On November 12, 2021 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing potentially first-in-class therapeutics that combine both targeted and immune-mediated mechanisms, reported in vitro and in vivo preclinical data demonstrating the potent dual mechanistic activity of TPST-1495, an orally-available small molecule designed to block the EP2 and EP4 receptors in the prostaglandin (PGE2) pathway (Press release, Tempest Therapeutics, NOV 12, 2021, View Source [SID1234595346]). The data show that TPST-1495 effectively promotes anti-tumor activity through both T cell-dependent and -independent mechanisms. TPST-1495 is currently being evaluated in an ongoing Phase 1a/1b dose and schedule optimization trial in patients with solid tumors.

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"We’re happy to present these data that build upon existing significant preclinical support for the hypothesis that selectively targeting the EP2 and EP4 receptors together, to the exclusion of EP1 and EP3, is the preferred approach to modulate the prostaglandin pathway for clinical benefit in cancer," said Tom Dubensky, president of Tempest. "We look forward to generating clinical data as TPST-1495 moves into a mechanism-based combination study with pembrolizumab this quarter, as well as into expansion studies in targeted patient populations in the first half of 2022."

Presentation Highlights

TPST-1495 therapy promotes anti-tumor activity through both T cell-independent and T-cell dependent mechanisms, as evidenced by TME infiltration of effector immune cell populations and tumor antigen-specific CD8+ T cells
TPST-1495 therapy confers a significant survival advantage compared to therapy with single EP2 or EP4 antagonists, or the NSAID Celecoxib, in the APCmin/+ spontaneous tumor mouse model of CRC
TPST-1495 confers near complete restoration of immune function including activation of human antigen-specific CD8+ T cells in vitro, even in the presence of elevated PGE2 concentrations at which single EP4 or EP2 inhibitors are not effective
A summary of the near-term clinical development strategy that focuses on patients with histologies known to be prostaglandin-driven, as well as patients with the PIK3CA mutation, a potential biomarker.
Presentation Information

Saturday, November 13, 2021, Hall E, Poster #850

About the PGE2 Pathway and TPST-1495

Elevated expression of COX-2 and overproduction of PGE2 is correlated with progression of diverse malignancies by stimulating tumor cell proliferation via autocrine signaling through the EP2 and EP4 PGE2 receptors, which facilitates survival, evasion and metastasis. PGE2 also suppresses anti-tumor immunity by inhibiting the function of critical anti-tumor immune effector cell populations such as dendritic cells, macrophages, NK cells, and T cells. Recent studies have shown that increased expression of COX-2 and production of PGE2 may play a role in the effectiveness of immune checkpoint inhibitor ("ICI") therapy and in the development of adaptive immune resistance to ICI therapy.

TPST-1495 is an orally available small molecule designed to block the EP2 and EP4 receptors in the prostaglandin (PGE2) pathway, while sparing the homologous but differentially active EP1 and EP3 receptors. PGE2 signaling through EP2 and EP4 has been observed both to enhance tumor progression and promote immune suppression. Tempest has conducted head-to-head preclinical studies comparing TPST-1495 to single antagonists of EP2 and EP4 and observed significantly enhanced activity of TPST-1495 in both overcoming PGE2-mediated suppression of human immune cells in vitro, as well as significantly increased anti-tumor activity in mouse models of human colorectal cancer. Tempest is currently evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and possible anti-tumor activity of TPST-1495 in a multicenter Phase 1a/1b dose and schedule optimization study in subjects with advanced solid tumors, with the potential to expand in indications known to be prostaglandin-driven, including colorectal cancer, or CRC, and in a tumor indication-agnostic, biomarker-selected cohort.

On November 12, 2021 Oncorus, Inc. (Nasdaq: ONCR), a viral immunotherapy company focused on driving innovation to transform outcomes for cancer patients, reported that initial safety, tolerability and immune activation and clinical response data from its ongoing Phase 1 open-label, multi-center, dose escalation and expansion clinical trial of ONCR-177 at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 36th Annual Meeting, taking place November 12-14th in Washington, D.C. and virtually (Press release, Oncorus, NOV 12, 2021, View Source [SID1234595342]). In the fully enrolled and completed surface lesion dose escalation part of the Phase 1 study, ONCR-177 was well tolerated with no dose-limiting toxicities. In addition, three of eight evaluable patients at RP2D (as of a November 8, 2021 data cut-off) with cutaneous melanoma, squamous cell carcinoma of the head and neck (SCCHN), and mucosal melanoma, experienced clinical benefit after two doses of ONCR-177. ONCR-177, Oncorus’ lead oncolytic HSV product candidate, is an intratumorally (iTu) administered viral immunotherapy being developed for multiple solid tumor indications.

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"I’m encouraged by the findings from the ONCR-177 Phase 1 trial we presented at SITC (Free SITC Whitepaper) today," said Jong Chul Park, M.D., Instructor, Harvard Medical School and Assistant in Medicine, Massachusetts General Hospital, and first author on the SITC (Free SITC Whitepaper) abstract. "We are evaluating ONCR-177 in heavily pretreated cancer patients with advanced disease and no available standard of care. I’m impressed by the overall favorable safety and tolerability profile of ONCR-177 observed to date and the clinical responses demonstrated in some patients after only four weeks of monotherapy treatment. I look forward to enrolling patients in the combination cohort with pembrolizumab with the potential for amplification of clinical benefit."

Oncorus has engineered its proprietary HSV platform to develop improved iTu-administered viral immunotherapies that have the potential to enhance potency without sacrificing safety, a challenge that has been encountered by earlier-generation programs in this class. ONCR-177 incorporates two innovative, orthogonal safety strategies — the use of microRNA target sequences and a proprietary mutation engineered in an HSV-1 protein known as UL37 — to allow for replication only in tumors (Kennedy, Mol Thera Onco, 2020). These innovations allow for ONCR-177 to keep its ability to resist interferon challenge, via the retention of γ34.5, which is deleted in other HSV-based viral immunotherapies either on the market or in development today, and to be armed with five immunomodulatory transgenes: IL-12, FLT3L, CCL4, and antagonists of clinically proven immune checkpoints PD-1 and CTLA-4.

Theodore (Ted) Ashburn, M.D., Ph.D., President and CEO of Oncorus, commented, "We are excited by these data as they provide strong proof of concept for our HSV platform. To see clinical benefit in heavily pretreated patients across multiple histologies is a testament to the promise of our platform, of ONCR-177, and of our ability to deliver a potent, multidimensional attack on cancer without sacrificing safety, thanks to our novel engineering. Furthermore, these data also support the development of ONCR-GBM, our HSV preclinical candidate being developed to specifically treat brain tumors, including glioblastoma multiforme, as well as potential future HSV programs. With several important milestones slated for 2022, we look forward to continuing to provide updates on ONCR-177 and the rest of our pipeline."

ONCR-177 Phase 1 Trial Design

The Phase 1 clinical trial is designed to evaluate the safety, tolerability and initial efficacy of ONCR-177 administered alone and in combination with Merck’s anti-PD-1 therapy, KEYTRUDA, in patients with advanced and/or refractory cutaneous, subcutaneous or metastatic nodal solid tumors or with liver metastases of solid tumors. The trial is composed of four primary parts:

Part 1: surface lesion dose escalation (to determine RP2D) and tissue-specific dose expansion monotherapy, including breast cancer, melanoma, non-melanoma skin cancer, and head and neck cancer expansion cohorts;
Part 2: surface lesion dose expansion combination with KEYTRUDA;
Part 3: visceral injection into liver metastases dose escalation (to determine RP2D) and dose expansion monotherapy; and
Part 4: visceral injection dose expansion combination therapy with pembrolizumab.
Key safety and exploratory biomarkers include ONCR-177 detection in skin swabs, anti-HSV-1 antibodies, ONCR-177 payloads in blood, peripheral inflammatory cytokines, immune infiltration of the tumor and PD-L1 immunohistochemistry, or IHC, expression.

Phase 1 Initial Safety and Efficacy Results

Today, Oncorus presented preliminary findings at SITC (Free SITC Whitepaper) from Part 1 of the trial, including the fully enrolled and completed dose escalation cohorts (n=14) and patients enrolled in the dose expansion monotherapy as of a November 1, 2021 data cut-off (n=5).

ONCR-177 administered to heavily pretreated patients with advanced, injectable solid tumors was well-tolerated with no dose-limiting toxicities, and the recommended RP2D was determined to be 4×108 PFU in 4 mL. No treatment-related adverse events exceeded Grade 3, and the most common Grade 1 and 2 adverse events were fatigue, chills, nausea, and mild, dose-dependent cytokine release syndrome, or CRS. No infectious virions were detected in skin swabs, in line with ONCR-177 safety expectations.

Seven heavily pretreated patients have been enrolled to date in the ongoing surface lesion, histology-specific monotherapy expansion cohorts. As of November 1, four of these expansion patients were evaluable at the time of the SITC (Free SITC Whitepaper) poster presentation; one patient went off study after a single dose and is not evaluable; two are too early in their treatment course to be evaluable. The four evaluable monotherapy expansion patients are in addition to four evaluable monotherapy escalation patients treated at the RP2D. After four weeks of ONCR-177 monotherapy treatment (two doses) at RP2D, three of these eight evaluable patients (all in the surface lesion monotherapy expansion cohorts) demonstrated clinical benefit as follows:

Partial response in a patient with cutaneous melanoma as measured by calipers per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (surface tumor not measurable by CT scan)
Investigator-reported clinical response in a squamous cell carcinoma of the head and neck (SCCHN) patient in injected lymph node after four weeks
Stable disease in a patient with mucosal melanoma as measured by RECIST 1.1 with improvement in cancer-related symptoms
Several findings from the study thus far suggest immune stimulation of the tumor microenvironment, including mild, dose-dependent CRS in association with increased interferon-γ (IFN-γ) and T cell proliferation in blood, as well evidence of tumor PD-L1 expression and immune cell infiltration.

Oncorus plans to initiate enrollment in the surface lesion dose combination expansion (Part 2) and the visceral lesion dose monotherapy escalation (Part 3) by the end of 2021. The company plans to report additional surface lesion monotherapy expansion data in mid-2022, and initial surface lesion combination expansion data (ONCR-177 + KEYTRUDA) and visceral lesion monotherapy dose escalation data in late 2022.

For more information on the ongoing Phase 1 study, please visit: View Source

Conference Call and Webcast Information
Oncorus will host a conference call and live webcast with slides and Q&A today at 8:30 a.m. ET. Igor Puzanov, M.D., MSCI, FACP, who serves as Director of Center for Early Phase Clinical Trials, Senior Vice President of Clinical Investigation, and Chief of the Melanoma Section, at the Roswell Park Comprehensive Cancer Center in Buffalo, New York, will join Oncorus management for the call. Dr. Puzanov is also participating as an investigator in the ONCR-177 Phase 1 clinical trial.

To participate in the conference call, please dial (833) 614-1530 (domestic) or (520) 809-9930 (international) and refer to conference ID 8556488. A live webcast of the presentation will be available at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the company’s website for 30 days following the call.

On November 12, 2021 OncoMyx Therapeutics, a privately-held oncolytic immunotherapy company, reported the presentation of new preclinical data at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 36th Annual Meeting & Pre-Conference Programs (SITC 2021) being held November 10-14, 2021, both virtually and in Washington, D.C (Press release, OncoMyx Therapeutics, NOV 12, 2021, View Source [SID1234595341]). The data demonstrate the potential of a multi-armed myxoma virotherapy for the treatment of solid tumors and heme malignancies. In addition to direct oncolytic effects on cancer cells, OncoMyx’s multi-armed myxoma platform show additional anti-tumor activity through immune activation and tumor microenvironment modulation. Furthermore, OncoMyx has previously established in a preclinical model of cancer that myxoma virus has anti-tumor efficacy following intravenous (IV) or intratumoral (IT) dosing (data presented at AACR (Free AACR Whitepaper) 2021).

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"Myxoma is a unique virus in that it naturally infects and kills cancer cells, but it is a nonhuman pathogen, so there’s no preexisting immunity, which allows for systemic dosing, a longer dosing window, and multi-dosing," said Steve Potts, Ph.D., MBA, cofounder and CEO of OncoMyx. "Furthermore, the large size of the myxoma genome allows for the insertion of multiple genes to arm the virus with immune modulators that can orchestrate the cancer-immunity cycle for optimal viral-mediated cancer-killing activity. These data show the unmatched potential of our myxoma platform to be effective across a broad range of cancers, from hematological malignancies to solid tumors. The data, along with previously published studies, support the advancement of these therapies into clinical development as a monotherapy and in combination with many cancer therapeutics and immunotherapies, including checkpoint inhibitors and chemotherapies."

Immune modulation is a key component of the anti-tumor activity of multi-armed myxoma virus in vivo. The data presented show myxoma multi-armed with decorin and IL-12 infects and kills primary human multiple myeloma cells in vitro and demonstrates efficacy in a mouse model of multiple myeloma. Additional data presented show multi-armed myxoma virus demonstrates efficacy in syngeneic and xenograft tumor models following IT or IV delivery and combinatorial efficacy with immune checkpoint inhibitors.

Titles of the presentations are as follows:

(742) Multi-armed myxoma virus induces potent anti-tumor responses in vitro and in vivo
(744) Multi-armed myxoma virus has therapeutic potential for treatment of multiple myeloma
Onsite posters will be presented in the Poster Hall at the Walter E. Washington Convention Center. The posters will be available for onsite viewing November 12-14 from 7am to 5pm EST. Even numbered posters will be presented Saturday, November 13. ePosters will be on display on the SITC (Free SITC Whitepaper) 2021 virtual meeting platform from 7am EST on Friday, November 12 until the virtual meeting platform is closed on January 9, 2022.

Posters for both presentations are available to view and download here (under publications).

About Oncolytic Immunotherapy and Myxoma Virus

Oncolytic viruses (OV) selectively replicate in and lyse tumor cells and provide stimulation to the immune system, representing a promising therapeutic option in development to treat cancers that do not respond well to treatment with immune checkpoint inhibitors. Myxoma virus (MYXV) is a member of the Pox family of double-stranded DNA viruses. The natural host of MYXV is a subset of rabbits and hares, but MYXV is able to infect cancer cell lines of humans and other species. The genome of MYXV is relatively large and is amenable to engineering for expression of transgenic proteins, making it an excellent oncolytic virus for introduction of immunomodulatory proteins.

On November 12, 2021 Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies to treat cancer, reported the presentation of four preclinical data abstracts focused on its natural killer cell platform and pipeline at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36TH Annual Meeting and Pre-Conference Programs (Press release, Nkarta, NOV 12, 2021, View Source [SID1234595340]).

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"The data we presented at this year’s SITC (Free SITC Whitepaper) meeting showcase the rapid and continuous advancement of our NK cell platform and its potential to deliver pioneering off-the-shelf cell therapies," noted James Trager, PhD, Chief Scientific Officer of Nkarta. "Nkarta’s ongoing research activities are designed to heighten the innate ability of NK cells to identify and kill tumor cells and to further build on our efficient and robust manufacturing process. Our findings reported at SITC (Free SITC Whitepaper) support further exploration of CISH gene-knockout CD70 CAR NK cells for clinical application, one focus of our ongoing collaboration with our partners at CRISPR Therapeutics."

Details of the preclinical poster presentations at SITC (Free SITC Whitepaper) follow. Each poster will be available for download shortly after the presentation at View Source

Title: A Combined Strategy of CD70 CAR Co-expression with Membrane-bound IL-15 and CISH Knockout Results in Enhanced NK Cytotoxicity and Persistence*
Abstract Number and Type:16439, oral
Poster Presentation Date and Time: November 10, 2021, 2:40 p.m. ET
This study illustrates multiple approaches to modify NK cells to target CD70, an antigen highly expressed in hematological malignancies and solid tumors, including renal cell carcinoma. Optimal CD70 chimeric antigen receptor (CAR) candidates were identified using high throughput screening approaches. Preclinical results showed that a combined editing and engineering strategy to armor primary NK cells via co-expression of the CD70 CAR and a membrane bound form of IL-15 (mbIL-15), together with knockout of CISH and CD70 genes using the CRISPR/Cas9 system enhanced the persistence in culture and the cytotoxicity of the cells against multiple tumor cell lines. The knockout of CISH also supported the resistance of primary NK cells to suppressive elements active in the tumor microenvironment.

Title: CISH Gene-knockout Anti-CD70-CAR NK Cells Demonstrate Potent Anti-tumor Activity Against Solid Tumor Cell Lines and Provide Partial Resistance to Tumor Microenvironment Inhibition*
Abstract Number and Type: 113, poster
Poster Presentation Date and Time:November 12, 2021, 7:00 am – 8:30 pm ET
Primary NK cells engineered with CD70 chimeric antigen receptor (CAR), membrane bound form of IL-15 (mbIL-15) and knockout of CISH and CD70 genes using the CRISPR/Cas9 system could be produced efficiently, demonstrating consistent knockout and transduction efficiency across donors. Memory like NK cell differentiation of the gene edited NK cells was achieved using a modified K562 stimulatory cell line expressing membrane-bound IL-15 and 4-1BBL with the addition of IL-12 and IL-18 during expansion. Various gene editing candidates were assessed; the knockout of CISH in particular enhanced not only tumor cell killing by CD70 CAR NK cells, but also their persistence in culture and resistance to suppressive molecules associated with the tumor microenvironment, such as TGFß and adenosine.

Title: Potentiating the Large-Scale Expansion and Engineering of Peripheral Blood-Derived CAR NK Cells for Off-the-Shelf Application
Abstract Number and Type: 151, poster
Poster Presentation Date and Time:November 12, 2021, 7:00 am – 8:30 pm ET
The study highlights novel methods for scaling the expansion of engineered NK cells to potentially supply a life cycle’s worth of commercial off-the-shelf product from a single donor. The methods entail sequential pulses with a proprietary K562 stimulatory cell line in the presence of IL-2 and use of IL-12 and IL-18 to achieve differentiation into memory-like NK cells. When these methods were used to achieve cell expansion greater than even 2 billion-fold, CAR expression was increased on the NK cell surface, engineered cells with CISH gene knockout, CAR and mbIL-15 were preferentially enriched during expansion, and the chromosomal integrity of the cells was well maintained.

Title: KIR Haplotype Can Inform Donor Selection in the Production of Allogeneic Memory-Like CAR NK Cells for Clinical Application
Abstract Number and Type: 128, poster
Poster Presentation Date and Time:November 13, 2021, 7:00 am – 8:30 pm ET
Study findings suggest that the profile of activating and inhibitory KIR genes expressed by healthy donors’ NK cells may serve as a future criterion for selecting donors whose NK cells can be engineered for enhanced cytotoxic activity. The optimal KIR profile may depend on the process used to generate NK cells. Engineered CD19 CAR NK cells whose expansion includes IL-12 and IL-18 added to a proprietary K562 stimulatory cell line containing mbIL-15 and 15-41BBL stimulatory cells showed enhanced potency and upregulation of NK memory associated cell surface markers and natural cytotoxicity markers. Finally, donor KIR haplotype correlated best with CAR NK activity in cells expanded in the presence of IL-12 and IL-18, showing that donor selection and expansion methods must be considered together for development of optimal CAR NK therapies.

* Presented jointly with CRISPR Therapeutics

On November 12, 2021 Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported financial results for the third quarter ended September 30, 2021 (Press release, Leap Therapeutics, NOV 12, 2021, View Source [SID1234595339]).

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Leap Third Quarter Highlights:

Completed a $103.6 million public offering of common stock and pre-funded warrants to purchase common stock, resulting in net proceeds of $96.8 million
Presented positive initial data from the DisTinGuish Study of DKN-01 plus tislelizumab and chemotherapy in gastric cancer patients at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021
"We presented positive new data at ESMO (Free ESMO Whitepaper) of DKN-01 in combination with BeiGene’s tislelizumab and chemotherapy demonstrating compelling overall response rates in patients with first-line gastric or gastroesophageal junction (G/GEJ) cancer, particularly those patients whose tumors expressed high levels of DKK1 or low PD-L1," said Douglas E. Onsi, President and Chief Executive Officer of Leap. "We look forward to presenting additional data from the DisTinGuish study early next year and aggressively advancing DKN-01 into the next stages of development in G/GEJ and other cancers."

Business Update

Leap Completed a $103.6 Million Public Offering of Common Stock and Pre-Funded Warrants to Purchase Common Stock – In September 2021, Leap announced the commencement and closing of an underwritten public offering of 27,568,072 shares of its common stock, including the sale of an additional 4,740,000 shares of its common stock pursuant to the full exercise of the underwriters’ option to purchase additional shares, and of pre-funded warrants to purchase 8,771,928 shares of its common stock. Aggregate gross proceeds to Leap from the offering were $103.6 million, including $7.25 million invested by its collaborator and existing investor BeiGene, Ltd., resulting in net proceeds after underwriting discounts and commissions and offering expenses of $96.8 million.
DKN-01 Clinical Milestones

DKN-01 is a humanized monoclonal antibody that binds to and blocks the activity of the Dickkopf-1 (DKK1) protein. DKK1 modulates the Wnt/Beta-catenin and PI3kinase/AKT signaling pathways, which play an important role in tumor cell signaling and in mediating an immuno-suppressive tumor microenvironment through enhancing the activity of myeloid-derived suppressor cells and downregulating NK cell ligands on tumor cells.

Initial Data from the DisTinGuish Clinical Trial of DKN-01 Plus Tislelizumab and Chemotherapy Presented at ESMO (Free ESMO Whitepaper) Congress 2021. The Company presented initial positive data from the first-line cohort of the Phase 2a study in patients with G/GEJ cancer. Of the 25 first-line HER2- G/GEJ patients who received a full cycle of DKN-01 therapy, overall response rate (ORR) was 68.2%, with 90% ORR in DKK1-high patients and 56% in DKK1-low patients. Among those patients with PD-L1-low expression, ORR was 79% (with 100% ORR in DKK1-high patients and 57% ORR in DKK1-low patients), and in patients with PD-L1-high expression, ORR was 67% (with 75% ORR in DKK1-high patients and 50% in DKK1-low patients), suggesting response to DKN-01 was independent of PD-L1 expression.
Selected Third Quarter 2021 Financial Results

Net Loss was $11.1 million for the third quarter 2021, compared to $7.1 million for the same period in 2020.

License revenues were $0.4 million for each of the third quarter 2021 and the same period in 2020, and relate to the Agreement with BeiGene for the development and commercialization of DKN-01 in Asia (excluding Japan), Australia, and New Zealand.

Research and development expenses were $10.1 million for the third quarter 2021, compared to $5.4 million for the same period in 2020. The increase of $4.7 million in research and development expenses was due to an increase of $3.3 million in manufacturing costs related to clinical trial material due to timing of manufacturing campaigns, an increase of $0.7 million in clinical trial costs due to timing of patient enrollment, an increase of $0.6 million in payroll and other related expenses due to an increase in headcount of our research and development full time employees, and an increase of $0.1 million in stock based compensation expense due to new stock options granted to research and development full time employees in 2021.

General and administrative expenses were $2.4 million for the third quarter 2021, compared to $2.5 million for the second quarter 2020. The decrease of $0.1 million in general and administrative expenses was due to a $0.4 million decrease in professional fees partially offset by an increase of a $0.2 million in stock based compensation expense due to new stock options granted to general and administrative full time employees in 2021 and an increase of $0.1 million in payroll and other related expenses.

Cash and cash equivalents totaled $124.8 million at September 30, 2021. Research and development incentive receivables totaled $1.6 million at September 30, 2021.