On August 11, 2021 MannKind Corporation (Nasdaq:MNKD) reported financial results for the quarter and six months ended June 30, 2021 (Press release, Mannkind, AUG 11, 2021, View Source [SID1234586317]).

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"I am really proud of how our team has executed so far in 2021 supporting the growth of Afrezza and preparing for the potential commercial launch of Tyvaso DPI," said Michael Castagna, Chief Executive Officer of MannKind Corporation. "With the issuance of the convertible debt in the first quarter and the pay-down and restructuring of our legacy debt in the second quarter, we have a stronger balance sheet with lower interest expense which sets the company up for commercial growth and pipeline advancement."

Second Quarter 2021 Results

Total revenues were $23.3 million for the second quarter of 2021, an increase of $8.2 million, or 54%, reflecting Afrezza net revenue of $10.0 million and collaboration and services revenue of $13.3 million. Afrezza net revenue increased $3.0 million, or 43%, compared to $7.0 million in the second quarter of 2020 as a result of higher prescription demand, the negative effects of the COVID-19 pandemic in the prior year period, a more favorable mix of Afrezza cartridges, and price (including a lower gross-to-net deduction percentage of gross sales). Collaboration and services revenue for the second quarter of 2021 increased $5.2 million, or 64%, compared to the second quarter of 2020, primarily due to the Company’s collaboration with United Therapeutics.

Afrezza gross profit for the second quarter of 2021 was $5.6 million compared to $3.3 million in the same period of 2020, a 68% increase that was driven primarily by higher Afrezza revenue and increased manufacturing activities which resulted in a higher amount of costs capitalized to inventory, partially offset by a $2.0 million fee for an amendment of the Company’s insulin supply agreement. Gross margin in the second quarter of 2021 was 56% compared to 47% for the same period in 2020. On a non-GAAP basis, which excludes the $2.0 million insulin supply amendment fee, gross margin was 76% for the second quarter of 2021 compared to 47% for the same period in 2020.

Research and development ("R&D") expenses for the second quarter of 2021 were $2.3 million compared to $1.5 million for the second quarter of 2020. This increase of $0.9 million, or 59%, was attributable to increased development activity related to our product pipeline.

Selling, general and administrative ("SG&A") expenses for the second quarter of 2021 were $20.1 million compared to $13.7 million for the second quarter of 2020, an increase of $6.4 million, or 47%, as we expanded our investment behind Afrezza and lowered expenses in the prior year period when we voluntarily reduced compensation and field force activities in response to the onset of the COVID-19 pandemic. As we continued to re-engage our selling activities behind Afrezza, we increased promotional and marketing expenses by $1.8 million and patient support services by $0.6 million. Personnel expenses increased $4.4 million due to the favorable impact of lower spending during the COVID-19 pandemic as well as increased headcount and stock compensation. The increased spending in SG&A in the second quarter of 2021 was partially offset by a reduction for the promotional cost for Thyquidity that was recognized as cost of revenue — collaboration and services in 2021.

For the second quarter of 2021, the loss on foreign currency translation for insulin purchase commitments denominated in Euros was $0.9 million compared to $1.9 million for the second quarter of 2020. The fluctuation was due to the change in the U.S. dollar to Euro foreign exchange rate.

Interest expense on debt for the second quarter of 2021 was $3.2 million compared to $2.4 million for the second quarter of 2020. This increase of $0.8 million was the result of interest on the $230.0 million 2.5% senior convertible notes, partially offset by a decrease in interest due to the repayment of $35.1 million of outstanding principal under the Mann Group non-convertible promissory note and the repayment of $10.0 million outstanding principal under the MidCap credit facility in the second quarter of 2021. In addition, the Company reduced the interest rates under the MidCap credit facility and the Mann Group convertible note through amendments to the respective agreements in the second quarter of 2021.

Loss on extinguishment of debt, a non-cash expense item, for the three months ended June 30, 2021 was $22.1 million as a result of the amendment to the Mann Group convertible note. The accounting for the $22.1 million loss on extinguishment did not result in a change in the financial position of the Company.

The net loss for the second quarter of 2021 was $35.5 million, or $0.14 per share, compared to a $10.3 million net loss in the second quarter of 2020, or $0.05 per share. The increased net loss of $25.3 million was primarily due to a non-cash loss on extinguishment of the Mann Group convertible note of $22.1 million as well as an increase in SG&A expenses and cost of revenue — collaboration and services, partially offset by an increase in Afrezza net revenue and revenues from collaboration and services. Non-GAAP net loss, adjusted to exclude the $22.1 million non-cash loss on extinguishment of the Mann Group convertible note was $13.4 million, or $0.05 per share, for the three months ended June 30, 2021 compared to $10.3 million, or $0.05 per share, for the prior year period.

Six Months June 30, 2021

Total revenues were $40.7 million for the six months ended June 30, 2021, an increase of $9.4 million, or 30%, reflecting Afrezza net revenue of $18.1 million and collaboration and services revenue of $22.6 million. Afrezza net revenue increased 21% compared to $15.0 million for the six months ended June 30, 2020, primarily as a result of higher prescription demand and the negative effects of the COVID-19 pandemic in the prior year period, a more favorable mix of Afrezza cartridges and price (including a lower gross-to-net deduction percentage of gross sales). Collaboration and services revenue for the six months ended June 30, 2021 increased $6.3 million, or 38%, compared to the six months ended June 30, 2020, primarily due to the Company’s collaboration with United Therapeutics.

Afrezza gross profit for the six months ended June 30, 2021 was $9.3 million compared to $7.1 million in the same period of 2020, a 31% increase that was driven primarily by higher Afrezza revenue. Cost of goods sold increased $0.9 million compared to the same period in 2020, primarily due to a $2.0 million fee for an amendment of the Company’s insulin supply agreement, partially offset by $0.8 million of costs associated with lower manufacturing cost per unit and the termination of the free goods program in December 2020, in addition to $0.5 million of inventory write-offs in 2020. Gross margin for the six months ended June 30, 2021 was 52% compared to 48% for the same period in 2020. On a non-GAAP basis, which excludes the $2.0 million insulin supply amendment fee, gross margin was 63% for the six months ended June 30, 2021 compared to 48% for the same period in 2020.

R&D expenses for the six months ended June 30, 2021 were $4.8 million compared to $3.2 million for the six months ended June 30, 2020. This increase of $1.6 million, or 48%, was attributable to increased development activity related to our product pipeline.

SG&A expenses for the six months ended June 30, 2021 were $37.5 million compared to $28.0 million for the six months ended June 30, 2020, an increase of $9.4 million, or 34%, as we expanded our investment behind Afrezza and lowered expenses in the prior year period when we voluntarily reduced compensation and field force activities in response to the onset of the COVID-19 pandemic. As we continued to re-engage our selling activities behind Afrezza, we increased promotional and marketing expenses by $2.4 million and patient support services by $0.9 million in the first half of 2021. Personnel expenses increased $6.4 million due to the favorable impact of lower spending during the COVID-19 pandemic as well as increased headcount and stock compensation. The increased spending in SG&A in the first half of 2021 was partially offset by a reduction for the promotional cost for Thyquidity that was recognized as cost of revenue — collaboration and services in 2021.

For the six months ended June 30, 2021, the gain on foreign currency translation for insulin purchase commitments denominated in Euros was $2.9 million compared to a $0.1 million loss for the six months ended June 30, 2020. The fluctuation was due to the change in the U.S. dollar to Euro foreign exchange rate.

Interest expense on debt for the six months ended June 30, 2021 was $9.6 million compared to $4.7 million for the six months ended June 30, 2020. This increase of $4.9 million was the result of a $3.7 million milestone obligation achieved in the first quarter of 2021, interest on the $230.0 million 2.5% senior convertible notes issued in the first quarter of 2021, partially offset by a decrease in interest due to the repayment of $35.1 million of outstanding principal under the Mann Group non-convertible promissory note and the repayment of $10.0 million outstanding principal under the MidCap credit facility in the second quarter of 2021. In addition, the Company reduced the interest rates on the outstanding principal balances under the MidCap credit facility and the Mann Group convertible note through amendments to the respective agreements in the second quarter of 2021.

Non-cash loss on extinguishment of debt for the six months ended June 30, 2021 was $22.1 million as a result of the amendment to the Mann Group convertible note. The accounting for the $22.1 million loss on extinguishment did not result in a change in the financial position of the Company.

The net loss for the six months ended June 30, 2021 was $48.4 million, or $0.20 per share, compared to a $19.6 million net loss in the six months ended June 30, 2020, or $0.09 per share. The increased net loss of $28.9 million was primarily due to the non-cash loss on extinguishment of the Mann Group convertible note of $22.1 million as well as an increase in SG&A expenses, cost of revenue – collaboration and services, and loss on purchase commitments, partially offset by an increase in Afrezza net revenues and revenues from collaboration and services. Non-GAAP net loss, adjusted to exclude the $22.1 million non-cash loss on extinguishment of the Mann Group convertible note was $26.3 million, or $0.11 per share, for the six months ended June 30, 2021 compared to $19.6 million, or $0.09 per share, for the same period in the prior year.

Cash, cash equivalents, and investments at June 30, 2021 were $201.4 million compared to $67.0 million at December 31, 2020. The increase in cash, cash equivalents and investments was primarily due to the issuance of $230.0 million of 2.5 % senior convertible notes in the first quarter of 2021.

Non-GAAP Measures

Certain financial information contained in this press release is presented on both a reported basis (GAAP) and a Non-GAAP basis. Reported results were prepared in accordance with GAAP whereas Non-GAAP measures exclude items described in the reconciliation tables below. Non-GAAP financial information is intended to portray the results of our baseline performance, supplement or enhance management, analysts and investors overall understanding of our underlying financial performance and facilitate comparisons among current and past periods. The Non-GAAP financial measures are in addition to, not a substitute for, or superior to measures of financial performance compared in accordance with GAAP.

The following tables reconcile our gross margin financial measure to a non-GAAP presentation as adjusted for the nonrecurring amendment fee related to an amendment to our Insulin Supply Agreement.

The following tables reconcile our financial measure for net loss and EPS as reported in our condensed consolidated statement of operations to a non-GAAP presentation as adjusted for the $22.1 million non-cash loss on extinguishment of the Mann Group convertible note, which did not result in a change in our financial position.

(1) There is no provision for income taxes associated with the non-cash loss on extinguishment of debt as a result of our full valuation allowance.

Conference Call

MannKind will host a conference call and presentation webcast to discuss these results today at 5:00 p.m. Eastern Time. Those interested in listening to the conference call live via the Internet may do so by visiting the Company’s website at www.mannkindcorp.com under Events & Presentations. A replay will be available on MannKind’s website for 14 days.

On August 11, 2021 Atreca, Inc. (Atreca) (NASDAQ: BCEL), a clinical-stage biotechnology company focused on developing novel therapeutics generated through a unique discovery platform based on interrogation of the active human immune response, reported financial results for the second quarter ended June 30, 2021, and provided an overview of recent developments (Press release, Atreca, AUG 11, 2021, View Source [SID1234586316]).

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"We recently announced initial summary data from the dose escalation portion of the Phase 1b trial evaluating ATRC-101 in multiple solid tumors," said John Orwin, Chief Executive Officer. "ATRC-101 was well-tolerated in the study, and we believe that the initial signs of activity, which were associated with expression of ATRC-101’s target, provide strong rationale for further evaluation. Additionally, we believe the data provide validation of the ability of our discovery platform to identify druggable tumor targets shared across broad groups of patients. We look forward to providing an update on our early-stage pipeline in the coming months as well as reporting additional monotherapy in 1H22, pembrolizumab combination data in mid-2022, and chemotherapy combination data in late 2022."

Recent Developments and Highlights

Atreca announced initial summary data from the dose escalation portion of the Phase 1b trial of ATRC-101 in multiple solid tumors. ATRC-101 was well-tolerated with no dose-limiting toxicities observed. Eight of the 20 participants (40%) evaluable prior to the data cut-off in this analysis experienced stable disease (SD) as their best RECIST response, including four with tumor size reduction. The disease control observed in the study was associated with ATRC-101 target expression, and preliminary biomarker analysis was consistent with the proposed mechanism of action for ATRC-101.The peak concentration of ATRC-101 was dose proportional and minimal accumulation was observed following multiple doses.
Phase 1b monotherapy dose expansion of ATRC-101 is ongoing at 30 mg/kg. A combination study evaluating ATRC-101 with pembrolizumab is active and another combination study with pegylated liposomal doxorubicin is expected to begin enrolling patients in 4Q21. Atreca expects to report additional monotherapy data in 1H22, pembrolizumab combination data in mid-2022 and chemotherapy combination data in late 2022.
Supported by data from the dose escalation portion of the trial, Atreca is developing a diagnostic to enable prospective patient selection based on target expression.
Second Quarter 2021 Financial Results

As of June 30, 2021, cash and cash equivalents and short-term investments totaled $182.3 million.
Research and development expenses for the three months ended June 30, 2021 were $19.0 million, including non-cash share-based compensation expense of $1.9 million.
General and administrative expenses for the three months ended June 30, 2021 were $8.0 million, including non-cash share-based compensation expense of $2.0 million.
Atreca reported a net loss of $26.7 million, or basic and diluted net loss per share attributable to common stockholders of $0.72, for the three months ended June 30, 2021.

On August 11, 2021 Biomea Fusion, Inc. ("Biomea") (Nasdaq: BMEA), a preclinical-stage biopharmaceutical company focused on the discovery and development of irreversible small molecules to treat patients with genetically defined cancers, reported financial results for the second quarter of 2021 (Press release, Biomea Fusion, AUG 11, 2021, View Source [SID1234586315]).

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"We continue to make notable progress as we rapidly advance BMF-219 toward a planned entry into the clinic and continue to grow our company and pipeline," said Thomas Butler, Biomea’s CEO and Chairman of the Board. "In the second quarter, we successfully completed IND-enabling studies for BMF-219 and are now in the final stages of completing our IND submission to the FDA to advance BMF-219 to a Phase I study for the treatment of patients with menin-dependent AML and ALL. We also continued to make important progress pursuing our broad, ambitious, preclinical strategy focused on exploring the potential of this novel irreversible small molecule across a number of menin-dependent liquid and solid tumors, including DLBCL."

Mr. Butler continued, "While our primary focus is oncology drug development, there are multiple diseases where the menin pathway is implicated and where an irreversibly binding small molecule approach may have an important impact, including for patients with type 2 diabetes. At our core, we feel a profound responsibility to help patients with our novel chemistry. To that end, we look forward to seeing the results of our exploratory pathway validation in type 2 diabetes next year."

Business Highlights

Completed IND-enabling studies with irreversibly binding menin inhibitor BMF-219. Biomea successfully conducted IND-enabling studies with BMF-219, an irreversible menin inhibitor for the treatment of patients with menin-dependent AML and ALL. Biomea anticipates submitting the IND during the second half of 2021.

Continued preclinical studies of BMF-219 in DLBCL. Biomea continues to explore the potential of BMF-219 for a number of menin-dependent liquid and solid tumor cancers, including a subset of DLBCL, with a number of preclinical studies currently underway. The Company plans to report its findings in DLBCL in the first quarter of 2022. Despite the high dependency of several cancers on menin, Biomea Fusion is not aware of any menin inhibitors currently in clinical development for these cancer types.

Initiated pathway validation studies in diabetes. Based on a growing body of internal and external scientific evidence, Biomea has initiated key preclinical studies to explore the potential of its irreversible menin inhibitors as a treatment for type 2 diabetes. The Company plans to report its findings in the first quarter of 2022. Biomea Fusion is not aware of any menin inhibitors currently in clinical development for diabetes.
Expanded team and in-house research capabilities to support long-term growth and clinical and preclinical development plans. Biomea strengthened its executive team with the appointments of Franco Valle as Chief Financial Officer, Alex Cacovean, M.D. as Executive Medical Director and Sasha Blaug Ph.D. as Senior VP of Corporate Development. Biomea has successfully grown its headcount this year to date by 29 for a total of 41 current team members. The Company has also completed the buildout of its own laboratory facilities to further support the research and preclinical pipeline development of its irreversible platform.
Strengthened the Company’s Board of Directors. In the second quarter Biomea appointed Sumita Ray J.D., Chief Legal and Administrative Officer at Calithera Biosciences, Inc., to its Board. Ms. Ray is an industry veteran with over 20 years of expertise in FDA regulatory law, global health care law and compliance, brand support, product launches, collaborations and alliances.
Financial Highlights

Second Quarter 2021 Year to Date Financial Results

Biomea reported a net loss attributable to common stockholders of $14.3 million for the first six months of 2021, compared to a net loss of $0.7 million for the same period in 2020.

Research and development expenses were $9.0 million for the first six months of 2021, compared to $0.6 million for the same period in 2020. The increase of $8.4 million was primarily due to an increase in personnel-related expenses, as well as an increase in pre-clinical development costs, including manufacturing and external consulting, related to the IND-enabling studies for BMF-219.

General and administrative expenses were $5.3 million for the first six months of 2021, compared to $0.1 million for the same period in 2020. The increase of $5.2 million was primarily due to higher personnel-related expenses and other corporate costs to support the Company’s expanding operations, including legal and accounting.

As of June 30, 2021, the Company had cash, cash equivalents, restricted cash, and investments of $203.0 million.

On August 11, 2021 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted cancer therapeutics and utilizing a cost efficient, CRO-independent product development platform to partner with ex-U.S. companies to develop and commercialize innovative products in the U.S., reported financial results for the second quarter ended June 30, 2021 (Press release, Tracon Pharmaceuticals, AUG 11, 2021, View Source [SID1234586314]). The Company will host a conference call and webcast today at 4:30 PM Eastern Time / 1:30 PM Pacific Time.

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"We remain on track to announce interim efficacy data from the pivotal ENVASARC trial by the end of this year and final data in 2022," said Charles Theuer, M.D., Ph.D., President and CEO of TRACON. "Last week the IDMC recommended the study proceed as planned following review of interim safety data and we will continue to focus our efforts on enrolling this pivotal trial. Following our recent public offering, our balance sheet provides us with cash runway into 2023."

Recent Corporate Highlights

Envafolimab

In June, we received orphan drug designation for envafolimab in soft tissue sarcoma based on clinical data demonstrating confirmed objective partial responses by RECIST with duration of response in excess of six months, in two of five patients with refractory metastatic alveolar soft part sarcoma (ASPS) who received single agent envafolimab in Phase 1 clinical trials conducted by our partners, 3D Medicines and Alphamab Oncology.

On August 6, the Independent Data Monitoring Committee (IDMC) recommended the ENVASARC trial proceed as planned following the review of more than three months of safety data from more than 20 patients enrolled in the trial as of May.

In June, we presented the study design of the pivotal Phase 2 ENVASARC trial of single agent envafolimab and envafolimab given with Yervoy (ipilimumab) at the 2021 ASCO (Free ASCO Whitepaper) virtual annual meeting.
Corporate

In July, we announced an underwritten public offering for gross proceeds of approximately $15.0 million. We estimate that the proceeds will extend our cash runway into 2023, past expected final top-line data for ENVASARC.

In the second quarter we enhanced our senior management team with multiple new hires, including a Head of Regulatory and Head of Biometrics, both of whom have BLA filing experience.

In July, the book Unnecessary Expense: An Antidote to the Billion Dollar Drug Problem, authored by TRACON senior management to be published by ForbesBooks became available for preorder on Amazon. Publication is expected in September.
Other

In June, we presented preliminary Phase 1 data for the CD73 antibody uliledlimab (TJ4309) at the 2021 ASCO (Free ASCO Whitepaper) virtual annual meeting.
Expected Key Upcoming Milestones

Interim ENVASARC efficacy data by end of 2021.

Request FDA breakthrough therapy designation or fast track designation for envafolimab by end of 2021, assuming positive interim efficacy data.

Decision on the envafolimab New Drug Application in MSI-H/dMMR cancer that is under priority review by the Chinese National Medical Products Administration.
Second Quarter 2021 Financial Results

Cash, cash equivalents and short-term investments were $25.6 million at June 30, 2021, compared to $36.1 million at December 31, 2020. The cash balance at June 30, 2021, does not include the proceeds from the $15 million underwritten public offering in July, which extends the Company’s cash runway into 2023.

Research and development expenses for the second quarter of 2021 were $3.1 million, compared to $2.2 million for the second quarter of 2020.

General and administrative expenses for the second quarter of 2021 were $6.1 million, compared to $2.1 million for the second quarter of 2020. The increase was primarily attributable to legal expenses incurred with the now stayed lawsuit filed by I-Mab in the Delaware Court of Chancery and ongoing arbitration on the TJ4309 and bispecific agreements. We expect the second quarter of 2021 to be the high point for general and administrative expenses this year.

Net loss for the second quarter of 2021 was $8.9 million, compared to $4.5 million for the second quarter of 2020.
Conference Call Details

Wednesday, August 11, at 4:30 PM Eastern Time / 1:30 PM Pacific Time
Domestic: 855-779-9066
International: 631-485-4859
Conference ID: 3067769
A live webcast of the conference call will be available online from the Investor/Events and Presentations page of the Company’s website at www.traconpharma.com.

After the live webcast, a replay will remain available on TRACON’s website for 60 days.

About Envafolimab

Envafolimab (KN035), a novel, single-domain antibody against PD-L1, is the first subcutaneously injected PD-(L)1 inhibitor to be studied in pivotal trials. Envafolimab is currently being studied in the ENVASARC Phase 2 pivotal trial in the U.S. sponsored by TRACON, has been studied in a completed Phase 2 pivotal trial as a single agent in MSI-H/dMMR advanced solid tumor patients in China and is being studied in an ongoing Phase 3 pivotal trial in combination with gemcitabine and oxaliplatin in advanced biliary tract cancer patients in China, with both Chinese trials sponsored by 3D Medicines. TRACON’s partners Alphamab Oncology and 3D Medicines submitted an NDA to the NMPA in China for envafolimab in MSI-H/dMMR cancer that was accepted for review in December 2020 and granted priority review in January 2021. In the Phase 2 MSI-H/dMMR advanced solid tumor trial, the confirmed objective response rate (ORR) by blinded independent central review in MSI-H/dMMR colorectal cancer (CRC) patients treated with envafolimab who failed a fluoropyrimidine, oxaliplatin and irinotecan was 32%, which was similar to the 28% confirmed ORR reported in the Opdivo package insert in MSI-H/dMMR CRC patients who failed a fluoropyrimidine, oxaliplatin, and irinotecan and the 33% confirmed ORR reported for Keytruda in MSI-H/dMMR CRC patients who failed a fluoropyrimidine, oxaliplatin and irinotecan in cohort A of the KEYNOTE-164 clinical trial.

About ENVASARC (NCT04480502)

The ENVASARC pivotal trial is a multicenter, open label, randomized, non-comparative, parallel cohort study at approximately 25 top cancer centers in the United States that began dosing in December 2020. TRACON expects the trial to enroll 160 patients with UPS or MFS who have progressed following one or two lines of prior treatment and have not received an immune checkpoint inhibitor, with 80 patients enrolled into cohort A of treatment with single agent envafolimab and 80 patients enrolled into cohort B of treatment with envafolimab and Yervoy. The primary endpoint is ORR by blinded independent central review with duration of response a key secondary endpoint.

About TRC102

TRC102 (methoxyamine) is a novel, small molecule inhibitor of the DNA base excision repair pathway, which is a pathway that causes resistance to alkylating and antimetabolite chemotherapeutics. TRC102 is currently being studied in multiple Phase 1 and Phase 2 clinical trials sponsored by the National Cancer Institute through a Cooperative Research and Development Agreement (CRADA) and has orphan drug designation from the U.S. FDA in malignant glioma, including glioblastoma.

About TJ004309

TJ004309 is a novel, humanized antibody against CD73, an ecto-enzyme expressed on stromal cells and tumors that converts extracellular adenosine monophosphate (AMP) to adenosine, which is highly immunosuppressive. TJ004309 is currently being studied in an ongoing Phase 1 trial to assess safety and preliminary efficacy as a single agent and when combined with the PD-L1 checkpoint inhibitor Tecentriq in patients with advanced solid tumors.

On August 11, 2021 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage precision oncology company focused on developing targeted drugs to inhibit frontier targets that drive and sustain RAS-addicted cancers, reported its financial results for the second quarter and six months ended June 30, 2021, and provided a corporate update (Press release, Revolution Medicines, AUG 11, 2021, View Source [SID1234586313]).

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"Treatment for RAS-addicted cancers reached an important milestone in the second quarter with the first FDA approval of a targeted medicine for lung cancer carrying the KRASG12C mutation, Amgen’s Lumakras, or sotorasib. Likewise, Revolution Medicines continued making excellent progress reinforcing our belief that our cohesive and innovative asset portfolio can lead to rational, mechanism-based and beneficial combination treatments for patients. We have made the decision to deprioritize indirect combination treatment strategies represented in the RMC-4630-02 study while expanding evaluation of combination regimens with direct inhibitors of RAS proteins combined with our SHP2 inhibitor, RMC-4630. We are particularly gratified to conduct the RMC-4630-03 study under a clinical trial collaboration and supply agreement with Amgen through which we will evaluate the combination for potential additional benefit to lung cancer patients with the KRASG12C tumor mutation. We also maintain strong momentum toward bringing our highly differentiated RAS(ON) Inhibitors to bear against a wide range of RAS-addicted cancers," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines.

R&D Highlights

RAS(ON) Inhibitors – Revolution Medicines continues to advance its first-in-class RAS(ON) Inhibitor platform, including an expansive collection of tri-complex inhibitors targeting diverse oncogenic RAS variants through highly differentiated chemical and pharmacologic profiles.

RMC-6291 (KRASG12C) – RMC-6291 is a first-in-class, potent, oral and selective tri-complex inhibitor of KRASG12C(ON) with a differentiated preclinical profile designed to address persistent unmet needs for patients with cancers caused by KRASG12C.

During the second quarter, the company reported additional data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting and in a subsequent presentation showing that RMC-6291 provides deeper and/or more sustained anti-tumor effects in xenograft KRASG12C cancer models compared to a first-generation RAS(OFF) inhibitor, expanding the evidence that RMC-6291 has the potential to be a best-in-class KRASG12C inhibitor.
The company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran’s team at the Massachusetts General Hospital/Harvard Medical School by demonstrating that RMC-6291 is active against all second-site resistance mutations reported thus far from patients treated with adagrasib. As many of these mutations also confer resistance to sotorasib and other KRASG12C(OFF) inhibitors, the activity of RMC-6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing, or treating, emergence of these resistance mutations.
The company remains on track to submit an Investigational New Drug (IND) application for RMC-6291 in the first half of 2022.
RMC-6236 (RASMULTI) – RMC-6236 is a first-in-class, potent, oral RAS-selective tri-complex, RASMULTI(ON) inhibitor that is designed to treat cancers caused by multiple RAS variants for which no targeted treatment is currently available.

During the second quarter, the company reported deep anti-tumor activity of RMC-6236 in preclinical lung, colorectal and pancreatic cancer models driven by various common mutations, including KRASG12V and KRASG12D, at the AACR (Free AACR Whitepaper) annual meeting and in a subsequent presentation, supporting its potential as a first targeted therapy for treating KRASG12V and/or KRASG12D tumors.
A study published by the Dana-Farber Cancer Institute in the New England Journal of Medicine identified "RAS oncogene switch" resistance mutations in patients treated with adagrasib. The company subsequently presented preclinical data demonstrating that RMC-6236 is active against all of these clinically observed variants, revealing important properties of RMC-6236 that may be useful for preventing, or treating, emergence of such resistance mutations.
The company remains on track to submit an IND for RMC-6236 in the first half of 2022.

Continued expansion of other RAS(ON) inhibitor programs – Revolution Medicines continues to progress its expanding portfolio of RAS(ON) Inhibitors designed to target RAS variants driving the vast majority of RAS-addicted cancers and remains on track to nominate a third development candidate from its RAS(ON) inhibitor portfolio in the second half of 2021.
RAS Companion Inhibitors – Revolution Medicines continues to advance and expand multiple clinical studies of its RAS Companion Inhibitors designed to provide maximum clinical benefit in RAS-addicted cancers.

RMC-4630 (SHP2 Inhibitor) – RMC-4630 a potent, oral, selective inhibitor of the SHP2 protein, is being advanced in collaboration with, and is primarily funded by, Sanofi.

RMC-4630 and KRASG12C inhibitor sotorasib
Amgen’s CodeBreaK 101c study continues evaluating sotorasib in combination with RMC-4630 in patients receiving second line or later treatment for advanced non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors. To date this combination has demonstrated acceptable tolerability and cleared early dose levels. The dose escalation work continues at the target dose for each compound: RMC-4630 200 mg on a Day 1 / Day 2 (D1D2) weekly schedule, in combination with sotorasib 960 mg daily. Amgen anticipates selecting a combination dose for this study in the second half of 2021.
Today, Revolution Medicines announces a global Phase 2 study that will evaluate further the combination of RMC-4630 and sotorasib in lung cancer. The protocol for the new study, RMC-4630-03, is informed by the CodeBreaK 101c work to date as well as the many important learnings in the field over the last few years. The study, sponsored by Revolution Medicines under its global partnership with Sanofi, will be conducted in collaboration with Amgen, including supply of drug by Amgen at ex-U.S sites. RMC-4630-03 will evaluate the combination in inhibitor-naïve patients with advanced NSCLC that builds on, and is complementary to, CodeBreaK 101c. Study startup activities are ongoing, and the company expects to dose the first patient in the second half of 2021 and to have preliminary findings in the second half of 2022.

RMC-4630 and MEK inhibitor cobimetinib (Cotellic)
Previously reported findings from the Phase 1b/2 study of this combination in patients with relapsed/refractory solid tumors harboring specific genomic mutations demonstrated acceptable tolerability, also observed among patients enrolled in expansion cohorts. Among 11 efficacy evaluable patients with NSCLC, one patient with a KRASG12V tumor mutation and gene amplification exhibited a confirmed partial response (PR) with a 45% tumor volume reduction. Among 25 efficacy evaluable CRC subjects, the best clinical response was stable disease. These results support the anti-tumor activity of RMC-4630 and its potential for clinical benefit in RAS-driven cancers and to be combined tolerably with other drugs. However, insufficient clinical benefit was observed to justify advancing this approach, and no additional patients will be enrolled in this study. The findings reinforce the company’s belief that the optimal treatment for RAS-addicted cancers may come from combining RMC-4630 with direct RAS inhibitors.

RMC-4630 and EGFR inhibitor osimertinib (Tagrisso)
The company initiated a Phase 1b study of this combination with the intent of suppressing adaptive resistance mechanisms that may eventually reduce the efficacy of osimertinib upon long-term treatment. To date, the company has not identified a combination dose and schedule with acceptable tolerability, indicating that the combined suppression of RAS signaling in normal tissues caused by these two agents presents too significant a safety hurdle to justify advancing this approach, and no further patients will be enrolled in this study. No clinical toxicity was observed that has been attributed to off-target effects of RMC-4630. Rather the company believes that osimertinib and RMC-4630 are both effective, and additive, on-pathway inhibitors. The company intends to increase its focus on RAS-addicted cancers by combining direct RAS inhibitors with RAS Companion Inhibitors including RMC-4630.

RMC-4630 and PD-1 inhibitor pembrolizumab (Keytruda)
The TCD16210 study sponsored by Sanofi continues evaluating RMC-4630 in combination with pembrolizumab, a PD-1 inhibitor. Today, the company reports that preparation is underway for Phase 2 expansion focused on evaluating this combination as front-line treatment for patients with PD-L1+ NSCLC.

RMC-4630 monotherapy
The company presented a dose escalation activity data set from its ongoing Phase 1 study at the 2021 AACR (Free AACR Whitepaper) annual meeting, showing anti-tumor activity and safety and tolerability that are consistent with on-pathway inhibition.
Additional data were presented at the AACR (Free AACR Whitepaper) meeting showing reduction of variant allele frequency in circulating tumor DNA (ctDNA) samples from select patients treated with RMC-4630, further validating its expected clinical mechanism of action.

RMC-5552 (mTORC1/4EBP1 Inhibitor) – RMC-5552 is a potent, selective bi-steric inhibitor of mTORC1 that suppresses phosphorylation and inactivation of 4EBP1.

Enrollment and dosing are underway in a Phase 1 monotherapy dose-escalation study. The company continues to expect initial safety, pharmacokinetic and single agent activity data in 2022.
The company reported preclinical data at the 2021 AACR (Free AACR Whitepaper) annual meeting demonstrating that bi-steric mTORC1-selective inhibitors drive significant anti-tumor activity as monotherapy and in combination with KRASG12C inhibitors in genetically-defined models of human cancers.
The company recently announced the publication of an original scientific paper in Nature Chemical Biology describing anti-tumor effects of bi-steric mTORC1-selective inhibitors that potently suppress phosphorylation of 4EBP1, a key translational regulator of oncogene expression. In preclinical models, a series of bi-steric inhibitors demonstrated the favorable anti-tumor effects and tolerability of such compounds compared to earlier generations of mTOR inhibitors.
The company intends to evaluate RMC-5552 in combination with RAS inhibitors for the treatment of tumors driven by co-occurring RAS mutations and genomic activation of the mTORC1 pathway.
RMC-5845 (SOS1 Inhibitor) – RMC-5845 is a potent, selective, oral inhibitor of SOS1, a major switch in the cycling of RAS(OFF) to RAS(ON).

The company expects RMC-5845 to be IND-ready in the second half of 2021. Due to its current focus on other priorities, including the continued advancement of its RAS(ON) Inhibitor programs and the initiation of the RMC-4630-03 study, the company no longer intends to submit an IND for RMC-5845 in 2021 and will determine timing for a potential IND at a future date.
Corporate Highlights

Flavia Borellini, Ph.D. elected to board of directors – Dr. Borellini has more than 25 years of executive management experience in the pharmaceutical and biotechnology industry, with a particular focus on global development of targeted oncology drugs, from preclinical to commercial stage.
Second Quarter 2021 Financial Highlights

Cash Position: Cash, cash equivalents and marketable securities were $646.3 million as of June 30, 2021, compared to $440.7 million as of December 31, 2020. The increase was primarily due to proceeds from the company’s equity public offering in February 2021.

Revenue: Total revenue, consisting of revenue from the company’s collaboration agreement with Sanofi, was $8.7 million for the quarter ended June 30, 2021, compared to $10.0 million for the quarter ended June 30, 2020. The decrease was due to lower reimbursed research and development services for RMC-4630 resulting from lower clinical trial costs.

R&D Expenses: Research and development expenses were $45.9 million for the quarter ended June 30, 2021, compared to $32.9 million for the quarter ended June 30, 2020. The increase was primarily due to an increase in research expenses associated with the company’s pre-clinical research portfolio, an increase in personnel-related expenses related to additional headcount, and an increase in stock-based compensation.

G&A Expenses: General and administrative expenses were $7.3 million for the quarter ended June 30, 2021, compared to $5.1 million for the quarter ended June 30, 2020. The increase was primarily due to stock-based compensation and personnel-related expenses related to additional headcount.

Net Loss: Net loss was $44.3 million for the quarter ended June 30, 2021, compared to a net loss of $27.2 million for the quarter ended June 30, 2020.

2021 Financial Guidance

Revolution Medicines continues to expect full year 2021 GAAP net loss to be between $170 million and $190 million, which includes estimated non-cash stock-based compensation expense of approximately $20 million.

Conference Call

Revolution Medicines will host a conference call and webcast this afternoon, August 11, 2021, at 4:30 PM EDT (1:30 PM PDT).

To listen to the conference call, please dial (833) 423-0425 or (918) 922-3069, provide conference ID: 9829729 and request the Revolution Medicines conference call. To listen to the live webcast, or access the archived webcast, please visit: View Source Following the live webcast, a replay will be available on the Company’s website for at least 14 days.