On January 11, 2022 2seventy bio, Inc. (Nasdaq: TSVT), an emerging immuno-oncology cell therapy company, reported an update on the company’s outlook for 2022 (Press release, 2seventy bio, JAN 11, 2022, View Source [SID1234598573]).

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"It has been a privilege to launch 2seventy bio with such a strong foundation out of the gate including a first-in-class CAR-T for multiple myeloma with $1-2B late lines global peak sales potential, a highly differentiated product engine already delivering candidates to the clinic, strong financial health with a disciplined operating structure and a team that has extensive experience in the cell therapy field," said Nick Leschly, chief kairos officer. "As we double down on our goal of leading the future of oncology cell therapy, our vision is simple: design, learn and iterate to build the most powerful T-cell based solutions for patients with cancer. We are one of few companies that have the tools, infrastructure, experience and heart to deliver these new medicines with potential to create more time for our patients."

ABECMA

Since receiving FDA approval for ABECMA on March 26, 2021, ABECMA has generated approximately $150M in total U.S. revenue, which is shared equally by 2seventy bio and Bristol Myers Squibb (BMS). In response to significant demand, 2seventy bio and BMS are investing to increase capacity across the supply chain, with the goal to improve capacity and treat substantially more patients in the U.S. commercial setting. We anticipate U.S. revenue of $250-300M in 2022. We expect revenue to be driven by continued strong demand in 2022-2023 and to grow into 2023 and beyond. We continue to invest in earlier lines of therapy with data anticipated from the proof-of-concept KarMMa-2 study in second-line patients by the end of 2022, and potentially pivotal data, anticipated in 2023, from the registrational KarMMa-3 study in third-line patients. Based on the forecasted commercial ramp and the investment in earlier lines of therapy, we expect that ABECMA’s success will contribute cash back to fund the rest of the 2seventy bio pipeline starting in 2023.

Recently presented results from the ongoing CRB-402 clinical study of bb21217, a next-generation anti-BCMA CAR T, confirmed the hypothesis that bb21217 has more naïve T cell-phenotype and delivered encouraging durability of responses for patients achieving complete response. Based on the strength of the ABECMA clinical data and high commercial interest, 2seventy bio and BMS do not plan to pursue further development of bb21217. 2seventy bio will leverage the learnings from this program to further strengthen its oncology pipeline.

PIPELINE

"With the IND for our first regulatable CAR T cell program (SC-DARIC33 for the treatment of pediatric and young adult AML), in collaboration with Seattle Children’s Therapeutics, cleared earlier in 2021 and the recent clearance of the IND for our bbT369 program for the treatment of B-NHL, we have achieved our goal of delivering two INDs in 2021," said Philip Gregory, D.Phil., chief scientific officer. "More than just numbers, each of these programs is an example of the type of bold and innovative product candidates that will be the hallmark of 2seventy bio’s medicines. Of course, this is just the beginning of what we anticipate emerging from our research engine, which is fueled by a suite of tools and technologies that enable us to focus on the biology of cancer and create fit-for-purpose cell therapies with the goal of achieving deep and durable responses."

bbT369 IND Cleared – In December 2021, the FDA cleared the Investigational New Drug (IND) application for bbT369, an investigational dual-targeted CAR T cell therapy with a gene edit for patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL). bbT369 has three layers of innovation. First, it targets a novel combination of antigens highly expressed in B cell lymphomas (CD79a and CD20) in an effort to achieve improved anti-tumor efficacy and to address antigen escape, a known mechanism of resistance to CD19-targeted CAR T cell therapy. Second, we provide split co-stimulation to drive robust T cell activation in response to either antigen. Third, the CAR T cell is also edited to remove CBLB, a negative regulator of T cell function, which we believe will drive increased expansion, resist anergy and maintain potency in sub-optimal conditions for T cell activation. Preclinical studies demonstrated bbT369 activity against single and low antigen tumors and achieved deep and durable responses. CRC-403 (NCT05169489), an open-label, multi-site Phase 1/2 dose-escalation study of bbT369, will begin enrollment in early 2022 and will serve as a proof-of-concept assessment of 2seventy bio’s proprietary gene editing platform, dual-targeting strategies and split co-stimulation signaling technology.

MUC-16 Program – Today, as part of a strategic collaboration between Regeneron and 2seventy bio, the companies named their first CAR-based solid tumor program utilizing bbT4015, an engineered CAR T cell therapy targeting MUC16. MUC16 is a large extracellular protein expressed on >80% of ovarian tumors. Preclinical data have shown robust single agent (CAR T alone) activity, including in stringent tumor rechallenge models. This program represents a platform for titratable pharmacologic combination approaches to enhance CAR T cell activity with the goal of developing a best-in-class cell therapy. The companies anticipate pursuing an IND in 2023.

FINANCIAL OUTLOOK

2seventy bio entered 2022 with approximately $360M in cash, cash equivalents and marketable securities. The company has done significant work and prioritization in order to reshape the cost structure and increase the proportion of investment on R&D while streamlining general and administrative costs. 2seventy bio anticipates a net cash spend of $220-250M for 2022 and a cash runway into the second half of 2023 based on existing cash, cash equivalents and marketable securities.

UPCOMING ANTICIPATED MILESTONES

ABECMA

Anticipate $250-300M total U.S. revenue in 2022
Increasing manufacturing capacity throughout 2022
KarMMa-2 study in 2L proof-of-concept data in 2022
KarMMa-3 study in 3L+ registrational data in 2023
Pipeline

Infusion of first patients in PLAT-08 study of SC-DARIC33 in AML in 2022
Initial assessment of feasibility of SC-DARIC33 drug product manufacturing and drug regulated anti-CD33 activity in 2H 2022
Infusion of first patients in CRC-403 study of bbT369 in B-NHL in 2022
Initial assessment of feasibility of bbT369 drug product manufacturing and patient safety in 2H 2022
Investor Content Available on 2seventybio.com

An updated corporate presentation can be found on the investor relations section of our website, View Source For more detail on 2seventy bio’s pipeline, programs and strategic vision, please visit View Source to view video messages from our leadership team.

About ABECMA (idecabtagene vicleucel; ide-cel)

ABECMA is the first-in-class B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immunotherapy approved in the U.S. for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody. ABECMA has also received approval in the European Union, Canada and Switzerland. ABECMA recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion and subsequent cytolytic killing of BCMA-expressing cells. ABECMA is being jointly developed and commercialized in the U.S. as part of a Co-Development, Co-Promotion and Profit Share Agreement with 2seventy bio and Bristol Myers Squibb. Bristol Myers Squibb continues to assume sole responsibility for ABECMA drug product manufacturing and commercialization outside of the U.S.

2seventy bio and Bristol Myers Squibb’s broad clinical development program for ABECMA includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4, KarMMa-7) in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.

On January 11, 2022 Neogene Therapeutics, Inc., a biotechnology company pioneering a new class of fully individualized T cell receptor (TCR) therapies to treat cancer, reported an exclusive, worldwide license agreement with the National Cancer Institute (NCI), an institute of the National Institutes of Health (NIH), for a portfolio of TCRs targeting KRAS and TP53 mutations for the treatment of patients with cancer (Press release, Neogene Therapeutics, JAN 11, 2022, View Source [SID1234598572]). These TCRs were discovered in the laboratory of Steven Rosenberg, M.D., Ph.D., Chief of Surgery at the NCI and a pioneer in the fields of immunotherapy and gene therapy for patients with advanced cancers.

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This portfolio of TP53 and KRAS targeted T cell therapies complements Neogene’s proprietary neoantigen TCR discovery and T cell engineering platform. Neogene’s platform aims to identify neoantigens and suitable TCRs to target for individual patients and enable the engineering of T cells with these neoantigen-specific TCRs for patients suffering from a broad spectrum of solid tumors.

"TP53 and KRAS are among the most commonly mutated genes in cancer, however, very few therapies specifically targeting these mutations are currently available, and there is a high unmet need for effective treatment options," said Raphaël Rousseau, M.D., Ph.D., Chief Medical Officer of Neogene Therapeutics. "We’re excited to have entered into this agreement with the NIH to expand our current development program and address this need through the development of TCR-engineered T cell therapies for patients with tumors that harbor these common mutations."

Neogene has been granted worldwide rights to develop, manufacture and commercialize this TCR portfolio of autologous and allogeneic T cell therapy product candidates that are engineered with CRISPR technology for the treatment or prevention of cancer.

"Adding these TCRs to our pipeline will enable Neogene to flexibly develop them alone or in combination with individualized neoantigen TCR cell therapies, providing us with the opportunity to diversify our pipeline and potentially target multiple neoantigens in individual patients," said Carsten Linnemann, Ph.D., President, Chief Executive Officer and Co-Founder of Neogene Therapeutics. "This is a strategic step toward strengthening Neogene’s breadth and position as a global leader in the development of TCR therapies for the treatment of solid cancers."

Pursuant to the terms of the license agreement, Neogene will provide an upfront payment and certain clinical, regulatory, and sales milestone payments, as well as royalties on net sales of products covered by the license.

On January 11, 2022 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported 2022 corporate priorities and anticipated clinical development and research milestones (Press release, Xencor, JAN 11, 2022, View Source [SID1234598571]).

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"The plug-and-play nature of Xencor’s XmAb Fc domains and our protein engineering expertise have enabled a broad portfolio of bispecific antibody and engineered cytokine drug candidates, as well as a multitude of partnerships, which have thus far produced three marketed products," said Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor. "In 2022, we expect emerging clinical data to continue to support our own mid-stage development plans for vudalimab and plamotamab, and we will continue to initiate new studies with potential to present new data that may define a path to registration for these programs. Additionally, we remain excited by the opportunities to use our technological competitive advantage to address challenging areas of biology and continually grow our portfolio, now with multiple reduced-potency cytokines and CD3 and CD28 T cell engagers in development, both internally at Xencor and with our partners."

Execute on development plans for mid-stage XmAb bispecific antibody programs

Vudalimab (PD-1 x CTLA-4), designed to activate intra-tumoral T cells
Xencor presented updated Phase 1 expansion cohort data in November 2021 and is enrolling a Phase 2 study in patients with metastatic castration-resistant prostate cancer (mCRPC), where vudalimab is being evaluated as a monotherapy or in combination depending on the tumor’s molecular subtype. Xencor plans to:

Initiate a second Phase 2 study, evaluating vudalimab in patients with advanced pelvic tumors, including clinically defined high-risk mCRPC and certain gynecologic malignancies.
Present initial data from the Phase 2 study in mCRPC, in the second half of 2022.
Plamotamab (CD20 x CD3), for B-cell malignancies
Xencor presented updated Phase 1 dose-escalation data in December 2021 and is currently recruiting non-Hodgkin lymphoma patients in expansion cohorts of plamotamab monotherapy at the Phase 2 recommended dose. Xencor entered a global collaboration and license agreement with Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, to expand the Company’s strategy to develop plamotamab as part of multiple highly active chemotherapy-free regimens across B-cell cancers. Xencor plans to:

Initiate potentially registration-enabling Phase 2 study, evaluating plamotamab in combination with tafasitamab and lenalidomide, in patients with relapsed or refractory DLBCL.
Incorporate subcutaneous administration into the ongoing Phase 1 monotherapy study.
Present data from Phase 1 expansion cohorts, in the second half of 2022.
Develop B-cell targeted CD28 bispecific antibodies to selectively enhance T-cell cytotoxic activity in combination with plamotamab.
Advance multiple potency-reduced XmAb cytokine programs in oncology and autoimmune disease

Xencor’s engineered, potency-reduced cytokines are designed to expand select immune cell populations, to have longer circulating half-life and to be tolerable, active and easy to administer. XmAb cytokines incorporate Xtend extended half-life technology.

XmAb306, potency-reduced IL15/IL15Rα-Fc fusion protein
Recently, Xencor announced encouraging initial dose-escalation data from an ongoing Phase 1 study in patients with advanced solid tumors, in which the preliminary safety profile, biological activity and signs of anti-tumor activity provide initial validation for the Company’s approach to engineering cytokine therapeutics. Xencor plans to:

Announce new clinical studies of XmAb306 in combination with other agents, such as NK- or T-cell recruiting therapies in collaboration with the Company’s co-development partner.
XmAb564, potency-reduced IL2-Fc fusion targeting regulatory T cells in autoimmune disease
Xencor plans to:

Present tolerability, durability and biomarker data from the ongoing Phase 1 single-ascending dose study in healthy volunteers.
Identify development indications and initiate a multiple-ascending dose study in select patient populations.
XmAb662, potency-reduced IL12-Fc fusion protein designed to increase tumor immunogenicity
Xencor plans to:

Submit an investigational new drug (IND) application in 2022, and initiate a Phase 1 study in patients with advanced solid tumors in 2023.
Xencor plans to present preclinical data from additional cytokine-Fc programs in 2022.

Expand the Company’s portfolio with the first internally developed XmAb 2+1 CD3 and XmAb CD28 bispecific antibodies advancing into Phase 1 clinical studies

XmAb819 (ENPP3 x CD3), XmAb 2+1 bispecific antibody for renal cell carcinoma (RCC)
The multivalent XmAb 2+1 bispecific antibody format enables greater selectivity for tumor cells compared to normal cells, which also express ENPP3 at lower levels. Xencor plans to:

Initiate a Phase 1 study evaluating XmAb819 in patients with RCC in the first half of 2022.
XmAb808 (B7-H3 x CD28), tumor-selective, co-stimulatory CD28 bispecific antibody
CD28 is a key immune co-stimulatory receptor on T cells; however, the ligands that activate T cells through CD28 are usually not expressed on tumor cells. Targeted CD28 bispecific antibodies may provide conditional co-stimulation of T cells, for example, to T cells recognizing neoantigens or in concert with CD3 T-cell engaging bispecific antibodies. XmAb808 targets the broadly expressed tumor antigen B7-H3. Xencor plans to:

Submit an IND application in the first half of 2022, and initiate a Phase 1 study in patients with advanced solid tumors in the second half of 2022.
Cash Position and Financial Guidance

Xencor ended the fourth quarter of 2021 with unaudited cash, cash equivalents, receivables and marketable debt securities totaling approximately $660 million. Based on current operating plans, Xencor expects to have sufficient cash resources to fund research and development programs and operations through 2025.

On January 11, 2022 Advaxis, Inc. (Nasdaq: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products, reported updated data from the Company’s ongoing Phase 1/2 study evaluating ADXS-503 in combination with KEYTRUDA (Press release, Advaxis, JAN 11, 2022, View Source [SID1234598570]). ADXS-503 is the first drug construct from the ADXS-HOT off-the-shelf, cancer-type specific, immunotherapy program which leverages Advaxis’ proprietary Lm technology platform to target hotspot mutations that commonly occur in specific cancer types as well as other proprietary, tumor-associated antigens.

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"NSCLC patients resistant to PD-1/-L1 checkpoint inhibitors (CPIs) have limited treatment options. Current treatment guidelines allow for CPI re-challenge but the overall response rate (ORR) seen with this approach is below 10% and disease control rate (DCR) of up to 45%. Thus, it is encouraging to report that in Part B of the study, the documented ORR has now increased to 15.4 % and DCR has reached 46% in the first 13 evaluable patients treated with ADXS-503 as an add-on therapy at progression with pembrolizumab," said Dr. Jonathan W. Goldman, Associate Professor of UCLA Hematology and Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology at UCLA Medical Center in Santa Monica, California. "These results now include a second additional patient with a partial response and 4 patients with stable disease. The durable nature of disease control is also encouraging and includes two patients with ongoing partial responses for 702 and 189 days, and three patients with stable disease sustained for 448, 175 and 117 days."

Dr. Goldman continued, "If the addition of ADXS-503 to patients progressing on pembrolizumab could achieve a durable response rate at or above 20%, with minimal added toxicity, this combination could become a new therapeutic option for this underserved patient population. We look forward to completing the enrollment of a total of 18 patients in Stage 1 of Part B."

Dr. Andres A. Gutierrez, Chief Medical Officer of Advaxis, said, "The enrollment of Part C of the study, evaluating NSCLC patients treated in first line with ADXS-503 in combination with pembrolizumab, has also started. Given the median progression free survival (PFS) achieved with CPIs alone in first line NSCLC is 7-10 months, and the encouraging results from Part B in this study, it is expected that the addition of ADXS-503 to pembrolizumab may achieve meaningful improvements in PFS above standard of care with a target of greater than or equal to 9 months. Three patients have thus far been evaluated showing a disease control rate of 67%, with two patients sustaining stable disease for 332 and 94 days. As expected, the combination therapy has been well tolerated with mild and transient flu-like syndrome a few hours after the infusion of the drugs but without increasing the frequency of immune-related adverse events."

Ken Berlin, Chief Executive Officer of Advaxis, said, "Major milestones for the ADXS-503 trial in the second half of 2022 include updated clinical and immunogenicity data for all patients in Stage 1 in Part B and from up to 10 patients in Part C. Also, initial clinical and immunogenicity data from the ADXS-504 trial in early prostate cancer are expected to be reported in the second half of this year."

Key Updates and Future Data Read-outs:

In Part B of the study, 14 patients have been treated and 13 are evaluable with ADXS-503 as an add on therapy to patients failing pembrolizumab as last therapy with all of them evaluable for safety and efficacy
Combination therapy was well tolerated with no dose-limiting-toxicity (DLT) or added toxicity of the two drugs. Grade 1 and 2, transient and reversible events included chills, fever, fatigue, in approximately half of the patients
The ORR was 15.4% (2/13) and DCR was 46% (6/13)
Clinical benefit was durable, with two partial responses (PR) sustained for 702 and 189 days, respectively, and 3 patients with stable disease (SD), sustained for 448, 175 and 117 days. Another patient with stable disease is still under evaluation
Available data demonstrate that patients who achieve clinical benefit include those with PD-L1 expression ≥50%, secondary resistance disease to pembrolizumab and those who show proliferation and/or activation of NK and CD8+ T cells within the first weeks of therapy
Additional translational studies, including flow cytometry, ELISPOT, cytokines/chemokine levels, mutational analysis, MSI TMB and cfDNA and their clinical correlates, will be presented at an upcoming medical meeting
In Part C of the study, 3 patients with newly diagnosed NSCLC have been treated with ADXS-503 plus pembrolizumab. Treatment has been well tolerated and disease control rate thus far is 67%, with two patients sustaining stable disease for 332 and 94 days.
Enrollment in Part B and Part C of the ongoing study will continue to further evaluate the clinical benefit and immune effects of adding on ADXS-503 to patients progressing on pembrolizumab
The Phase 1/2 clinical trial of ADXS-503 is seeking to establish the recommended dose, safety, tolerability and clinical activity of ADXS-503 administered alone and in combination with a KEYTRUDA in approximately 50 patients with NSCLC, in at least five sites across the U.S. The two dose levels with monotherapy in Part A, (1 X108 and 5 X108 CFU) have been completed. Part B with ADXS-503 (1 X108 CFU) in combination with KEYTRUDA is currently enrolling its efficacy expansion for up to 18 patients at dose level 1 (1 X108 CFU + KEYTRUDA) with the potential to proceed to dose level 2 (5 X108 CFU + KEYTRUDA) at a later date. Part C of this ADXS-503 trial evaluating ADXS-503 in combination with KEYTRUDA (1 X108 CFU + KEYTRUDA) as a first line treatment for patients with NSCLC with PD-L1 expression ≥ 1% or who are unfit for chemotherapy, is currently enrolling patients.

About ADXS-503
ADXS-503 is a live attenuated Listeria monocytogenes (Lm)-based, off-the-shelf immunotherapy that is under clinical development as a single agent and in combination with other cancer therapies for the treatment of squamous and non-squamous non-small cell lung cancer (NSCLC). ADXS-503 is bioengineered to secrete an antigen-adjuvant fusion protein consisting of a truncated fragment of listeriolysin O (tLLO) fused to 22 NSCLC-associated tumor antigens. The proposed mechanism of action of Advaxis’ Lm-based immunotherapy is to stimulate both the innate and adaptive immune systems to initiate a coordinated antitumor response culminating in the generation of tumor antigen-specific T cells that are capable of infiltrating and destroying the tumor.

On January 11, 2022 Amgen (NASDAQ:AMGN) and Arrakis Therapeutics reported a research collaboration focused on the discovery and development of RNA degrader therapeutics against a range of difficult-to-drug targets in multiple therapeutic areas (Press release, Amgen, JAN 11, 2022, https://www.prnewswire.com/news-releases/amgen-and-arrakis-therapeutics-announce-multi-target-collaboration-to-identify-novel-rna-degrader-small-molecule-therapeutics-301458380.html [SID1234598569]). This new class of "targeted RNA degraders" consists of small molecule drugs that selectively destroy RNAs encoding disease-causing proteins by inducing their proximity to nucleases.

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Under the terms of the agreement, Arrakis will lead research activities for the identification of RNA-targeted small molecule (rSM) binders against a broad set of targets nominated by Amgen. Both parties will collaboratively design and functionalize these molecules to specifically degrade targeted RNAs, and Amgen will lead further preclinical and clinical development activities. Amgen will pay $75 million upfront to Arrakis for five initial programs and will have the option to nominate additional programs. For each program, Arrakis will be eligible for additional payments from Amgen for preclinical, clinical, regulatory and sales milestones, and royalties up to low double digits. Arrakis could potentially receive several billion dollars in future payments if all milestones are met and future program options are exercised.

"Targeted RNA degradation is an exciting area that is pushing the boundaries of drug discovery and design," said Raymond Deshaies, Ph.D., senior vice president of Global Research at Amgen. "The collaboration with Arrakis combines Amgen’s induced proximity expertise in discovering multispecific molecules to target the biologic mechanisms of disease and Arrakis’ pioneering discovery platform to predict RNA structures and identify small molecules that bind to them, significantly broadening the possibilities of addressing difficult protein targets considered undruggable because they may not have binding sites needed for conventional medicines. Combining this approach with Amgen’s targeted protein degradation induced proximity research already underway has the potential to significantly expand the druggable genome."

By integrating the capabilities of the two innovative discovery platforms from Amgen and Arrakis, the collaboration creates an opportunity to design and engineer targeted RNA degraders. Amgen has built its Induced Proximity Platform to identify multispecific molecules that harness the power of cell biology by forming novel connections between natural effectors and targets. One end of the molecule binds to the target to be altered (inhibited, activated or destroyed) and the other end binds to a cellular effector that acts on the target, offering the potential to engage a broad range of cellular mechanisms to treat disease. With targeted RNA degraders, the effector, such as a ribonuclease or other RNA modulator, is brought into proximity of the RNA to degrade or otherwise modify the disease-causing RNA of interest. This complements Amgen’s existing efforts to target RNA with siRNA. In this collaboration, Arrakis’ rSM platform will be applied as a drug discovery engine to identify small molecules that bind target RNA. These rSMs will then be functionalized with nuclease recruiters to create heterobifunctional molecules that trigger degradation of disease-relevant RNA targets.

"We are excited to partner with Amgen’s strong research team to pursue a shared goal of creating a new class of medicines that induce degradation of disease-causing RNAs. This collaboration further demonstrates the utility of our proprietary rSM discovery platform for targeting RNA with small molecules and paves the way for creating powerful new treatments for patients," said Michael Gilman, Ph.D., chief executive officer of Arrakis. "Based on our long-term goal to build a broad and industry-leading platform that adapts state-of-the-art drug discovery tools to target RNA biology, we have enabled a range of different applications and collaborations to leverage our science, a strong capital position and the ability to grow our business and our impact to advance RNA-targeted drug programs for diseases unaddressed by today’s medicines."