On November 8, 2022 Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage gene editing company developing ARCUS-based ex vivo allogeneic CAR T and in vivo gene editing therapies, reported financial results for the third quarter ended September 30, 2022 and provided a business update (Press release, Precision Biosciences, NOV 8, 2022, View Source [SID1234623425]).

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"Over the last year, Precision has made considerable progress against our corporate and development objectives. We executed a disciplined portfolio strategy to focus on human therapeutics, advanced our lead clinical stage CAR T programs, leveraged platform partnerships, and made data-informed decisions designed to maximize patient impact and extend our expected cash runway to the end of 2024," said Michael Amoroso, Chief Executive Officer of Precision BioSciences. "We have refined the scope of our CAR T portfolio, focusing on PBCAR0191, known as azer-cel, in the growing CAR T-relapsed population, which has shown high complete response rates, long-term responses, and peak CAR T expansion on par with autologous CAR T in durable responders. We are also exploring the potential of our immune-evading stealth cell technology with PBCAR19B in earlier line DLBCL patients with the goal of displacing autologous CAR T treatment options. Looking ahead, our team is focused on executing and advancing our clinical stage CD19 targeted CAR T programs and providing a clinical update in late Q4 2022 or early Q1 2023, depending on patient accrual and follow-up."

Mr. Amoroso continued, "We also advanced multiple in vivo gene editing programs, independently and with partners, highlighted by our research collaboration with Novartis in June and recent preclinical data shared at ESGCT. As a result of ARCUS’ versatility, recent high efficiency in vivo gene insertion data, and scientific progress with wholly-owned and partnered programs, we have commenced a portfolio review of our in vivo gene editing programs. We are exploring ways to expedite key programs, advance new indications, and maximize ARCUS’ core features which have the potential to enable high efficiency gene insertion and complex edits aimed at restoring genomic function and treating the underlying root cause of specific genetic diseases. Our aim is to focus on programs in which ARCUS is most differentiated and where we see potential for a clear and rapid path to market, while providing a potentially curative therapeutic solution to patients with the highest unmet need. We look forward to providing meaningful progress updates along the way."

Recent Developments and Upcoming Milestones:

Ex Vivo Allogeneic CAR T Portfolio:

PBCAR0191: PBCAR0191, azercabtagene zapreleucel (azer-cel), is Precision’s lead investigational anti-CD19 allogeneic CAR T candidate in a Phase 1/2a clinical trial of adult subjects with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). An abstract on the cell dose and functional attributes of azer-cel that may be associated with positive safety and efficacy results for CAR T therapy in R/R B-cell lymphoma was accepted for poster presentation at the 64th ASH (Free ASH Whitepaper) Annual Meeting taking place December 10-13, 2022. The poster presentation will highlight the first analysis of an allogeneic CD19 CAR T product composition to demonstrate that strategies intended to maximize stem central memory T-cell fraction (CCR7+) while limiting CD4+ CCR7+ differentiated fraction may improve safety and efficacy of CAR T therapy.

Precision continues dosing subjects with optimized azer-cel CAR T cells in the CAR T relapsed population in which it has shown high and durable complete response rates, while further reducing the dose of lymphodepletion to standard levels in pursuit of best therapeutic index for this patient population.

PBCAR19B: PBCAR19B is Precision’s second generation, anti-CD19 targeting allogeneic CAR T candidate designed to evade immune rejection by host T cell and natural killer (NK) cells with a single-gene edit to knock-down beta-2 microglobulin and insert an HLA-E transgene. Precision continues to recruit patients at Dose Level 2 (flat dose of 540 million cells) with the intent to complete the Phase 1 dose escalation.

Precision expects to provide an update in late Q4 2022 or early Q1 2023, depending on patient accrual and follow-up, on its two distinct CD19 targeted products, including azer-cel which is aiming to achieve a potential first-in-class allogeneic CAR T therapy in the CAR T relapsed population, and PBCAR19B which is seeking to displace autologous CAR T in the second/third line DLBCL population.

PBCAR269A + GSI: PBCAR269A is Precision’s investigational allogeneic CAR T cell candidate targeting B-cell maturation antigen (BCMA) for R/R multiple myeloma in combination with nirogacestat, a gamma secretase inhibitor (GSI) developed by SpringWorks Therapeutics, Inc. The combination therapy and increased dose of PBCAR269A resulted in improved cell expansion, which correlated with increased clinical activity when compared to dose-matched PBCAR269A monotherapy treatment. However, in light of the competitive landscape of BCMA targeted therapies in multiple myeloma, Precision has made the strategic decision not to continue the PBCAR269A clinical program. All subjects enrolled in the study and evaluated for treatment with PBCAR269A and nirogacestat had acceptable tolerability results. While no clinical spending is planned, Precision researchers will evaluate further modifications to the BCMA construct aimed at enabling an allogeneic approach similar to that of autologous CAR T in multiple myeloma. Precision thanks the patients and clinicians for their participation in the PBCAR269A clinical program.

In Vivo Gene Editing Portfolio:

Precision believes that in vivo applications are particularly well suited to ARCUS because they require extremely low levels of off-target editing and efficient delivery. As a gene editing tool, ARCUS can be differentiated by unique attributes which are designed for precise, specific and versatile gene editing. By nature of its origin from a homing endonuclease, ARCUS can be particularly applicable to gene insertion and complex edits designed for gene repair aimed at restoring function, as well as more simple gene knock outs. ARCUS is also unique in its relatively small size which allows delivery to a wider range of cells and tissues using viral and non-viral gene delivery methods.

Novartis In Vivo Gene Editing Collaboration Precision is advancing its gene editing research and development collaboration and license agreement with Novartis to develop a single, custom ARCUS nuclease designed to insert a therapeutic transgene, in vivo, at a "safe harbor" location in the genome. This has the potential to be a one-time transformative treatment option for diseases including certain hemoglobinopathies such as sickle cell disease and beta thalassemia. In conjunction with the close of the agreement, Novartis made a $25 million equity investment in Precision in the second quarter of 2022 and Precision received $50 million in cash in the third quarter of 2022.

Lilly In Vivo Gene Editing Collaboration: Precision continues its in vivo gene editing collaboration with Lilly and is applying ARCUS nucleases for three initial targets, including Duchenne muscular dystrophy in muscle, a central nervous system directed target and a liver directed target.

PBGENE-HBV: Precision’s gene editing program for chronic Hepatitis B applies ARCUS to knock out persistent covalently closed circular DNA (cccDNA) and inactivate integrated hepatitis B genomes, potentially achieving durable HBV S-antigen (HBsAg) loss and reducing viral persistence. Preclinical data from this program were presented during ESGCT in October 2022. Data presented demonstrated that ARCUS efficiently targeted and degraded hepatitis B virus (HBV) cccDNA by 85% and reduced expression of HBsAg by 77% in HBV-infected primary human hepatocytes (PHH). Importantly, the optimized specificity of the ARCUS nuclease completely prevented detectable chromosomal translocations in the PHH model.

PBGENE-PH1: Precision has initiated IND-enabling activities for its PBGENE-PH1 candidate designed to knock out the HAO1 gene as a potential one-time treatment for primary hyperoxaluria type 1 (PH1).

PBGENE-PCSK9: In 2021, Precision initiated a collaboration with iECURE, pursuant to which iECURE is expected to advance Precision’s PBGENE-PCSK9 candidate through preclinical activities as well as a Phase 1 study in familial hypercholesterolemia. As of this date, IND enabling activities for PBGENE-PCSK9 have not been completed. Precision is in discussions with iECURE and will provide an update on the program when more information is available.

Other ARCUS Research:

International Conference on Ureagenesis Defects and Allied Conditions 20221: Preclinical data were presented by researchers from the University of Pennsylvania’s Gene Therapy Program in collaboration with iECURE, Precision’s partner, highlighting an ARCUS-based gene insertion approach for the treatment of ornithine transcarbamylase (OTC) deficiency. Non-human primate (NHP) data demonstrated stable insertion of the therapeutic gene one year post-dosing in newborn and infant NHPs In the follow up data, 12-month biopsies continued to demonstrate construct stability, with transduction efficiency up to 28.2% as measured by in-situ hybridization (ISH). These data further demonstrate the preclinical feasibility of using an ARCUS-mediated gene insertion approach.

ESGCT 29th Congress: Additional abstracts on ARCUS in vivo gene editing were presented in addition to Precision’s HBV program, including one poster presentation each on Precision’s Apolipoprotein C3 and mitochondrial DNA preclinical research.

APOC3 poster presentation: ARCUS gene editing of Apolipoprotein C3 results in substantial reduction in serum triglycerides in vivo
Mito DNA poster presentation: Specific elimination of m.3243A>G mutant mitochondrial DNA using mitoARCUS in cultured cells and a novel xenograft mouse model
Quarter Ended September 30, 2022 Financial Results:

Cash and Cash Equivalents: As of September 30, 2022, Precision had approximately $212.1 million in cash and cash equivalents. The Company expects that existing cash and cash equivalents, expected operational receipts, and available credit will be sufficient to fund its operating expenses and capital expenditure requirements to the end of 2024.

Revenues: Total revenues for the quarter ended September 30, 2022 were $7.4 million, as compared to $24.0 million for the same period in 2021. The decrease of $16.6 million in revenue during the quarter ended September 30, 2022 was primarily the result of the absence of $17.9 million in revenue recognized under the iECURE Agreement in August 2021 subsequent to the full satisfaction of the performance obligation. These decreases in revenue were partially offset by an increase of $3.6 million in revenue recognized under the Novartis Agreement.

Research and Development Expenses: Research and development expenses were $20.0 million for the quarter ended September 30, 2022, as compared to $25.9 million for the same period in 2021. The decrease of $5.9 million was primarily due to a decrease of $3.6 million in external development costs associated with our allogeneic CAR T product candidates, a decrease of $0.9 million in employee-related and other operational costs driven by the separation of Elo in 2021, and a decrease of $1.4 million in clinical manufacturing organization and research costs related to our preclinical studies.

General and Administrative Expenses: General and administrative expenses were $10.3 million for the quarter ended September 30, 2022, as compared to $9.6 million for the same period in 2021. The increase of $0.7 million was primarily due to increased share-based compensation expense.

Other Income and Expense: Total other expense was $1.0 million for the quarter ended September 30, 2022, as compared to total other income of $0.3 million for the same period in 2021.

Net Loss: Net loss was $23.9 million, or $(0.22) per share (basic and diluted), for the quarter ended September 30, 2022, as compared to net loss of $11.3 million, or $(0.19) per share (basic and diluted), for the same period in 2021. Weighted average shares of common stock outstanding were approximately 110.8 million for the quarter ended September 30, 2022, as compared to approximately 59.7 million for the quarter ended September 30, 2021. The increase in weighted average shares of common stock outstanding was primarily due to a $50 million underwritten offering of common stock and Novartis’ $25 million equity investment in the nine months ended September 30, 2022.

Corporate:

Executive Leadership: In September 2022, Cindy Atwell, formerly Senior Vice President of Business Development and Alliance Management, was promoted to Chief Business Officer and continues to oversee the Business Development and Alliance functions with added responsibility for Project and Portfolio Management. Jeff Smith, Ph.D., co-founder and formerly Chief Technology Officer, was promoted to Chief Research Officer and assumed responsibility for the management and direction of the Company’s research programs, reporting directly to the CEO. Derek Jantz, Ph.D., co-founder and Chief Scientific Officer is focusing his time partnering with Michael Amoroso in formulating company strategy and managing relationships with external stakeholders, including current and potential collaboration partners.

On November 8, 2022 Bicycle Therapeutics plc (NASDAQ:BCYC), a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported updates from the Phase I/II trial of BT8009 in patients with numerous cancer types where Nectin-4 is expressed (Press release, Bicycle Therapeutics, NOV 8, 2022, View Source [SID1234623424]). BT8009 is a potential first in class Bicycle Toxin Conjugate (BTC) targeting Nectin-4, a protein located on the surface of cells that is highly expressed in urothelial cancer (UC) and other solid tumors.

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"Dosing our first patient in the Phase II expansion portion of the BT8009 trial is a key development milestone for Bicycle," said Kevin Lee, Ph.D., Chief Executive Officer. "Based on the data presented to date, we believe we are making an important step towards hopefully providing a clinically meaningful, differentiated therapy compared to what is currently available for UC as well as for other tumors that express Nectin-4, such as non-small cell lung cancer (NSCLC)."

"The results from the Phase I dose escalation portion of the BT8009 Phase I/II trial are very encouraging and we are excited to move rapidly forward with the dose expansion portion of the trial," said Dominic Smethurst, MRCP, Chief Medical Officer of Bicycle Therapeutics. "BT8009 continues to exhibit potential best-in-class anti-tumor activity and a favorable tolerability profile, with a confirmed overall response rate from the latest cohorts consistent with previous findings from the trial, and we are pleased to see UC patients at the 5mg/m2 dose remaining on therapy and continuing to respond. We are also pleased to report a confirmed partial response in an NSCLC patient and look forward to providing additional data from the Phase I escalation cohorts at a medical meeting in the first half of 2023."

Phase I dose escalation portion of the Phase I/II trial is complete. Two doses have been selected as the recommended Phase II doses (RP2Ds): 5mg/m2 weekly and 7.5mg/m2 2-weeks on, 1-week off (over a 21-day cycle). Updated results from the completed escalation portion of the trial include 49 patients and the company intends to present these results at a medical meeting in the first half of 2023.
In addition to clinical activity of BT8009 in UC as previously reported, confirmed clinical responses were observed in the 7.5mg/m2 RP2D cohort as well as in the 10mg/m2 every other week dose cohort.
The confirmed Response Evaluation Criteria in Solid Tumors (RECIST) overall response rate in each of the 7.5mg/m2 RP2D and 10mg/m2 every-other-week cohorts was consistent with the findings observed and previously reported from the 5mg/m2 weekly cohort.
At the 7.5mg/m2 RP2D, confirmed RECIST responses were observed in UC and NSCLC patients. The overall median number of prior treatments was four. This dose was selected as a second RP2D based on its clinical activity and its alternative dosing schedule, which could provide improved convenience particularly in checkpoint inhibitor (CPI) combination settings.
All responding patients previously reported in the 5mg/m2 weekly cohort remain on therapy. The median duration of response has not yet been reached. As of the September 20, 2022 cutoff, all patients previously reported as having responses and on therapy have remained on therapy with ongoing responses.
Confirmed RECIST response in an NSCLC patient. A confirmed partial response was observed in a 76-year-old patient with Nectin-4 positive metastatic adenocarcinoma. The patient entered the 7.5mg/m2 RP2D cohort after four prior lines of therapy, including a CPI. As of the September 20, 2022 data cutoff, the patient remains on therapy after cycle seven with an ongoing response.
First patient dosed in Phase II expansion cohort. The Phase II multi-center, open label trial will evaluate BT8009 administered at the RP2Ds of 5mg/m2 and 7.5mg/m2.
First-line metastatic UC in cisplatin ineligible patients in combination with a CPI is a priority for fast-to-market development.
This is an indication with high unmet need as many patients have limited access to chemotherapy, often due to renal impairment.
The ongoing dose expansion includes cohorts evaluating the activity of BT8009 in CPI combination cohorts as well as in cohorts of patients with renal impairment.
Additionally, a Phase II study enrolling over 100 patients in combination with a CPI is being planned to start in 2023. The trial will include interim analyses that could be used to engage with regulatory authorities.
The company also intends to rapidly pursue multiple indications for BT8009, including in combination with a CPI. These include the following:
Peri-operative muscle invasive UC in combination with a CPI
Second and third-line metastatic UC in patients who have been exposed to enfortumab vedotin as well as naïve patients as a monotherapy
Tumors outside of UC (NSCLC, triple negative breast cancer, and ovarian cancer) in combination with a CPI and as a monotherapy

On November 8. 2022 Aclaris Therapeutics, Inc. (NASDAQ: ACRS), a clinical-stage biopharmaceutical company focused on developing novel drug candidates for immuno-inflammatory diseases, reported its financial results for the third quarter of 2022 and provided a corporate update (Press release, Aclaris Therapeutics, NOV 8, 2022, View Source [SID1234623423]).

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"The third quarter of this year marked another period of important milestone achievement – the successful completion of enrollment in the Phase 2a trial of zunsemetinib in hidradenitis suppurativa," said Dr. Neal Walker, Chief Executive Officer of Aclaris. "We also recently successfully completed the Phase 1 SAD trial for ATI-2138. We are very pleased with the results from the Phase 1 SAD trial which we believe support us proceeding to a multiple ascending dose (MAD) trial. Additionally, we have selected ulcerative colitis as the first target indication for ATI-2138 given the compelling pre-clinical profile and high medical need that persists for this debilitating disease."

Research and Development Highlights:

Clinical Programs

Zunsemetinib, an investigational oral small molecule MK2 inhibitor:
Currently being developed as a potential treatment for immuno-inflammatory diseases
Rheumatoid Arthritis (ATI-450-RA-202): This Phase 2b dose ranging trial to investigate the efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple doses (20 mg and 50 mg twice daily) of zunsemetinib in combination with methotrexate in subjects with moderate to severe rheumatoid arthritis (RA) is ongoing. Aclaris expects topline data in the second half of 2023.
Hidradenitis Suppurativa (ATI-450-HS-201): This Phase 2a trial to investigate the efficacy, safety, tolerability, PK and PD of zunsemetinib (50 mg twice daily) over 12 weeks in subjects with moderate to severe hidradenitis suppurativa (HS) has completed enrollment with 95 patients randomized and is ongoing. Aclaris expects topline data in mid-first half of 2023.
Psoriatic Arthritis (ATI-450-PsA-201): This Phase 2a trial to investigate the efficacy, safety, tolerability, PK and PD of zunsemetinib (50 mg twice daily) in subjects with moderate to severe psoriatic arthritis (PsA) is ongoing. Aclaris expects topline data in the second half of 2023.
ATI-1777, an investigational topical "soft" Janus kinase (JAK) 1/3 inhibitor:
Currently being developing as a potential treatment for moderate to severe atopic dermatitis (AD)
Atopic Dermatitis (ATI-1777-AD-202): This Phase 2b trial to determine the efficacy, safety, tolerability, and PK of ATI-1777 in subjects with moderate to severe AD is ongoing. Aclaris continues to expect topline data in the first half of 2023.
ATI-2138, an investigational oral covalent ITK/TXK/JAK3 (ITJ) inhibitor:
Currently being developed as a potential treatment for T cell-mediated autoimmune diseases
ATI-2138-PKPD-101: This Phase 1 first-in-human randomized, observer-blind, placebo-controlled single ascending dose (SAD) trial to investigate the safety, tolerability, PK and PD of ATI-2138 in healthy subjects is complete.
The primary objective was to assess the safety and tolerability of ATI-2138. Secondary endpoints included the assessment of PK, including the effect of food. The study also explored the PD response to ATI-2138. An additional cohort compared the capsule formulation to a tablet formulation.
Sixty-four male and female healthy volunteer subjects were randomized 3:1 into seven doses in eight cohorts. Each cohort consisted of eight randomized subjects (ATI-2138: n=6; placebo: n=2). Single dose levels were 1 mg, 3 mg, 5 mg, 15 mg, 25 mg, 50 mg, and 80 mg.

Preliminary data:
ATI-2138 was generally well tolerated at all doses tested in the trial. No serious adverse events or severe adverse events were reported. The most common adverse events in subjects treated with ATI-2138, headache (four subjects) and lightheadedness (two subjects), were mild and transient.
ATI-2138 demonstrated linear PK data and absorption with a favorable PK profile up to the 80 mg single dose.
There was no significant food effect at 15 mg (fasted versus fed) observed.
Similar PK was observed with the capsule versus tablet formulations at 25 mg.
Dose-dependent inhibition of both ITK and JAK3 exploratory PD biomarkers was observed; near complete inhibition of the dual ITK and JAK3-stimulated interferon production was observed at the 15 mg through 80 mg doses.
Aclaris has selected ulcerative colitis as the intended first clinical development target for ATI-2138. Aclaris is also exploring additional indications that are relevant to the mechanism of action.
Aclaris submitted a new IND for this program to the U.S. Food and Drug Administration’s (FDA) Gastroenterology Division in October 2022 for the treatment of ulcerative colitis. If allowed, Aclaris intends to initiate a Phase 1 MAD trial of ATI-2138 in healthy subjects by the end of 2022.
Preclinical Programs

ATI-2231, an investigational oral MK2 inhibitor compound:
Currently being explored as a potential treatment for pancreatic cancer and metastatic breast cancer as well as in preventing bone loss in patients with metastatic breast cancer
Second MK2 inhibitor generated from Aclaris’ proprietary KINect drug discovery platform and designed to have a long half-life.
IND-enabling studies are underway, and Aclaris expects to submit an IND by the end of 2022.
Financial Highlights:

Liquidity and Capital Resources

As of September 30, 2022, Aclaris had aggregate cash, cash equivalents and marketable securities of $248.1 million compared to $225.7 million as of December 31, 2021. Aggregate cash, cash equivalents and marketable securities as of September 30, 2022 included proceeds received during the quarter under a non-exclusive patent license agreement with Eli Lilly and Company (Lilly). Under the non-exclusive patent license agreement, Aclaris granted Lilly non-exclusive rights under certain patents and patent applications for the use of baricitinib, Lilly’s JAK inhibitor, to treat alopecia areata. Aclaris exclusively licenses patents and patents applications from a third party relating to the use of JAK inhibitors to induce hair growth and treat hair loss disorders.

Aclaris continues to anticipate that its cash, cash equivalents and marketable securities as of September 30, 2022 will be sufficient to fund its operations through the end of 2025, without giving effect to any potential business development transactions or financing activities.

Financial Results

Third Quarter 2022

Net loss was $20.0 million for the third quarter of 2022 compared to $21.1 million for the third quarter of 2021.
Total revenue was $19.0 million for the third quarter of 2022 compared to $1.7 million for the third quarter of 2021. The increase was driven by $17.9 million of licensing revenue in the quarter, including $17.6 million from the non-exclusive patent license agreement with Lilly.
Research and development (R&D) expenses were $23.7 million for the quarter ended September 30, 2022 compared to $14.0 million for the prior year period.
The $9.7 million increase was primarily the result of higher:
Zunsemetinib development expenses, including costs associated with clinical activities for a Phase 2b trial for RA, a Phase 2a trial for HS, and a Phase 2a trial for PsA.
ATI-1777 development expenses related to drug candidate manufacturing and other preclinical activities and costs associated with a Phase 2b clinical trial for AD.
IND submission preparation and preclinical development activities related to ATI-2231.
Compensation-related expenses due to an increase in headcount.
General and administrative (G&A) expenses were $5.8 million for the quarter ended September 30, 2022 compared to $6.0 million for the prior year period.
Licensing expenses were $7.3 million for the quarter ended September 30, 2022, resulting from separate third-party contractual obligations related to the non-exclusive patent license agreement with Lilly. There were no licensing expenses for the quarter ended September 30, 2021.
Revaluation of contingent consideration was $2.2 million for the quarter ended September 30, 2022, compared to a revaluation of contingent consideration expense of $0.9 million for the prior year period.
Year-to-date 2022

Net loss was $59.3 million for the nine months ended September 30, 2022 compared to $68.1 million for the nine months ended September 30, 2021.
Total revenue was $22.0 million for the nine months ended September 30, 2022 compared to $5.3 million for the nine months ended September 30, 2021. The increase was driven by $18.4 million of licensing revenue in 2022, including $17.6 million from the non-exclusive patent license agreement with Lilly.
R&D expenses were $56.7 million for the nine months ended September 30, 2022 compared to $29.7 million for the prior year period.
The $27.0 million increase was primarily the result of higher:
Zunsemetinib development expenses, including costs associated with clinical activities for a Phase 2b trial for RA, a Phase 2a trial for HS, and a Phase 2a trial for PsA.
ATI-1777 development expenses related to drug candidate manufacturing and other preclinical activities and costs associated with a Phase 2b clinical trial for AD.
IND submission preparation and preclinical development activities related to ATI-2231.
Compensation-related expenses due to an increase in headcount.
G&A expenses were $18.0 million for the nine months ended September 30, 2022 compared to $16.7 million for the prior year period.
The $1.3 million increase was primarily the result of higher compensation-related costs, including stock-based compensation, due to increased headcount and the impact of equity awards granted during the nine months ended September 30, 2022.
Licensing expenses were $7.3 million for the nine months ended September 30, 2022 resulting from separate third-party contractual obligations related to the non-exclusive patent license agreement with Lilly. There were no licensing expenses for the nine months ended September 30, 2021.
Revaluation of contingent consideration resulted in a $2.4 million reduction of expense for the nine months ended September 30, 2022, compared to a revaluation of contingent consideration expense of $22.1 million for the prior year period.

On November 8, 2022 IDEAYA Biosciences, Inc. (Nasdaq:IDYA), a synthetic lethality focused precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported financial results for the third quarter ended September 30, 2022 (Press release, Ideaya Biosciences, NOV 8, 2022, View Source [SID1234623422]).

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"Our clinical portfolio is maturing, with four potential first-in-class clinical-stage programs anticipated in the first half of 2023 – darovasertib (PKC), IDE397 (MAT2A), IDE161 (PARG) and our Pol Theta Helicase inhibitor development candidate. This broad pipeline of precision medicine therapeutics reflects our commitment to develop transformative therapies with the potential to improve patient lives," said Yujiro S. Hata, President and Chief Executive Officer, IDEAYA Biosciences. "We have built a unique platform in synthetic lethality and an organization with the capabilities to effectively discover and advance our growing preclinical and clinical precision medicine oncology pipeline. Importantly, we own or control all development and commercial rights and interests in our three most advanced programs," continued Mr. Hata.

IDEAYA’s most advance clinical program is darovasertib, a potential first-in-class small molecule oral protein kinase C (PKC) inhibitor for patients having tumors with GNAQ/11 mutations. The company reported positive Phase 2 interim clinical data for darovasertib and crizotinib synthetic lethal combination in metastatic uveal melanoma (MUM) in September 2022 and is targeting initiation of a potential registrational trial in MUM in the first quarter of 2023. IDEAYA also reported preliminary clinical proof-of-concept for a potential expansion opportunity in (neo)adjuvant uveal melanoma (UM) and is targeting initiation of company-sponsored trial for darovasertib monotherapy in neoadjuvant UM in the fourth quarter of 2022.

IDEAYA’s clinical pipeline also includes IDE397, a potential first-in-class Phase 2 MAT2A inhibitor, for patients having tumors with MTAP deletion, which represents approximately 15% of all solid tumors. Clinical data from Phase 1 monotherapy dose escalation reflects robust target engagement and an observed therapeutic window, positioning IDE397 to evaluate clinical efficacy – as monotherapy and multiple combination therapies. IDEAYA’s clinical development plan includes an emphasis on combination strategies, based on observed in vivo efficacy in preclinical studies. The company believes that IDE397 combination therapies could potentially enhance clinical efficacy in patients having tumors with MTAP deletion.

The company’s preclinical pipeline includes several potential first-in-class synthetic lethal therapeutics advancing toward the clinic. IDEAYA is targeting an IND in the fourth quarter of 2022 for IDE161, its PARG inhibitor, for patients having tumors with HRD. In collaboration with GSK, the company is targeting first-in-human clinical evaluation in the first half of 2023 for its Pol Theta Helicase inhibitor development candidate in combination with niraparib for patients having tumors with HRD. Its Werner Helicase program continues in collaboration with GSK toward development candidate nomination in 2023.

Program Updates
Key highlights for IDEAYA’s pipeline programs include:

Darovasertib (PKC)
IDEAYA continues to advance its Phase 1/2 clinical trial evaluating darovasertib (IDE196), a potent and selective PKC inhibitor, in combination with crizotinib, a cMET inhibitor, in metastatic uveal melanoma (MUM). The company is also clinically evaluating darovasertib in (neo)adjuvant uveal melanoma (UM) as monotherapy through an investigator sponsor clinical trial (IST).

IDEAYA is planning to initiate a company-sponsored clinical trial to evaluate darovasertib in (neo)adjuvant uveal melanoma. The company is also evaluating other potential darovasertib expansion opportunities, including in cMET driven tumors and in KRAS-mutation tumors.

Darovasertib / Crizotinib Combination Therapy in Metastatic Uveal Melanoma (MUM)
IDEAYA is continuing patient enrollment into the darovasertib / crizotinib combination arm of the Phase 1/2 clinical trial in MUM under clinical trial collaboration and supply agreements with Pfizer, with continued emphasis on enrollment of first-line MUM patients. Highlights:

IDEAYA presented interim Phase 2 darovasertib and crizotinib clinical combination data in September 2022. The reported data, based on an unlocked database with a data analyses cutoff date of June 26, 2022, showed robust clinical activity. These investigator-reviewed data by RECIST 1.1 include, as of the data analysis cutoff date:
89% of patients show tumor shrinkage in Any-Line MUM: 31 of 35 evaluable patients showed tumor shrinkage as determined by target lesion size reduction;
83% Disease Control Rate (DCR) in Any-Line MUM: 29 of 35 evaluable patients showed stable disease or better as determined by target lesion size reduction;
50% Overall Response Rate (ORR) in First-Line MUM: 4 of 8 evaluable patients had a confirmed partial response;
31% Overall Response Rate (ORR) in Any-Line MUM: 11 of 35 evaluable patients had a confirmed partial response;
43% of patients with >30% Tumor Reduction in Any-Line MUM: 15 of 35 evaluable patients observed partial responses with >30% tumor reduction, including 11 confirmed and 4 unconfirmed partial responses;
Median Study Follow-Up of 6.5 months for First-Line MUM patients and 7.8 months for Any-Line MUM patients;
Median Duration of Response (DOR) in evaluable First-Line MUM patients has not yet been reached and 4 of 4 patients with confirmed PR’s in First-Line MUM remain in response; median DOR in evaluable Any-Line MUM patients has not yet been reached and 7 of 11 patients with confirmed PR’s in Any-Line MUM remain in response;
Median Progression Free Survival (PFS) in First-Line MUM patients has not yet been reached and is >5 months in evaluable First-Line MUM patients; median PFS for evaluable Any-Line MUM patients is ~5 months; and
The darovasertib and crizotinib combination therapy has indicated a manageable adverse event profile in MUM patients (n=37) at the combination expansion doses, with a low rate of drug-related serious adverse events (SAEs) and with no Grade 4 or Grade 5 drug-related adverse events observed as of the data analysis cutoff date of June 26, 2022;
Targeting initiation of a potential registration-enabling trial for the darovasertib and crizotinib combination in MUM in Q1 2023, subject to FDA feedback and guidance, in collaboration with Pfizer under a clinical collaboration and supply agreement
In April 2022, the U.S. FDA designated darovasertib as an Orphan Drug in Uveal Melanoma, including MUM
Darovasertib – (Neo)Adjuvant Uveal Melanoma (UM)
IDEAYA is evaluating the potential for darovasertib in neoadjuvant and/or adjuvant uveal melanoma. Highlights:

(Neo)adjuvant UM represents a significant expansion opportunity – with a potential annual incidence of approximately 8,700 patients aggregate in US and Europe
Initiated an Investigator Sponsored Trial in coordination with St. Vincent’s Hospital Sydney Limited to evaluate darovasertib monotherapy in (neo)adjuvant UM patients
Reported preliminary clinical proof-of-concept data in September 2022, with observed clinical activity supporting potential darovasertib use in the (neo)adjuvant uveal melanoma setting. As of a data cut-off date of August 19, 2022, these data include observed tumor shrinkage by investigator review of primary ocular lesions in 5 of 5 (100%) UM or MUM patients treated as monotherapy or in combination with crizotinib and observed improvement in visual symptoms in the affected eye in two MUM patients having intact primary tumors
Targeting initiation of an IDEAYA-sponsored clinical trial in Q4 2022 to further evaluate darovasertib monotherapy in neoadjuvant UM patients, including potential clinical endpoints such as vision and organ preservation which would be temporally proximal to primary interventional treatments
Darovasertib – Other Potential Indications
IDEAYA is evaluating the potential for darovasertib in other oncology indications, including in cMET-driven tumors and RAS-mutation tumors. Highlights:

Evaluating darovasertib in combination with crizotinib, an investigational cMET inhibitor, in preclinical studies in cMET-driven tumors, such as NSCLC or HCC. Subject to preclinical evaluation and portfolio priorities, we may evaluate this combination in a Phase 1/2 clinical trial in collaboration with Pfizer under a clinical collaboration and supply agreement
Evaluating darovasertib in combination with a KRAS inhibitor in preclinical studies in KRAS-driven solid tumors
IDE397 (MAT2A)
IDEAYA is clinically evaluating IDE397, a potent and selective small molecule inhibitor targeting methionine adenosyltransferase 2a (MAT2A), in patients having solid tumors with methylthioadenosine phosphorylase (MTAP) deletion, a patient population estimated to represent approximately 15% of solid tumors. IDEAYA is continuing clinical development of IDE397 in its Phase 1/2 clinical trial, IDE397-001 (NCT04794699). Highlights:

Patients are being identified by next generation sequencing (NGS) or by MTAP immunohistochemistry (IHC) assay with confirmatory NGS
Initiated and actively enrolling patients into monotherapy expansion cohorts, with a focus on squamous cell NSCLC and esophagogastric cancer, consistent with preclinical efficacy and translational data
Initiated combination dose escalation cohorts with enrollment open for combinations of IDE397 with pemetrexed and taxanes, each of which are standard-of-care agents used as early-line therapies in NSCLC, mesothelioma and other solid tumor indications. The combination of IDE397 with pemetrexed is a novel and potential first-in-class combination of a MAT2A inhibitor with an antifolate agent.
Entered into Clinical Trial Collaboration and Supply Agreement with Amgen to clinically evaluate IDE397 MAT2A inhibitor in combination with AMG 193, Amgen’s investigational small molecule MTA-cooperative inhibitor of PRMT5, in MTAP-null solid tumors. The combination of IDE397 with AMG 193 is a novel and potential first-in-class synthetic lethality combination which targets two distinct and mechanistically complementary nodes of the MTAP methylation pathway – MAT2A and PRMT5, providing a complementary approach for targeting MTAP-deletion tumors.
IDEAYA owns all right, title and interest in and to IDE397 and the MAT2A program, including all worldwide commercial rights thereto, following GSK waiver in August 2022 of its right to exercise its option to obtain an exclusive license to further develop and commercialize IDE397, as well as other IDEAYA compounds, if any, directly targeting MAT2A
Demonstrated IDE397 clinical tumor pharmacodynamic modulation based on ctDNA Molecular Responses observed in thirteen evaluable patients with liquid biopsy samples available at baseline and after first treatment cycle, including:
31% (n=4 of 13) of evaluable patients treated with IDE397 across all dose escalation Cohorts 1 thru 6 observed ctDNA molecular responses
75% (n=3 of 5) of evaluable patients treated with IDE397 at higher doses in Cohorts 5 and 6 observed ctDNA molecular responses
100% (n=2 of 2) of evaluable NSCLC patients observed ctDNA molecular responses
PARG
IDEAYA is advancing its poly (ADP-ribose) glycohydrolase (PARG) inhibitor development candidate, IDE161, in patients having tumors with a defined biomarker based on genetic mutations and/or molecular signature. IDE161 is a potential first-in-class PARG inhibitor development candidate for patients having tumors with homologous recombination deficiencies (HRD), including BRCA1 and BRCA2, and potentially other alterations, in solid tumors such as breast cancer or ovarian cancer. PARG is a novel target in the same clinically validated biological pathway as poly (ADP-ribose) polymerase (PARP). IDEAYA owns or controls all commercial rights in its PARG program. Highlights:

Targeting IND for IDE161 in the fourth quarter of 2022
Considering potential development approaches based on observed activity of IDE161 in PARPi resistant and/or platinum-resistant tumors, differentiated sensitivity relative to PARP inhibitors, and improved preliminary safety profile relative to PARP inhibitors
Pol Theta
IDEAYA’s DNA Polymerase Theta, (Pol Theta) program targets tumors with BRCA or other homologous recombination (HR) mutations or homologous recombination deficiency (HRD). IDEAYA and GSK are collaborating on ongoing preclinical research and GSK will lead clinical development for the Pol Theta program. Highlights:

Selected a potential first-in-class Pol Theta Helicase inhibitor development candidate (DC) in collaboration with GSK
Observed tumor regressions in preclinical combination studies of Pol Theta Helicase DC with niraparib in multiple in vivo PDX and CDX HRD models
Targeting first-in-human clinical evaluation of Pol Theta Helicase inhibitor DC combination with niraparib in H1 2023 for patients having tumors with HRD
IDEAYA achieved the first preclinical development milestone in connection with ongoing IND-enabling studies to support evaluation of Pol Theta Helicase Inhibitor DC
IDEAYA is eligible to receive total development and regulatory milestones of up to $485 million aggregate from GSK, with up to $20 million in aggregate for advancing a Pol Theta Helicase inhibitor from preclinical to early Phase 1 clinical, including up to $10 million aggregate through IND effectiveness
Werner Helicase
IDEAYA is advancing preclinical research for an inhibitor targeting Werner Helicase for tumors with high microsatellite instability (MSI). IDEAYA and GSK are collaborating on ongoing preclinical research, and GSK will lead clinical development for the Werner Helicase program. Highlights:

Targeting selection of a Werner Helicase development candidate in 2023
IDEAYA is eligible to receive future development and regulatory milestones of up to $485 million aggregate from GSK, with potential for up to $20 million in aggregate for advancing a Werner Helicase inhibitor from preclinical to early Phase 1 clinical
Other Synthetic Lethality Pipeline Programs
IDEAYA is advancing additional preclinical research programs to identify small molecule inhibitors for an MTAP-synthetic lethality target, as well as for multiple potential first-in-class synthetic lethality programs for patients with solid tumors characterized by proprietary biomarkers or gene signatures.

General
IDEAYA continues to monitor Covid-19 and its potential impact on clinical trials and timing of clinical data results. Initiation of clinical trial sites, patient enrollment and ongoing monitoring of enrolled patients, including obtaining patient computed tomography (CT) scans, may be impacted for IDEAYA clinical trials evaluating IDE397 and darovasertib; the specific impacts are currently uncertain.

Corporate Updates
IDEAYA’s net income was $1.6 million for the three months ended September 30, 2022 and its net loss was $22.1 million for the three months ended June 30, 2022. As of September 30, 2022, the company had an accumulated deficit of $211.2 million.

As of September 30, 2022, IDEAYA had cash, cash equivalents and marketable securities of $393.9 million. IDEAYA believes that its cash, cash equivalents and marketable securities will be sufficient to fund its planned operations into 2026. These funds will support the company’s efforts through potential achievement of multiple preclinical and clinical milestones across multiple programs.

Our updated corporate presentation is available on our website, at our Investor Relations page: View Source

Financial Results
As of September 30, 2022, IDEAYA had cash, cash equivalents and short-term marketable securities totaling $393.9 million. This compared to cash, cash equivalents and short-term and long-term marketable securities of $323.8 million at June 30, 2022. The increase was attributable to receipt of aggregate net proceeds of $86.1 million from the sale of shares of IDEAYA common stock in an underwritten public financing in September 2022 and net proceeds of $8.9 million from the sale of shares of IDEAYA common stock under an at-the-market offering program during the three months ended September 30, 2022, partially offset by cash used in operations.

Collaboration revenue for the three months ended September 30, 2022 totaled $29.7 million compared to $5.9 million for the three months ended June 30, 2022. Collaboration revenue was recognized for the performance obligations satisfied through September 30, 2022 under the GSK Collaboration Agreement. The increase was primarily driven by non-recurring revenue recognized upon achievement of the Pol Theta preclinical development milestone, GSK’s waiver of its option related to MAT2A program and an increase in collaboration revenue for R&D services performed related to the Pol Theta and Werner Helicase programs. Generally, revenue recognition related to the GSK Collaboration Agreement, including as related to the previously received upfront payment or to certain development milestone payments, may vary considerably by period and certain components thereof may generally decrease year-over-year as we satisfy remaining performance obligations, for example, relating to the Pol Theta and WRN R&D Services.

Research and development (R&D) expenses for the three months ended September 30, 2022 totaled $22.4 million compared to $22.8 million for the three months ended June 30, 2022. The decrease was primarily due to lower clinical trial and external research expenses, partially offset by higher consulting expenses.

General and administrative (G&A) expenses for the three months ended September 30, 2022 totaled $6.7 million compared to $5.6 million for the three months ended June 30, 2022. The increase was primarily due to higher operational, consulting and personnel-related expenses.

The net income for the three months ended September 30, 2022 was $1.6 million compared to the net loss of $22.1 million for the three months ended June 30, 2022. Total stock compensation expense for the three months ended September 30, 2022 was $3.0 million compared to $3.0 million for the three months ended June 30, 2022.

On November 8, 2022 ARS Pharmaceuticals, Inc. (Nasdaq: SPRY) (ARS or the Company), a biopharmaceutical company dedicated to empowering at-risk patients and caregivers to better protect themselves from severe allergic reactions that could lead to anaphylaxis, reported the closing of its merger with Silverback Therapeutics, Inc. (Silverback) (Press release, Silverback Therapeutics, NOV 8, 2022, View Source [SID1234623421]). This follows the satisfaction of all customary closing conditions, including approval of the merger by the stockholders of Silverback. The combined company will operate as ARS Pharmaceuticals, Inc., and shares of its common stock will commence trading under the trading symbol "SPRY" on November 9, 2022, on the Nasdaq Global Select Market. Effective as of the closing of the merger, ARS has over $280 million in cash and marketable securities.

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ARS has designed and developed neffy to provide injection-like absorption of epinephrine, in a small, easy-to-carry, easy-to-use, rapidly administered, and reliable nasal spray device for the treatment of Type I severe allergic reactions, including anaphylaxis. With its needle-free administration, neffy may help eliminate the anxiety and hesitation associated with using an epinephrine injection device.

The Company’s New Drug Application (NDA) submission for neffy is currently under review by the U.S. Food and Drug Administration (FDA) with an anticipated Prescription Drug User Fee Act (PDUFA) date in mid-2023. ARS has also filed and cleared validation of a Marketing Authorization Application (MAA) in Europe, which is currently under review by the European Medicines Agency (EMA).

"This is a transformative time for ARS, enabling our move to a publicly traded organization and providing important resources to support the potential launch and commercialization of neffy, upon approval," said Richard Lowenthal, co-founder, president and CEO of ARS. "Millions of individuals suffer from severe allergic reactions, and unfortunately, too many do not treat their symptoms in time or at all with injection devices, leading to disease progression and potentially dangerous or life-threatening outcomes. With neffy, our goal is to eliminate the fear of administering epinephrine with a small, needle-free and easy-to-use nasal spray. Our team at ARS believes that neffy can add significant clinical value to the community by providing an alternative to the currently approved injection devices for patients and caregivers that either do not carry, avoid using or hesitate to use their epinephrine injection device. With the funding from our merger with Silverback, ARS is also dedicated to significant efforts on patient education and support of advocacy groups working to protect the community of allergy patients with this disease."

Post-merger, ARS has approximately 94 million shares of common stock outstanding. Prior ARS equityholders collectively own approximately 62% of the combined company and prior Silverback equityholders collectively own approximately 38% of the combined company, in each case on a fully diluted basis using the treasury stock method and excluding out-of-the-money options of Silverback.

Effective as of the closing of the merger, the board of directors of ARS (Board) will be comprised of eleven directors, including three directors of Silverback:

Pratik Shah, Ph.D., chairman of the Board;

Rajeev Dadoo, Ph.D., managing partner, SR One Capital Management, L.P.;

Saqib Islam, J.D. chief executive officer of Springworks Therapeutics, Inc.;

Michael Kelly, former president of U.S. operations for Adapt Pharma, Inc.;

Peter Kolchinsky, Ph.D., managing partner, RA Capital Management, L.P.;

Jonathan Leff, partner, Deerfield Management and chairman of the Deerfield Institute;

Richard Lowenthal, M.Sc., MSEL, co-founder, president and chief executive officer of ARS;

Brent Saunders, executive chairman of The Beauty Health Company

Phillip Schneider, board member of Longboard Pharmaceuticals Inc., former chief financial officer & senior vice president of IDEC Pharmaceuticals Corporation;

Laura Shawver, Ph.D., chief executive officer of Capstan Therapeutics and former chief executive officer of Silverback;

Peter Thompson, M.D., private equity partner at Orbimed Advisors LLC.

SVB Securities LLC acted as financial advisor to Silverback, and Cooley LLP served as legal counsel to Silverback for the merger. Inceptiv Law served as legal counsel to ARS for the merger.

About Type I Allergic Reactions including Anaphylaxis

Type I severe allergic reactions are serious and potentially life-threatening events that can occur within minutes of exposure to an allergen and require immediate treatment with epinephrine, the only FDA-approved medication for these reactions. While epinephrine autoinjectors have been shown to be highly effective, there are well published limitations that result in many patients and caregivers delaying or not administering treatment in an emergency situation. These limitations include fear of the needle, lack of portability, needle-related safety concerns, lack of reliability, and complexity of the devices. There are approximately 25 to 40 million people in the United States who experience Type I severe allergic reactions. Of those, only 3.3 million currently have an active epinephrine autoinjector prescription, and of those, only half consistently carry their prescribed autoinjector. Even if patients or caregivers carry an autoinjector, more than half either delay or do not administer the device when needed in an emergency.