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Lilly and Rigel Enter Strategic Collaboration to Develop RIPK1 Inhibitors for the Potential Treatment of Immunological and Neurodegenerative Diseases

On February 18, 2021 Eli Lilly and Company (NYSE: LLY) and Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) reported a global exclusive license agreement and strategic collaboration to co-develop and commercialize Rigel’s R552, a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor, for all indications including autoimmune and inflammatory diseases (Press release, Rigel, FEB 18, 2021, View Source [SID1234577529]). Pursuant to the collaboration, Lilly will also lead all clinical development of brain penetrating RIPK1 inhibitors in central nervous system (CNS) diseases.

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Rigel’s lead RIPK1 inhibitor, R552, has completed Phase 1 clinical trials and will begin Phase 2 clinical trials in 2021 as part of the collaboration. Rigel also has ongoing pre-clinical activities with its lead CNS penetrant RIPK1 inhibitor candidates.

Under the terms of the agreement, Lilly will pay an upfront cash payment to Rigel of $125 million. Rigel may also be eligible to receive up to $835 million in potential development, regulatory, and commercial milestone payments, as well as tiered royalties ranging from the mid-single digit to high-teens that will vary depending upon Rigel’s clinical development investment. Lilly and Rigel will co-develop R552 at specified contribution levels. Lilly will be responsible for all costs of global commercialization for R552, and Rigel will have the right to co-commercialize R552 in the U.S. Lilly will be solely responsible for all clinical development and commercialization of brain penetrating RIPK1 inhibitors in CNS indications.

RIPK1 is a critical signaling protein implicated in a broad range of key inflammatory cellular processes including necroptosis, a type of regulated cell death, and cytokine production. In necroptosis, cells rupture leading to the dispersion of cell contents which can trigger an immune response and enhance inflammation. Inhibiting RIPK1 may be a new approach to treating various autoimmune, inflammatory, and neurodegenerative disorders. In pre-clinical studies, Rigel’s R552 demonstrated prevention of joint and skin inflammation in a RIPK1-mediated murine model of inflammation and tissue damage.

"At Lilly, our immunology strategy is focused on the pursuit of novel targets that have the potential to develop into best-in-class medicines for patients with autoimmune conditions," said Ajay Nirula, M.D., Ph.D., vice president of immunology at Lilly. "RIPK1 inhibitors are a promising approach, and R552 is an exciting addition to our immunology pipeline. We look forward to working with Rigel to advance its clinical development."

"We are very excited to form this strategic partnership with Lilly. This collaboration will provide significant resources and expertise to support a broad investigation in multiple disease indications with our RIPK1 inhibitors," said Raul Rodriguez, Rigel’s president and CEO. "With Lilly’s extensive knowledge in immune and CNS diseases, they are our ideal partner to ensure the clinical and commercial success of our RIPK1 inhibitor program."

This transaction is subject to customary closing conditions, including clearance under the Hart-Scott-Rodino (HSR) Antitrust Improvements Act of 1976. This transaction will be reflected in Lilly’s reported results and financial guidance according to Generally Accepted Accounting Principles (GAAP). There will be no change to Lilly’s 2021 non-GAAP earnings per share guidance as a result of this transaction.

Lilly and Rigel Enter Strategic Collaboration to Develop RIPK1 Inhibitors for the Potential Treatment of Immunological and Neurodegenerative Diseases

On February 18, 2021 Eli Lilly and Company (NYSE: LLY) and Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) reported a global exclusive license agreement and strategic collaboration to co-develop and commercialize Rigel’s R552, a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor, for all indications including autoimmune and inflammatory diseases (Press release, Rigel, FEB 18, 2021, View Source [SID1234577481]). Pursuant to the collaboration, Lilly will also lead all clinical development of brain penetrating RIPK1 inhibitors in central nervous system (CNS) diseases.

Year-End Report, 2020

On February 18, 2021 Calliditas Therapeutics reported that Year-End Report, 2020 (Press release, Calliditas Therapeutics, FEB 18, 2021, View Source [SID1234576690])

Positive Topline Results from Pivotal Phase 3 NefIgArd Trial
"On November 8, 2020, we announced positive topline readout of Part A of our Phase 3 pivotal trial, NefIgArd. The results were statistically significant and clinically relevant: proteinuria showed a 31% reduction versus baseline, a stronger effect than what was seen in the Phase 2b (27%), which is generally not expected when moving from Phase 2 to Phase 3. In addition, eGFR was stabilised in the treated patient population, which in the end is the true treatment goal. This potentially disease modifying effect is to our knowledge unique to Nefecon, which we find extremely exciting, and we look forward to our interactions with regulators during the year as we progress towards potential approval.

We also concluded the purchase of a controlling block in Genkyotex in Q4. This is a company we had followed and where we found the clinical data intriguing and their approach clearly differentiated. Genkyotex had positive interactions with the FDA in 2020, which resulted in an adaptive pivotal Phase 2/3 design in PBC and they also initiated a Phase 1 PK study to look into higher dosing, which read out positively in early 2021. We feel excited about taking on a pioneering role in the area of NOX inhibitors and to initiate studies in PBC, as well as on the basis of comprehensive and compelling animal-based data launch a proof of concept trial in head and neck cancer where today’s immunotherapy has limited reach."

Renée Aguiar-Lucander, CEO

Summary of Q4 2020
October 1 – December 31, 2020

Net sales amounted to SEK 0.4 million and SEK 46.6 million for the three months ended December 31, 2020 and 2019, respectively.
Operating loss amounted to SEK 135.9 million and SEK 18.0 million for the three months ended December 31, 2020 and 2019, respectively.
Loss before income tax amounted to SEK 173.3 million and SEK 23.0 million for the three months ended December 31, 2020 and 2019, respectively.
Loss per share before and after dilution amounted to SEK 3.41 and SEK 0.60, for the three months ended December 31, 2020 and 2019, respectively.
Cash amounted to SEK 996.3 million and SEK 753.5 million as of December 31, 2020 and 2019, respectively
Significant events during Q4 2020, in summary
In November 2020, Calliditas announced positive topline results from Part A from the pivotal Phase 3 NefIgArd trial.
In November 2020, Calliditas acquired a controlling interest in Genkyotex SA followed by a simplified mandatory offer to the shareholders of Genkyotex, after which Calliditas controlled 86.2 percent of the shares in Genkyotex.
Significant events after the end of reporting period, in summary
In January 2021, Calliditas shared the clinical development plan for setanaxib and additional data from Part A of the NefIgArd study at the R&D Day.
Investor Presentation February 18, 14:30 CET
Audio cast with teleconference, Q4 2020, February 18, 2021, 14:30 (Europe/Stockholm)

Webcast: View Source

Teleconference: SE: +46850558356 UK: +443333009262 US: +18338230586

Financial calendar
Publication of the Annual Report 2020 April 27, 2021

Interim Report for the period January 1 – March 31, 2021 May 13, 2021

Interim Report for the period January 1 – June 30, 2021 August 19, 2021

Interim Report for the period January 1 – September 30, 2021 November 18, 2021

Year-end Report for the period January 1 – December 31, 2021 February 24, 2022

The information in the press release is information that Calliditas is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact persons set out above, at 07:00 CET on February 18, 2021.

Neoadjuvant combination immunotherapy improves outcomes for early stage non-small cell lung cancer

On February 18, 2021 MD Anderson reported that The first randomized Phase II clinical trial to report on single and combined neoadjuvant immune checkpoint inhibitor therapy in stage I-III non-small cell lung cancer (NSCLC) found combination therapy produced a significant clinical benefit, as assessed by major pathologic response (MPR) rate, as well as enhanced tumor immune cell infiltration and immunological memory (Press release, MD Anderson, FEB 18, 2021, https://www.mdanderson.org/newsroom/neoadjuvant-combination-immunotherapy-improves-outcomes-for-earl.h00-159458478.html [SID1234575347]). Researchers from The University of Texas MD Anderson Cancer Center published the study results today in Nature Medicine.

The NEOSTAR trial tested combined neoadjuvant therapy of nivolumab plus ipilimumab, as well as neoadjuvant nivolumab monotherapy in patients with operable NSCLC. The trial met its prespecified primary endpoint efficacy threshold in the combination arm, with eight of 21 treated patients (38%) achieving major pathological response, defined as ≤10% viable tumor at surgery. MPR has been shown to correlate with improved survival outcomes after neoadjuvant chemotherapy in NSCLC. The prespecified efficacy boundary for each treatment to be considered promising for further testing was six or more MPRs in 21 evaluable patients. With MPR in five of 23 treated patients (22%), monotherapy did not meet the efficacy boundary.

While combination immunotherapy has been approved for a subset of patients with metastatic NSCLC, this is the first randomized study to report on the role of combination checkpoint inhibitors for operable, early stage disease.

"More than 50% of patients with localized non-small cell lung cancer will relapse if treated with surgery alone. Adding chemotherapy produces only a modest improvement in overall survival, and it comes with toxicity," said Tina Cascone, MD., Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology and lead author of the study. "The results from our study with neoadjuvant combination immunotherapy are particularly encouraging in that we found that this dual treatment can induce higher pathologic responses and trigger immunological memory. This may translate into a reduced risk for tumor relapse in more patients with early stage non-small cell lung cancer."

Study design and secondary endpoints

The Phase II single-institution study enrolled 44 patients with surgically resectable stage IA to IIIA NSCLC between June 2017 and November 2018. The median age of trial participants was 66 years old, and 64% were male. Participants were 84% white, 9% Black and 5% Asian. Most participants had a history of smoking: 23% identified as current smokers and 59% as former smokers.

Patients were randomized to one of two treatment arms with immune checkpoint inhibitors prior to surgery: 23 received three doses of nivolumab alone and 21 received three doses of nivolumab plus one dose of ipilimumab. Each arm was compared against historical controls of neoadjuvant chemotherapy. Overall, 41 patients completed the planned three doses of therapies, 37 patients had surgery on trial and two patients underwent surgery off trial after additional therapies.

Among the 37 patients who had surgical resection on the study, the combination arm showed higher MPR rates (50% versus 24%) and fewer viable tumor cells at resection than monotherapy (a median of 9% versus 50%). Combination therapy also showed better pathological complete response rates than monotherapy (38% versus 10%). After a median follow-up of 22 months, median overall survival and lung cancer-related recurrence-free survival were not reached.

Toxicities were manageable overall, with no new safety concerns compared to known adverse event profiles of either drug. The median time to surgery was 31 days after the last dose of nivolumab. Some patients experienced nodal immune flare (NIF), or the appearance of nodal disease progression on radiographic imaging, which invasive node biopsy revealed to be immune cell infiltration rather than malignant disease.

Exploratory analyses reveal immune impact, potential biomarkers

In an exploratory analysis of resected tissues, investigators found ― and reported for the first time ― higher levels of immune cell infiltration in tumors treated with combination therapy, including an abundance of CD3+ and CD3+CD8+ T lymphocytes, tissue-resident memory and effector memory T cells. Tumors that responded better to treatment had higher PD-L1 expression at baseline, but responses were also observed in those without PD-L1 expression in tumor cells.

The researchers analyzed the gut microbiome, as well, and found that pathologic response to combination therapy was associated with the presence of certain fecal microbes that also have been correlated with immunotherapy response in melanoma and other cancers. Immune checkpoint inhibitor therapy did not significantly affect the diversity or composition of the microbiome in this study.

"Our exploratory results suggest the gut microbiome may play a role in responses to neoadjuvant immune checkpoint inhibitors in lung cancer," Cascone said. "The immune microenvironment findings also give us an opportunity to look at immune cell populations and potential biomarkers that can be evaluated in the future to identify those patients who are most likely to benefit from these agents in new prospective trials."

The NEOSTAR trial has been amended to a modular platform design, which provides the opportunity to add treatment arms to rapidly test and advance promising new neoadjuvant therapeutic combinations. Results from a third arm testing neoadjuvant nivolumab plus chemotherapy are expected later this year. A fourth arm testing the combination of dual immunotherapy plus chemotherapy is ongoing.

"The NEOSTAR trial results set the stage for evaluating the role of dual immunotherapy added to neoadjuvant chemotherapy, which we are currently exploring, and expediting the investigation of novel agents in the perioperative setting," Cascone said. "This is a population with potentially curable disease. We should do whatever it takes to minimize the risk of relapse and increase the cure rates for these patients."

The NEOSTAR trial was supported by the Lung Cancer Moon Shot, part of MD Anderson’s Moon Shots Program, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives. Boris Sepesi, M.D., associate professor of Thoracic and Cardiovascular Surgery, served as co-principal investigator of the study. A full list of co-authors and author disclosures can be found in the paper.

Additional research support was provided by Bristol Myers Squibb, the National Institutes of Health/National Cancer Institute (5P50CA070907, P30 CA016672), the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Conquer Cancer Foundation Career Development Award, the Connie Rasor Endowment for Cancer Research, the Bruton Endowed Chair in Tumor Biology, the Translation Molecular Profiling Immuno-profiling Laboratory, the MD Anderson Physician Scientist Program, the Khalifa Bin Zayed Al Nahyan Foundation, the Ford Petrin Donation, Rexanna’s Foundation for Fighting Lung Cancer and the Bob Mayberry Foundation.

NKarta Therapeutics’ NKT Cells Elicit Better Response than CAR-T Cells Alone

On February 18, 2021 NKarta Therapeutics is using engineered chimeric antigen receptor natural killer cells (CAR-NK cells) for allogeneic therapy, reported that it showing substantial benefits both in vitro and in vivo, according to James Trager, CSO, speaking Wednesday at the virtual CAR-TCR Summit – Europe (Press release, Nkarta, FEB 18, 2021, View Source [SID1234575345]).

Specifically, one of NKarta’s two lead compounds, NKX019, "showed robust activity, longer half-life than non-engineered NK cells, faster onset of activity, and the production of fewer cytokines than CAR T cells. A first-in-human trial of NKX019 in B cell malignancies is planned for 2H 2021," Trager said.

"Natural killer cells are the cornerstone of innate immune surveillance," Trager said. They offer allogeneic, "off-the-shelf" accessibility.

NKarta’s engineering enhances their persistence and tumor targeting.

"They are more potent when used allogeneically, and can be scaled to a large degree. They also can be cryopreserved, which lowers the cost of manufacturing," Trager said.

The company’s engineered NK cell program is based on four core technologies. For expansion, the program co-cultures cells with a stimulatory cell line to achieves high doses. Persistence is achieved by expressing membrane-bound IL-15 (mbIL15). For tight targeting, the cells are engineered to express optimized CARs.

"Researchers can put on different targeting heads to change the tropism of the cells," Trager said.

Cryopreservation, the fourth technology, exacts no toll on the cells. Their effectiveness matches that of non-cryopreserved cells.

Notably, NKarta expands the cells before transducing them.

"This puts the expensive part of the process up front," he explained. "Efficacy is much greater when cells are in a robustly proliferatively state, so the expansion and retroviral engineering occur during the first few days." Although such early expansion is not necessarily easy to achieve, "working with small cell numbers lowers cost of goods."

"After that, we’re expanding in a bioreactor," he continued, where continued expansion is driven by the expression of mbIL-15.

This approach drives large-scale manufacturing, enabling NK cells to be expanded more than 1,000-fold (including viral transduction) in two weeks. Trager shared a chart showing the expansion level at 3,364 cells after 15 days. Projected cost estimates for commercial manufacturing, at 500 doses per batch, are approximately $2,000 per dose.

"That’s very competitive in the cell therapy field," Trager said.

"A lot of work goes into this," he pointed out, discussing NK cell engineering. "NK cells, even before we engineer them, provide initial control over tumor cells, but they lose control after a couple of challenges."

NKarta’s engineered, but-not-yet optimized CAR NK cells, in contrast, can withstand six to seven challenges. Optimized CAR-NK cells withstood more than seven challenges by tumor cells.

"Cryopreservation is difficult to achieve while maintaining potency," Trager noted, but NKarta seems to have succeeded. In a chart comparing the activity of cryopreserved and thawed CAR-NK cells to fresh and non-engineered NK cells, the differences in activity among fresh cells and three runs of frozen and thawed NKX101 cells were minuscule.

The real difference was between engineered and non-engineered cells. Tumor activity was approximately three-fold lower for fresh and frozen/thawed CAR-NK cells than non-engineered NKs, and approximately six-fold lower than for controls, thus reinforcing the superiority of the engineered cells.

As Trager said, NKX019, a CD-19-targeted CAR NK, provides "stunning potency" and "options for patients the point of need with, possibly, less risk or toxicity."

Others are reporting beneficial results, too. A trial at MD Anderson Cancer Center (published in the New England Journal of Medicine last year) involving Takeda’s CAR19-NK showed complete responses in more than half of patients with advanced B cell malignancies, and no instances of cytokine release syndrome, graft versus host disease, or neurotoxicity.

NKarta’s studies in mice indicated that cryopreserved NKX019 inhibited tumor activity in lymphoma models, as well as prolonged persistence in tumor-naïve mice. Non-engineered NK cells "have a half-life of about nine days. We can roughly double that with engineering," Trager elaborated.

The goal of this therapy is to maintain the NK cells’ potency while delivering a large number of cells and to ensure acceptable safety profiles. In the case of NKX019, cytokine generation is one-to-two levels of magnitude lower than with unengineered CAR T cells so, Trager surmised, "there’s low risk of triggering cytokine release syndrome."

Additionally, NKX019 works swiftly, with a faster onset of activity and enhanced potency that combine to kill tumor cells faster than CAR19 T cells.

NKarta also is exploring the synergy between NK and T cells for enhanced potency. "When we combine the two cell types, we see greater potency, and additive activity… that is greater than the sum of the individual components," he said.

That synergy between NK and T cells stimulated NK cell proliferation and depressed – but did not halt – T cell proliferation. Furthermore, combining CAR19-NK and CAR19-T cells lowered the accumulation of cytokines associated with cytokine release syndrome. "NK cells act as a sink for cytokines," Trager pointed out.

In mouse models, "The NK or T cells provided limited control but, when combined, survival extended to four months (and in one mouse, six months) before dying of natural causes.

NKarta is eager to learn, later this year, whether such benefits translate to humans.