On November 9, 2021 Shattuck Labs, Inc. (Shattuck) (NASDAQ: STTK), a clinical-stage biotechnology company pioneering the development of bi-functional fusion proteins as a new class of biologic medicine for the treatment of patients with cancer and autoimmune disease with three ongoing Phase 1 clinical trials, reported financial results for the third quarter ended September 30, 2021, and provided recent business highlights (Press release, Shattuck Labs, NOV 9, 2021, View Source [SID1234594797]).

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"We designed the ARC platform to simultaneously block immune checkpoint targets and activate immune costimulatory receptors in the TNF superfamily. The clinical data presented this week at SITC (Free SITC Whitepaper) demonstrate evidence of anti-tumor activity, target receptor binding, and dose-dependent immune activation specific to each of CD40 and OX40," said Taylor Schreiber, M.D., Ph.D., and Chief Executive Officer of Shattuck. "Both compounds have been well tolerated and are demonstrating predictable dose-response relationships in humans. The doses we have explored to date remain below the recommended Phase 2 doses of benchmark CD47 inhibitors and PD-L1 inhibitors, and we look forward to continuing dose escalation of both SL-172154 and SL-279252 into dose levels that we believe will maximize the pharmacodynamic activity and anti-tumor activity of each compound."

"We are very encouraged by the initial data from the Phase 1 trial of SL-172154. The data show an excellent safety profile, high CD47 receptor occupancy and clear evidence of CD40 engagement, which collectively differentiate SL-172154 from other CD47 inhibitors," said Nehal Lakhani, M.D., Ph.D., South Texas Accelerated Research Therapeutics (START) Midwest, Grand Rapids, MI. "We desperately need new therapies for late-stage ovarian cancer patients, particularly in the platinum resistant setting. The combined actions of CD47 inhibition and CD40 activation provided by SL-172154 represents a strategy that has not yet been examined in this disease and may initiate anti-tumor immune responses that could provide lasting benefits in late-stage ovarian cancer."

"SL-172154 is emerging as a highly differentiated CD47 inhibitor. The clinical data indicate that this compound can safely engage CD40 in a manner that has evaded other CD40-targeted biologics for over twenty years. At the same time, we can compare and contrast the relative potency of CD40 versus OX40 activation, and the clinical data indicate that CD40 targeting provides substantially more immunologic activity than OX40 activation. There are some parallels to these observations in the checkpoint space, where blockade of targets like LAG3, TIM3, and TIGIT has been far more subtle than blockade of CTLA-4 or PD-1," continued Dr. Schreiber. "The current data suggests that we may be coming close to a recommended Phase 2 dose selection for SL-172154 as monotherapy. We are excited to transition to the combination with liposomal doxorubicin in ovarian cancer, and with azacitidine and venetoclax in AML, and azacitidine in higher-risk MDS and TP53 mutant AML. More importantly, these data help to establish the ARC platform more broadly as a novel class of biologic medicine, which opens opportunities for the rest of our vast pipeline of candidates developed internally at Shattuck."

Third Quarter 2021 Recent Business Highlights and Other Recent Developments

Agonist Redirected Checkpoint (ARC) Platform Clinical-Stage Pipeline

Initial Data from Ongoing SL-172154 (SIRPα-Fc-CD40L) Phase 1 Dose-Escalation Clinical Trial in Platinum Resistant Ovarian Cancer Demonstrate Favorable Safety Profile and High Target Occupancy at the 36th Annual SITC (Free SITC Whitepaper) Meeting: The Phase 1 trial is an open-label, multi-center, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamic effects of SL-172154 administered intravenously in patients with platinum resistant ovarian cancer. Shattuck will continue dose escalation to 10mg/kg.

Data reported at SITC (Free SITC Whitepaper) was in 14 evaluable patients as of July 6, 2021, across four dose levels on two schedules: schedule 1 (day 1, 8, 15, 29, then every two weeks) at 0.1, 0.3 mg/kg and schedule 2 (weekly) at 0.3, 1.0, 3.0 mg/kg. To date, no dose limiting toxicities have been observed.
Preliminary pharmacodynamic parameters for SL-172154 demonstrate on-target, CD40-mediated immune activation. The binding of SL-172154 to CD40+ B cells and monocytes led to rapid activation and margination of these cells post infusion.
High target occupancy was observed on CD47+ leukocytes at the doses studied, with preferential binding to leukocytes as compared to red blood cells.
Cyclical increases in certain innate and adaptive serum cytokines were consistent with CD40 receptor engagement and activation following dosing. There were no notable increases in IL-6 or TNFα, or evidence of bell-shaped dose responses.
SL-172154 has been well tolerated at doses which achieve near-complete target occupancy for both CD40 and CD47, with evidence of on-target pharmacodynamic activity which has not yet plateaued, warranting further dose escalation.
Combination Study of SL-172154 with Liposomal Doxorubicin Expected to Begin First Half of 2022: A Phase 1B clinical trial of SL-172154 in combination with liposomal doxorubicin to evaluate safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamics is planned to begin enrolling in the first half of 2022. Shattuck continues to evaluate additional combination agents for SL-172154 for the treatment of patients with ovarian cancer.
Open IND for SL-172154 in AML and HR-MDS: Shattuck submitted an investigational new drug application to the U.S. Food and Drug Administration for a Phase 1A/B clinical trial for SL-172154 in patients with acute myeloid leukemia, or AML and, higher-risk myelodysplastic syndromes, or HR-MDS, in September. The IND is now open, and the trial will evaluate safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamic effects of SL-172154, as both monotherapy and in combination. In AML, Shattuck plans to evaluate SL-172154 in combination with both azacitidine and venetoclax. In both HR-MDS and TP53 mutant AML, Shattuck plans to evaluate SL-172154 in combination with azacitidine. Initial data from the trial are expected in the second half of 2022.
Continued Enrollment of SL-172154 Phase 1 Clinical Trial in Squamous Cell Carcinoma of the Head and Neck or Skin: Shattuck continues to enroll patients in a Phase 1 clinical trial for SL-172154, in patients with squamous cell carcinoma of the head and neck or skin. The Phase 1 trial is evaluating the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamic effects of SL-172154, administered intratumorally as monotherapy. Initial dose-escalation data from the trial are expected in the first half of 2022.
Initial Data from Ongoing SL-279252 (PD1-Fc-OX40L) Phase 1 Dose-Escalation Clinical Trial in Advanced Solid Tumors Demonstrate Evidence of Anti-Tumor Activity at the 36th Annual SITC (Free SITC Whitepaper) Meeting: The ongoing Phase 1 trial is an open-label, multi-center, dose-escalation, and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamic effects of SL-279252 as monotherapy in patients with advanced solid tumors. Today, Shattuck reported continued enrollment at the next dose level, 12 mg/kg.

Data reported at SITC (Free SITC Whitepaper) as of June 11, 2021, was in 43 patients, dosed intravenously, with 30 patients treated on schedule 1 (day 1, 8, 15, 29, then every 2 weeks) from dose level 0.0001-6 mg/kg, and 13 patients treated on schedule 2 (weekly) from dose level 0.3-3 mg/kg. SL-279252 was well-tolerated in heavily pretreated subjects with refractory solid tumors with no maximum tolerated dose reached. A total of 16 patients were treated at doses of 1 mg/kg or higher on schedule 1.
Best response was one confirmed partial response (iPR) (ocular melanoma, four prior systemic regimens, including PD-1 and CTLA-4 inhibitors) in a patient who remained on treatment for more than one year, and stable disease (iSD) in 12 patients (including 1 unconfirmed iPR). iSD for > 24 weeks occurred in 5/12 patients.
58% of patients had received PD-1/L1 therapy, and of available tumor biopsies most tumors lacked PD-L1 expression as measured by TPS.
SL-279252 exhibited high OX40 target engagement and OX40-dependent PD effects.
Shattuck is currently enrolling patients with known PD-L1 positive tumors at dose levels of 12 mg/kg, to fully characterize PK, PD, and anti-tumor activity.
Corporate Updates

Shattuck and Takeda Mutually Agree to Termination of Collaboration Agreement: In November 2021, Shattuck and Takeda mutually agreed to termination of the Collaboration Agreement for SL-279252 and SL-115154, originally executed in 2017. Shattuck is no longer required to satisfy any remaining performance obligations, the Company will not make any payments to or receive any future milestone or royalty payments from Takeda, and all options to license and rights of first negotiation held by Takeda under the Collaboration Agreement were terminated.
Changes to Shattuck’s Board: In October 2021, Shattuck announced changes to its board of directors.

Dr. Carrie Brownstein was appointed to the board and serves as a member of the Nominating and Corporate Governance Committee. Dr. Brownstein brings over 15 years of clinical research and development experience having held clinical leadership roles at Roche, Regeneron, Celgene and Cellectis and as a practicing pediatric hematologist oncologist.
Dr. George Golumbeski was appointed chairman of the Board. Dr. Golumbeski has served on Shattuck’s Board as an independent director since 2018. Dr. Golumbeski replaces Josiah Hornblower as chairman of the board. Mr. Hornblower resigned from the board in October 2021.
Third Quarter 2021 Financial Results

Cash Position: As of September 30, 2021, cash and cash equivalents and short-term investments were $290.2 million, as compared to $335.4 million as of December 31, 2020.
Research and Development (R&D) Expenses: R&D expenses for the third quarter ended September 30, 2021, were $15.1 million, as compared to $11.8 million for the third quarter ended September 30, 2020. The increase was primarily driven by increases in clinical development, personnel-related costs, and laboratory capabilities.
General and Administrative (G&A) Expenses: G&A expenses for the third quarter ended September 30, 2021, were $4.3 million, as compared to $2.5 million for the third quarter ended September 30, 2020. The increase was primarily driven by an increase in personnel related costs to support the operational expansion and costs associated with being a public company.
Net Loss: Net loss was $17.4 million for the third quarter ended September 30, 2021, or $0.41 per basic and diluted share, as compared to a net loss of $11.8 million for the third quarter ended September 30, 2020, or $1.54 per basic and diluted share.
2021 Financial Guidance

Shattuck believes its cash and cash equivalents and short-term investments will be sufficient to fund its operations into the second half of 2024, which is beyond results from its Phase 1 clinical trials of SL-172154 and SL-279252. The reduction in cash runway guidance from our last issued guidance is primarily attributable to increased clinical activities for SL-172154 and ongoing process development and manufacturing to support our ongoing and future clinical trials, including the development of a manufacturing process suitable for registrational trials. This cash runway guidance is based on the Company’s current operational plans and excludes any additional funding that may be received or business development or additional clinical development activities that may be undertaken.

About SL-172154

SL-172154 (SIRPα-Fc-CD40L) is an investigational ARC fusion protein designed to simultaneously inhibit the CD47/SIRPα checkpoint interaction and activate the CD40 costimulatory receptor to bolster an anti-tumor immune response in patients with advanced cancers. Two Phase 1 clinical trials are ongoing, the first for patients with advanced and platinum resistant ovarian cancer (NCT04406623) and the second for patients with advanced squamous cell carcinoma of the head, neck or skin (NCT04502888).

About SL-279252

SL-279252 (PD1-Fc-OX40L) is an investigational ARC fusion protein designed to simultaneously inhibit the PD-1/PD-L1 checkpoint interaction and activate the OX40 costimulatory receptor to bolster an anti-tumor immune response receptor in patients with advanced solid tumors. A Phase 1 trial in patients with solid tumors and lymphoma is ongoing (NCT03894618).