HER2 x TLR8

Pictured: A white blood cell charging an ADC/Taylor Tieden for BioSpace The antibody drug conjugate market is one of the fastest growing in the pharmaceutical industry, expanding from $1 billion to $10 billion in yearly sales between 2015 to 2023—and expected to rise to $28 billion by 2028, according to Evaluate. But despite their high level of efficacy in delivering cytotoxic payloads directly to tumor cells, antibody-drug conjugates (ADCs) are “unfortunately not curing people,” Tim Lowinger, senior vice president and chief science and technology officer at Mersana Therapeutics, told BioSpace. There are real benefits, he said, including prolonged life and extended progression-free survival, yet reemergence occurs. With 15 ADCs approved as of February 2024 and many more in company pipelines, drug developers are expanding their focus to ask how they can build on the success of ADCs. Enter immunostimulatory ADCs (iADCs), sometimes called immune-stimulating antibody conjugates (iSACs). Immunotherapies are already proven cancer drugs, and delivering these treatments via ADC offers the potential to precisely target tumor cells while protecting normal cells, said Jane Chung, president and chief operating officer at Sutro Biopharma. “Engineering very targeted therapies so that you can dial up the potency of whatever payload you’re using, that’s going to . . . really move the needle on advancing cancer care,” Chung told BioSpace. Hitting the Gas on Immune Response The excitement around iADCs stems from the success of checkpoint inhibitors, said Nathan Tumey, an associate professor at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences. Tumey told BioSpace that checkpoint inhibitors essentially take the brakes off of the immune system, enabling it to attack cancer cells. iADCs offer the potential to take this further and “step on the gas,” ramping up the immune response. Some of the cytotoxic payloads carried by current ADCs are also known to cause immunostimulatory cell death by creating more neoantigens in the tumor, Lowinger explained, driving companies like Pfizer to combine its auristatin-based ADC with a checkpoint inhibitor for a synergistic effect. For Lowinger, this aspect raises the question: “If a secondary mechanism of immunostimulatory cell death can have a benefit, what if you made this your primary mechanism of action?” That idea is driving interest now in iADCs. Biopharma companies are targeting a number of pathways to activate the innate immune system. Mersana, for example, is developing a stimulator of interferon genes (STING) agonist. While STING activation has known anti-cancer effects, it’s been a historically difficult target because activating it throughout the body can be toxic. The drug needs to be activated only once bound to tumor cells—which is precisely what ADCs were made to do. Using its immunosynthen platform, Mersana designed its STING agonist to stay put once delivered inside the cell with a stable, cleavable linker scaffold. Its lead asset is currently in Phase I trials against multiple HER2-positive solid tumor types. Instead of using the monoclonal antibody trastuzumab often paired with current HER2-targeting ADCs, Mersana developed a novel antibody. Therefore, it could potentially be used in combination with established, cytotoxic ADCs, as the two would not be competing for the same binding site. Meanwhile, Burlingame, CA–based Tallac Therapeutics has TAC-001, a TLR9 agonist ADC in a Phase I/II trial for solid tumors. While most ADCs carry small molecule payloads, Tallac’s platform can conjugate an oligonucleotide to an antibody, allowing modalities beyond cytotoxicity, Hong Wan, CEO of Tallac, told BioSpace. Because TLR9 is part of the innate immune system and expressed near-exclusively on immune cells, it has potential for a durable response via “immune memory,” in addition to increased safety and tolerability, Wan said. Wan pointed to the high toxicity of many current ADCs and the very high target protein expression required in the tumor to elicit the cytotoxic effect, which can restrict the efficacy to a limited patient population. In contrast, iADCs don’t require very high target expression, she said, so they could potentially benefit a broader patient population. Though data from a Phase I/II dose escalation trial have not yet been disclosed, Wan indicated the company has seen a positive response to TAC-001 in melanoma. The candidate has also been studied in the preclinical setting alongside a cancer vaccine, with positive results shared in April. And it has been combined with multiple chemotherapies preclinically. Next, Tallac is planning to test the candidate in combination with a PD1 checkpoint inhibitor. In a twist on the combination approach, South San Francisco’s Sutro—in partnership with Astellas—is taking a dual conjugation approach with its iADC. “When we put both elements, the chemotherapy and the PD1 immune activator, on an antibody . . . we reduce the tumor volume and activate the immune system to get rid of the remaining tumor cells,” said Hans-Peter Gerber, chief scientific officer at Sutro. Balancing ratios between the two elements can be precarious and the technology is critical, Gerber told BioSpace, adding that he believes Sutro stands alone in being able to dial in the correct balance. While the Astellas-partnered program does not yet have a disclosed target, Gerber said the obvious strategy would be to start in indications where immune checkpoint inhibitors already work, such as melanoma and lung and kidney cancers, then expand to populations that cannot benefit from a checkpoint inhibitor. Colorectal cancer is a “bold goal” for the company, he added. A Difficult Path The path has not been a smooth one for iADCs, though. Thanks to some highly visible clinical failures, “the field has a bad rap,” Tumey said. In 2022, an iADC combining an anti-HER2 MAB with a TLR8 agonist failed. Its developer, Silverback Therapeutics, ceased operations and became a shell company for a reverse merger with a different biotech. Two years later, Bolt Therapeutics had essentially the same results for a similar treatment. A HER2-targeting iSAC developed by Novartis also failed a Phase I trial for non-breast malignancies in 2021. “This remains a challenging area for drug discovery with considerable technical risk, as the common targets such as TLR-7, -8, -9 and STING have not yet been successfully drugged with any type of therapy,” Dan Chancellor, vice president of thought leadership at pharma solutions provider Norstella, told BioSpace in an email. He added that the iADC technology is in the beginning stages of development. However, the aforementioned three failures really amount to one, Tumey said. The companies were doing essentially the same thing—using non-cleavable linkers and effector function ADCs targeting HER2—so if one failed, “of course they’re all going to fail.” Additionally, “I think maybe a mistake that the field made early on was trying to go after breast cancer,” he said. While it seemed like the lowest hanging fruit, it’s difficult because it is an immunologically cold tumor. Like Gerber, Tumey said he believes iADCs have the highest potential in areas checkpoint inhibitors have been most successful, like non-small cell lung cancer or bladder cancer. Thanks to the success on the cytotoxic side of the ADC space, Tumey said companies appear to be more willing to take risks, potentially opening the field for meaningful success. iADCs in the Limelight In a notoriously tough biopharma funding climate, iADCs are one area drawing investment from companies. Mersana, for example, has partnerships with both GSK and Merck KGaA. The GSK deal, worth up to $1.4 billion, involves a HER2-targeted iADC currently in a Phase I dose-escalation trial. In 2022, Merck KGaA dropped $30 million up front with another $800 million on the line to conjugate Mersana’s preclinical STING-agonist to Merck KgaA’s proprietary antibodies for up to two targets. Additionally, Astellas Pharma has invested $90 million up front with Sutro to develop iADCs for three targets. Sutro could receive an additional $422.5 million in milestone payments, plus royalties. Lowinger shared the story of a study Mersana conducted treating tumors in mice with the company’s STING iADC: their tumors disappeared. Mersana then rechallenged the mice, and in mice treated with an iADC, tumors would not regrow. “This allows for the hope and dream that there’s a chance to cure patients,” Lowinger said. “I think that’s the big differentiator and why there’s interest in this approach.” Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.

San Francisco-based Bolt Biotherapeutics on Tuesday said it is ending development of its lead cancer drug, laying off half its staff and changing up its leadership.Alongside announcing first quarter earnings, the biotechnology company revealed it will no longer advance its antibody-drug conjugate trastuzumab imbotolimod, or BDC-1001, after concluding the program was unlikely to meet its high bar for advancement.Instead, the company will focus on two earlier-stage candidates: BDC-3042, an agonist antibody now in Phase 1 testing, and BDC-4182, currently in preclinical evaluation. The latter is a product of Bolts immune-stimulating antibody conjugate, or ISAC, platform, which is meant to trigger anti-tumor immune responses. Its aimed at a protein called Claudin 18.2 thats becoming an increasingly popular target among cancer drug developers.The companys ISAC research will continue to be supported by collaborations with Genmab and Toray. The former is funding up to three ISAC candidates through early-stage development, while the latter is funding one ISAC candidate through Phase 1 testing.In a client note downgrading her rating on Bolts stock, Leerink Partners analyst Daina Graybosch described the two newly prioritized programs as at the high end of risk, given novelty and early nature of development. While Graybosch expressed confidence in the promise of Bolts platform, she expects multiple surprises and restarts to come.Bolt is laying off 50% of its workforce, or approximately 50 people, as part of its pipeline reprioritization. The company expects the cuts to extend its cash runway into the second half of 2026.Additionally, Willie Quinn, who was previously Bolts chief financial officer, has replaced Randal Schatzman as CEO. Chief Business Officer Grant Yonehiro will be promoted to chief operating officer, and Chief Medical Offier Edith Perez will move into an advisory role.Shares for Bolt fell around 34% in Wednesday morning trading. The company is now worth about $33 million. '

Nov. 10, 2021 21:05 UTC SEATTLE--(BUSINESS WIRE)-- Silverback Therapeutics (Nasdaq: SBTX) (“Silverback”), a clinical-stage biopharmaceutical company leveraging its proprietary ImmunoTAC technology platform to develop systemically delivered, tissue targeted therapeutics for the treatment of cancer, chronic viral infections, and other serious diseases, today reported financial results for the third quarter ended September 30, 2021, and provided a business update. “In the third quarter, we provided our first interim clinical update for the dose escalation arms of the SBT6050-101 trial, establishing proof-of-mechanism for SBT6050 as evidenced by the activation of the innate and adaptive immune system in patients,” said Laura Shawver, Ph.D., chief executive officer of Silverback. “In a short period of time, we have accumulated a robust clinical data set that has informed our development strategy. We are focused on advancing SBT6050 in patients with HER2-expressing cancers such as gastroesophageal and non-small cell lung, in combination with agents that we believe will maximize the therapeutic potential of our first-in-class TLR8 agonist conjugate. We also look forward to continuing to advance our pipeline, including SBT6290 for patients with bladder, triple negative breast, non-small cell lung, and head & neck cancers, and SBT8230 for patients with chronic hepatitis B virus.” Recent Business Updates: SBT6050 (HER2-TL8 ImmunoTAC) Interim clinical data presented at the European Society for Medical Oncology (ESMO) 2021 Annual Meeting. In September 2021, Silverback presented interim clinical results from the ongoing Phase 1/1b study of SBT6050, including data that establish proof-of-mechanism through SBT6050’s ability to activate myeloid, T and NK cells, as well as evidence of SBT6050 payload localization in the tumor microenvironment. Adverse events reported were consistent with on-mechanism immune activation, and early signals of anti-tumor activity were observed. Selected go forward dose of 0.3 mg/kg SBT6050 in combination with anti-PD-1 therapy in expansion cohorts. Silverback is prioritizing combination with Libtayo in gastroesophageal and non-small cell lung cancers and plans to initiate these expansion cohorts in the fourth quarter of 2021. SBT6050 expanded clinical development strategy announced, leveraging combination with trastuzumab-containing regimens. In the first quarter of 2022, Silverback plans to initiate SBT6050-201, a Phase 1/2 study of SBT6050 combined with Enhertu, or with Herceptin and Tukysa with or without capecitabine, in patients with HER2-expressing or HER2-amplified cancers. SBT6290 (Nectin4-TL8 ImmunoTAC) SBT6290 Investigational New Drug application submitted to the U.S. Food and Drug Administration. Silverback remains on track to initiate the phase 1/1b trial in the first quarter of 2022, and plans to enroll patients with bladder, non-small cell lung, triple negative breast, and head and neck cancers in dose escalation. SBT8230 (ASGR1-TLR8 ImmunoTAC for chronic HBV) SBT8230 preclinical development continues with GLP toxicology studies expected to commence in the first quarter of 2022. Silverback will be providing a preclinical update on the SBT8230 program at the American Association for the Study of Liver Diseases (AASLD) 2021 conference held from November 12-14, 2021. Third Quarter Financial Results For the third quarter ended September 30, 2021, Silverback reported a net loss of $22.7 million, compared to a net loss of $8.1 million for the comparable period in 2020. For the nine months ended September 30, 2021, Silverback reported a net loss of $66.0 million, compared to a net loss of $19.9 million for the comparable period in 2020. Included in the net losses for the three and nine months ended September 30, 2021 were $5.0 million and $14.0 million of non-cash stock-based compensation, respectively, compared to $0.2 million and $0.4 million for the same periods in 2020, respectively. Research and development expenses for the third quarter ended September 30, 2021 were $15.6 million, compared to $6.2 million for the same period in 2020. Research and development expenses for the nine months ended September 30, 2021 were $45.6 million compared to $15.7 million for the same period in 2020. The increases in the Company’s research and development expenses in 2021 were primarily attributable to the advancement of pipeline programs, including SBT6290 and SBT8230, through preclinical development and the continued clinical development of SBT6050. Silverback also incurred additional personnel-related expenses as operations grew in support of program advancements. General and administrative expenses for the third quarter ended September 30, 2021 were $7.0 million, compared to $1.9 million for the same period in 2020. General and administrative expenses for the nine months ended September 30, 2021 were $20.4 million, compared to $4.1 million for the same period in 2020. The increases in general and administrative expenses were primarily attributable to an increase in personnel-related expenses due to increased headcount in 2021, including new executives, as well as increases in salaries, bonuses, and stock-based compensation. The increases in general and administrative expenses were also due to an increase in legal fees, professional fees, and other various general and administrative expenses as we now operate as a public company. As of September 30, 2021, Silverback reported cash, cash equivalents, and investments of $340.6 million compared to cash and cash equivalents of $386.6 million at December 31, 2020, which is expected to fund operating expenses and capital expenditure requirements into 2024. About Silverback Therapeutics Silverback Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on leveraging its proprietary ImmunoTAC technology platform to develop systemically delivered and tissue targeted therapeutics for the treatment of cancer, chronic viral infections, and other serious diseases. Silverback’s platform enables the strategic pairing of proprietary payloads that modulate key disease modifying pathways with monoclonal antibodies directed at specific disease sites. Initially, Silverback is creating a new class of targeted immuno-oncology agents that direct a TLR8 agonist myeloid cell activator to the tumor microenvironment in solid tumors to promote cancer cell killing. Silverback Therapeutics is located in Seattle, Washington. To learn more, visit . Forward-Looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, Silverback’s plans and ability to bring new treatments to patients in need, including potential combination efforts, the progress and expected timing of Silverback’s drug development programs and clinical trials, and the strength of Silverback’s balance sheet and the adequacy of cash on hand. Factors that may cause actual results to differ materially include the risk that compounds that appeared promising in early research or clinical trials do not demonstrate safety and/or efficacy in later preclinical studies or clinical trials, the risk that Silverback may not obtain approval to market its product candidates, uncertainties associated with performing clinical trials, regulatory filings and applications, risks associated with reliance on third parties to successfully conduct clinical trials, the risks associated with reliance on outside financing to meet capital requirements, and other risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "believes," "estimates," "projects," "promise," "potential," "expects," "plans," "anticipates," "intends," "continues," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties that Silverback faces, please refer to Silverback’s periodic and other filings with the Securities and Exchange Commission, which are available at . Such forward-looking statements are current only as of the date they are made, and Silverback assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Silverback Therapeutics, Inc. Condensed Balance Sheets (in thousands, except share and par value data) September 30, December 31, 2021 2020 (unaudited) Assets Current assets: Cash and cash equivalents $ 300,660 $ 386,569 Prepaid expenses and other current assets 4,695 4,087 Total current assets 305,355 390,656 Investments 39,938 — Restricted cash 350 350 Right-of-use asset 5,011 2,180 Property and equipment, net 1,907 1,618 Total assets $ 352,561 $ 394,804 Liabilities and stockholders’ equity Current liabilities: Accounts payable $ 1,720 $ 2,583 Accrued expenses 12,537 5,278 Term loan payable, net — 844 Current portion of lease liability 1,090 896 Total current liabilities 15,347 9,601 Lease liability, net of current portion 5,080 2,326 Total liabilities 20,427 11,927 Commitments and contingencies Stockholders’ equity: Preferred Stock, $0.0001 par value per share; 10,000,000 shares authorized at September 30, 2021 and December 31, 2020; no shares issued and outstanding at September 30, 2021 and December 31, 2020 — — Common stock, $0.0001 par value per share; 200,000,000 shares authorized at September 30, 2021 and December 31, 2020, 35,067,751 and 34,801,537 shares issued and 35,037,136 and 34,701,274 shares outstanding at September 30, 2021 and December 31, 2020, respectively 4 3 Additional paid-in capital 494,916 479,608 Accumulated other comprehensive loss (34 ) — Accumulated deficit (162,752 ) (96,734 ) Total stockholders’ equity 332,134 382,877 Total liabilities, and stockholders’ equity $ 352,561 $ 394,804 Silverback Therapeutics, Inc. Condensed Statements of Operations and Comprehensive Loss (in thousands, except share and per share data) (unaudited) Three Months Ended September 30, Nine Months Ended September 30, 2021 2020 2021 2020 Operating expenses: Research and development $ 15,641 $ 6,200 45,630 $ 15,740 General and administrative 7,040 1,912 20,447 4,077 Total operating expenses 22,681 8,112 66,077 19,817 Loss from operations (22,681 ) (8,112 ) (66,077 ) (19,817 ) Interest income (expense), net 26 (4 ) 59 (45 ) Net loss $ (22,655 ) $ (8,116 ) (66,018 ) $ (19,862 ) Unrealized gain (loss) on available-for-sale securities (34 ) — (34 ) — Comprehensive loss attributable to common stockholders $ (22,689 ) $ (8,116 ) (66,052 ) $ (19,862 ) Net loss per share applicable to common stockholders, basic and diluted $ (0.65 ) $ (11.97 ) $ (1.89 ) $ (29.53 ) Weighted-average shares used in computing net loss per share attributable to common stockholders, basic and diluted 35,001,466 678,048 34,884,656 672,531