demonstrate that TTI-622 induces the phagocytosis of a broad panel of tumor cells derived from patients with both hematological and solid tumors. As a monotherapy, TTI-622 treatment resulted in decreased tumor growth and improved survival in a B cell lymphoma xenograft model, and enhanced the efficacy of cetuximab (anti-EGFR) and daratumumab (anti-CD38) antibodies in solid and hematological xenograft models, respectively. Unlike CD47-blocking antibodies, TTI-622 bound minimally to human erythrocytes and did not induce hemagglutination in vitro.

"The preclinical data presented at AACR (Free AACR Whitepaper) reinforce our confidence in this target and provide a solid foundation for initiating a clinical program with TTI-622," said Dr. Niclas Stiernholm, President and CEO of Trillium Therapeutics. This second SIRPaFc decoy receptor complements TTI-621, and allows us to evaluate the effects of CD47 blockade using different levels of Fc receptor engagement. Importantly, we believe the minimal binding of TTI-622 to human red blood cells distinguishes this agent from other IgG4-based CD47 targeted therapies."

A two-part, multicenter, open-label, phase 1a/1b study of TTI-622 in patients with advanced relapsed or refractory lymphoma or multiple myeloma is being initiated, with the first patient expected to be dosed in Q2 2018. In the phase 1a dose-escalation study, patients will be enrolled in sequential dose cohorts to receive TTI-622 once weekly to characterize safety, tolerability, pharmacokinetics, and to determine the maximum tolerated dose. In the phase 1b study, patients will be treated with TTI-622 in combination with rituximab, a PD-1 inhibitor or a proteasome inhibitor-containing regimen.

On April 18, 2018 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer therapeutics, presented preclinical data during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting related to two of its therapeutic candidates, anti-TIGIT (OMP-313M32), currently in the Phase 1a portion of a Phase 1a/b study, and GITRL-Fc trimer (OMP-336B11), currently in a Phase 1a study (Press release, OncoMed, APR 18, 2018, View Source [SID1234525498]). In addition, preclinical data was presented exploring the ability of OncoMed’s Wnt antagonist vantictumab (anti-FZD, OMP-18R5) to potentiate immune responses to checkpoint agents.

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TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an inhibitory checkpoint receptor that binds to PVR ligand, a protein broadly expressed on tumor cells and tumor-infiltrating cells, and, in doing so, blocks T-cell activation. OncoMed’s presentation (Abstract 5627) showed that anti-TIGIT treatment reduced the abundance of regulatory T-cells (Tregs) within tumors in animal models, and mechanistic studies demonstrated an important contribution of effector function for anti-tumor efficacy. "These investigations highlight the potential of our anti-TIGIT antibody," said Ann Kapoun, Ph.D., OncoMed’s Vice President of Translational Medicine. "These translational research efforts inform our biomarker strategies and may help us identify patients whose tumors are most likely to benefit from our therapeutic candidates."

A series of preclinical studies (Abstract 70, Abstract 2726, Abstract 3826) from OncoMed highlighted the ability of GITRL-Fc, a novel linkerless ligand trimer that binds to the co-stimulatory receptor GITR (glucocorticoid-induced TNF receptor family-related protein), to function as a robust GITR agonist by both stimulating T-cell and NK responses and reducing the abundance of Tregs in tumors. The studies also investigated the impact of aging on anti-tumor immune response, an important and often underappreciated parameter impacting the efficacy of immuno-oncology strategies.

Another preclinical study (Abstract 1733) examined the synergistic impact of OncoMed’s Wnt pathway antagonist vantictumab on the ability of checkpoint agents to promote an effective anti-tumor immune response. These data add to a growing recognition of the importance of the Wnt pathway in shaping immune function.

"The data detailed in these AACR (Free AACR Whitepaper) presentations exemplify the ongoing extensive efforts to deepen our understanding of the mechanisms of action of our agents" said Austin Gurney Ph.D., OncoMed’s Senior Vice President of Research and Chief Scientific Officer. "With both our anti-TIGIT and GITRL-Fc programs advancing in Phase 1 studies, these research efforts will have direct impact on informing our clinical programs."

Below are additional highlights from the OncoMed poster presentations:

Abstract 5627 – Anti-TIGIT biomarker study: Inhibition of TIGIT induces loss of Tregs from tumors and requires effector function for tumor growth inhibition

Using a surrogate anti-TIGIT antibody, potent single-agent dose-dependent anti-tumor efficacy was demonstrated on large established CT26 WT tumors. Anti-TIGIT efficacy was shown to require effector function for tumor growth inhibition and biomarker analysis demonstrated reduction of Treg frequency and activation of T-cells and NK cells as part of the mechanism of action of anti-TIGIT. CD226, a co-receptor for TIGIT’s ligands PVR and PVRL2, was significantly upregulated in T-cells, Tregs and NK cells, reflecting a feedback loop activated by the inhibition of TIGIT activity. Anti-TIGIT gene signatures in tumors and in blood were identified from multiple syngeneic models and may be potential biomarkers for measuring anti-TIGIT activity. Additionally in a human tissue study, TIGIT expression on Tregs was found to be considerably higher than on CD8+ T-cells in multiplexed IHC panels across a panel of multiple solid tumors types.

Abstract #70 – Effect of aging on the antitumor activity of GITRL-Fc

It is now appreciated that the immune system changes in response to aging. In this study, the activity of GITRL-Fc protein was compared in both young and older mice. Compared to young mice, tumors grew faster in older mice. This may be due in part to an observed greater prevalence of myeloid-derived suppressor cells (MDSC) in older mice. GITRL-Fc significantly inhibited tumor growth in both older and younger mice with efficacy more pronounced in young mice. In older mice, GITRL-Fc (mIgG2a) was still able to deplete Tregs in tumor and increase Tregs in the spleen as has been previously shown with GITRL-Fc in young mice. A GITRL-Fc protein deficient in effector function (mIgG2a (N297A)) did not deplete Tregs in the tumor but did retain anti-tumor growth activity. Collectively, these data demonstrate that Treg depletion and activation of GITR signaling contribute to the anti-tumor efficacy of GITRL-Fc in older mice.

Abstract #2726 – In vitro functional activity of OMP-336B11, a GITRL-Fc fusion protein, on primary human immune cells

In this study, functional characterization of OMP-336B11 in various human immune cell assays was presented. OMP-336B11 enhanced activated human T-cell proliferation and augmented IL-2 induced IFNγ from human NK cells. Notably, OMP-336B11 demonstrated superior activity compared to agonist anti-GITR antibodies. OMP-336B11 is designed with an IgG1 Fc domain in order to elicit NK-mediated cytotoxicity of high GITR-expressing cells (i.e., Tregs). Co-incubation of primary human NK cells (effector) and GITR expressing cells (target) resulted in an OMP-336B11 dependent dose-titratable increase in target cytotoxicity.

Abstract #3826 – GITRL-Fc biomarker and mechanism study: GITRL-Fc reduces Treg frequency in tumors and requires effector function for inhibition of tumor growth

Using a surrogate GITRL-Fc molecule, potent single agent dose-dependent anti-tumor efficacy was demonstrated on large established CT26.WT tumors. Biomarker analysis showed that loss of Tregs, activation of T-cells and Fc-mediated effector function are key elements in the mechanism of action of the molecule. Immuno-phenotyping of tumor-associated immune cells revealed a reduction in Treg frequency in the tumor by 24 hours post-dose that was maintained at 7 and 14 days. GITRL-Fc treatment increased proliferation and activation markers on tumor-associated CD4+ and CD8+ T-cells, suggesting an increased cytotoxic environment within the tumor. GITRL-Fc gene signatures were identified in tumors and blood from multiple syngeneic models and may be used as potential biomarkers along with multiplexed IHC panels (e.g. GITR+CD4+ T-cells, GITR+CD8+ T-cells) that were developed. Additional studies comparing intratumoral (IT) vs intraperitoneal GITRL-Fc injection demonstrated both routes of administration produced similar efficacy, suggesting IT administration may be an alternative route of administration.

Abstract #1733 – Wnt antagonists synergize with immune checkpoint inhibitors to enhance anti-tumor responses

While enhanced Wnt signaling has been shown to play a major role in cancer stem cell biology, more recent studies have implicated Wnt in the development of resistance to anti-tumor immune responses. In murine tumor models, targeting Wnt signaling using the Fzd receptor monoclonal antagonist antibody vantictumab in combination with immune checkpoint inhibitors anti-CTLA-4 or anti-PD1 induces enhanced anti-tumor responses leading to decreased tumor volume and increased infiltration of activated CD8+ T-cells into the tumor microenvironment. In addition, the data showed that combined Wnt and immune checkpoint inhibition decreased Tregs and immune suppressive myeloid cell populations, enhanced cytotoxic T-cell activity and increased antigen presentation by APCs. These results suggest that co-targeting Wnt and immune checkpoint proteins may provide valuable opportunities for novel combination strategies for immunotherapeutic clinical development.

These posters are available on the Pipeline section of OncoMed’s website, www.oncomed.com.

Additional information on the meeting can be found on the AACR (Free AACR Whitepaper) website www.aacr.org.