On March 10, 2022 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company developing the next generation of cancer and infectious disease immunotherapies, reported financial results for the fourth quarter and full year ended December 31, 2021 and provided recent clinical and corporate updates (Press release, Gritstone Oncology, MAR 10, 2022, View Source [SID1234609883]).

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"2021 was a transformational year for Gritstone, as we extended our unique understanding of T cell antigens and proprietary vaccine delivery platforms to infectious disease, expanding our pipeline to include novel programs in COVID-19 (CORAL) and human immunodeficiency virus (HIV). Furthermore, we made significant progress with our tumor-specific neoantigen oncology programs, GRANITE and SLATE, which are advancing into later-stage trials," said Andrew Allen, M.D., Ph.D., Co-Founder, President and Chief Executive Officer of Gritstone. "In CORAL, we have demonstrated the potential for our T cell enhanced samRNA vaccine candidates to drive broad and durable immune responses in humans against both current and future variants against COVID-19, a credible first step toward developing a pan-coronavirus vaccine given the high conservation of many T cell antigens across different coronaviruses. Within oncology, we have continued to demonstrate the ability to drive a large and sustained T cell response, including the challenging CD8+ killer T cells, against tumor-specific neoantigens. These T cell responses are potentially driving the molecular and radiological responses observed in our "off the shelf" program, SLATE, which is focused on KRAS mutations, and also appear to be driving molecular response and extended overall survival in the end-stage colorectal cancer patients treated in our individualized program, GRANITE."

"Our collective experience with cancer immunotherapy suggests that as these programs move into earlier stages of disease, immune responses may be stronger and the potential benefits of our approach will be further accentuated," Dr. Allen continued. "Consequently, we are excited to have initiated randomized Phase 2/3 trials with GRANITE in colorectal cancer (CRC) patients where unmet need persists and checkpoint inhibitor therapy has had little impact to date in the vast majority of patients. We believe Gritstone is well-positioned to continue advancing our programs and platforms, and look forward to sharing updates as the year progresses."

Clinical Program Updates

Tumor-Specific Neoantigen (TSNA) Oncology Programs

GRANITE – Individualized, tumor specific neoantigen (TSNA)-directed immunotherapy using an adenoviral priming vector and self-amplifying mRNA boost vector to deliver relevant neoantigens

To date, an ongoing Phase 1/2 study assessing GRANITE in combination with an anti-PD-1 checkpoint inhibitor, nivolumab, and subcutaneous anti-CTLA-4 antibody, ipilimumab, has demonstrated a favorable safety and tolerability profile for patients treated in the study and demonstrated consistent induction of neoantigen-specific CD8+ T cells, and reduction in circulating tumor DNA (ctDNA), an increasingly recognized biomarker within utility in immunotherapy in advanced solid tumors.

Additionally, colorectal cancer patients who demonstrated a molecular response (ctDNA reduction >50% from baseline) had median overall survival of >17 months (median not reached) whereas those without molecular response exhibited a median overall survival of 7.8 months, the latter being consistent with expected outcome in 3rd line treatment of metastatic, microsatellite-stable colorectal cancer (MSS-CRC) patients. These data support the potential for GRANITE to offer benefit in a disease setting such as MSS-CRC where patients do not traditionally respond to checkpoint inhibitor therapy.

Given the results of the Phase 1/2 study, Gritstone has initiated two studies assessing GRANITE in earlier stages of disease: GRANITE-CRC-1L (a Phase 2/3 randomized, controlled trial evaluating the individualized neoantigen vaccine GRANITE in combination with immune checkpoint blockade for the first line (1L) maintenance treatment of newly diagnosed patients with metastatic MSS-CRC) and GRANITE-CRC-ADJUVANT (Randomized, controlled phase 2 trial of adjuvant GRANITE immunotherapy in high risk MSS-CRC patients with stage II/III disease who are ctDNA+ after definitive surgery). In January 2022, Gritstone announced the first patient was enrolled for inclusion in the GRANITE-CRC-1L trial. As of March 2022, the first patient was enrolled for inclusion in the GRANITE–CRC-ADJUVANT study.
SLATE – "Off-the-shelf" shared neoantigen-directed immunotherapy using an adenoviral priming vector and self-amplifying mRNA boost vector to deliver a cassette of shared TSNA

Preliminary data from an ongoing Phase 1/2 trial in advanced disease patients indicated a favorable safety and tolerability profile and induction of CD8+ T cells against multiple KRAS TP53 driver mutations. Clinical activity was observed in NSCLC patients who had all progressed on prior chemoimmunotherapy, including 6 NSCLC patients with the G12C KRAS mutation. Among these G12C patients, ctDNA responses were observed in 2 of 3 eligible for analysis, which correlated with clinical benefit, and a RECIST radiologic response (unconfirmed) was observed in one 2nd line patient with aggressive disease who had progressed after 3 months of 1st line chemo-immunotherapy. There were no safety signals of note; the most common adverse events being low grade, self-limiting fever and injection site reactions. An optimized SLATE cassette (SLATE-KRAS, v2), which exclusively includes KRASmut epitopes, exhibited immunogenic superiority over version 1 in preclinical studies. This next-generation SLATE-KRAS cassette is now in Phase 2 testing in patients with advanced non-small cell lung cancer (NSCLC) and CRC, and initial data are expected in 2H 2022.
Infectious Disease Programs

CORAL – second-generation SARS-CoV-2 vaccine program delivering both spike and highly conserved non-spike T cell epitopes (TCEs) with a focus on the samRNA vector. This approach offers potential for more durable clinical protection and broader immunity against SARS-CoV-2 variants than first generation products by inducing potent CD8+ T cells in addition to neutralizing antibody responses.

To date, the CORAL program has demonstrated positive preclinical and clinical data supporting the approach of a T cell enhanced samRNA vaccine against COVID-19, indicating a favorable safety profile and induction of both neutralizing antibodies and T cells.

In January 2022, Gritstone announced positive clinical data from the first cohort of CORAL-BOOST, a Phase 1 study evaluating the safety, reactogenicity, and immunogenicity of a samRNA vaccine directed against Spike and highly conserved non-Spike TCEs as a booster against SARS-CoV-2 in healthy adults ≥60 years who previously received two doses of AstraZeneca’s first-generation COVID-19 vaccine AZD1222 (Vaxzevria). Enrollment of the second cohort of CORAL-BOOST has since concluded and based on the favorable immunogenicity and reactogenicity seen with the 10µg dose, the study is proceeding to additional cohorts utilizing this dose.

Two additional Phase 1 trials, CORAL-CEPI and CORAL-IMMUNOCOMPROMISED, were initiated in 1Q 2022. The CORAL-CEPI trial, which is evaluating T cell enhanced omicron- and beta-spike constructs in virus-naïve, convalescent, and HIV+ patients, is being run in South Africa with support from the Coalition for Epidemic Preparedness Innovations (CEPI). The CORAL-IMMUNOCOMPROMISED trial, which is evaluating T cell enhanced samRNA and chimpanzee adenovirus (ChAd) vaccines in B cell deficient subjects, is being run in the United Kingdom.

CORAL-NIH, a Phase 1 study evaluating the immunogenicity and safety of samRNA and/or ChAd vaccines in healthy adult subjects that is supported by the National Institute of Allergy and Infectious Diseases (NIAID) is being conducted through their Infectious Diseases Clinical Research Consortium (IDCRC). Initial data is expected in 1H 2022.

All four clinical trials within the CORAL program are now enrolling and Gritstone expects to provide data updates on each of these trials throughout the remainder of 2022.
HIV – Collaboration with Gilead Sciences, Inc (Gilead) under their HIV Cure Program to research and develop vaccine-based HIV immunotherapy treatment

Following initiation of the collaboration with Gilead in early 2021, an IND was submitted and subsequently cleared in December 2021.
2021 Funding Highlights and Recent Corporate Updates

2021 Funding Highlights

Gritstone entered into a funding agreement of up to $20.6 million with the Coalition for Epidemic Preparedness Innovations (CEPI) to advance the clinical development of Gritstone’s CORAL second generation mRNA COVID-19 vaccine program.
Gritstone secured $55 million Private Placement led by Frazier Life Sciences Public Fund, Redmile Group and Gilead Sciences.
Gritstone secured $60 million payment from Gilead at closing of HIV program collaboration, consisting of a $30 million upfront cash payment and a $30 million equity investment at a premium.
Recent corporate updates

The funding agreement with CEPI was expanded for up to $5 million to advance the clinical development of Gritstone’s CORAL second generation mRNA COVID-19 vaccine program targeting the omicron variant in South Africa (December 2021).
Clare Fisher, Senior Vice President of Business Development and Mergers & Acquisitions at BeiGene, was appointed to the Gritstone Board of Directors effective as of January 1, 2022 (December 2021).
Gritstone was added to the Nasdaq Biotechnology Index (December 2021).
Full Year 2021 Financial Results

Cash, cash equivalents, marketable securities and restricted cash were $223.5 million as of December 31, 2021, compared to $172.1 million as of December 31, 2020.
Research and development expenses were $97.5 million for the year ended December 31, 2021, compared to $88.6 as of December 31, 2020. The increase was primarily due to increases in personnel-related expenses and clinical trial expenses.
General and administrative expenses were $25.9 million for the year ended December 31, 2021, compared to $21.4 million as of December 31, 2020. The increase was primarily attributable to an increase in personnel-related costs as we expanded our headcount, and an increase in outside services for legal, finance, recruiting and other professional services to support our ongoing operations and operate as a public company.
Collaboration and license revenue was $46.7 million for the year ended December 31, 2021, compared to $3.5 million for the prior year. During the year ended December 31, 2021, we recorded $38.6 million in license revenue and $5.1 million in collaboration revenue related to the Gilead Collaboration Agreement, and $3.0 million in collaboration revenue related to the 2seventy bio Agreement.