On November 25, 2023 (the "Effective Date"), Personalis, Inc. (the "Company") and Tempus Labs, Inc. ("Tempus") reported to have entered into a Commercialization and Reference Laboratory Agreement (the "Tempus Agreement") pursuant to which Tempus will market the Company’s NeXT Personal Dx assay (the "Assay") in the United States and the Company will conduct development activities to validate the Assay in breast cancer, lung cancer and immuno-oncology monitoring indications (the "Indications") (Filing, 8-K, Personalis, NOV 25, 2023, View Source [SID1234638011]). The term of the Tempus Agreement is five years from the Effective Date, which may be extended for successive one-year renewal terms upon the parties’ mutual agreement (the "Term").

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Tempus will use commercially reasonable efforts to market and promote the Assay in the same or substantially same manner that it markets and promotes its own tests. The Company will use commercially reasonable efforts to validate the Assay in the Indications and to generate evidence to seek reimbursement from payors in each such Indication. The Company will perform tests using the Assay ordered by customers through Tempus and will bill such customers or payors for the performance of such tests. The Company granted to Tempus a license to certain intellectual property of the Company necessary for Tempus to perform the Assay, which license is exercisable by Tempus upon certain failures by the Company to perform tests using the Assay ordered under the Tempus Agreement, subject to certain limitations.

In consideration of the Company performing such development activities, Tempus will pay to the Company fees of up to $12,000,000 in the aggregate (the "Market Development Fee"), consisting of an activation fee of $3,000,000 (the "Activation Fee"), a first milestone fee of $3,000,000 (upon achievement of a specified clinical validation milestone), and a second milestone fee payable in six quarterly installments totaling $6,000,000 (subject to the Company achieving certain specified additional clinical validation milestones (collectively, the "Second Milestone")). If the Company does not achieve the Second Milestone by a specified date, Tempus may withhold such installment payments until the Company achieves such Second Milestone, and Tempus will have the right to terminate the Tempus Agreement or convert it to a non-exclusive arrangement; upon any such termination or conversion, the Company will refund to Tempus any Market Development Fee other than the Activation Fee paid to Tempus as of the date of such termination or conversion, subject to certain reductions. If the Company is unable to offer the Assay for use in any Indication in accordance with a schedule set forth in the Tempus Agreement, the Company will refund to Tempus any Market Development Fee other than the Activation Fee paid to Tempus as of the date of such failure to meet such schedule and subject to certain reductions.

From the Effective Date through a specified period for each Indication, the Company will not allow any third party (other than an acquiror of the Company or any affiliates of such acquiror) to market the Assay in such Indication and Tempus will not market another tumor-informed molecular residual disease assay indicated for use in such Indication (whether its own or that of a third party), in each case subject to certain exceptions. Such exclusivity obligations terminate on December 31, 2027 to the extent they do not expire earlier. In addition, each party has the right to convert the Tempus Agreement to a non-exclusive arrangement upon the occurrence of certain specified events.

The Company will compensate Tempus for the fair market value of order requisition and results delivery services rendered with respect to tests using the Assay ordered under the Tempus Agreement on a per-test basis. In addition, the parties will perform certain co-promotion activities with respect to Personalis’ reference laboratory services and Personalis will compensate Tempus for the fair market value of promotional and commercialization services provided by Tempus in connection therewith in an amount up to $9,600,000.

The Tempus Agreement also grants Tempus access to certain initial and longitudinal genomic data derived from performance of the Assay and Tempus will have the right to use such data in accordance with applicable laws. If Tempus or its affiliate licenses such data to a third party and Tempus recognizes revenue from such license, Tempus will pay to the Company a percentage of its gross revenue received that is attributable to such license in the range of 10 to 20 percent. Such revenue share shall be payable during the Term and for 10 years thereafter.

Additionally, in consideration of Tempus’ obligations to the Company under the Tempus Agreement, on November 28, 2023, the Company issued to Tempus (1) a warrant to purchase up to 4,609,400 shares of the Company’s common stock (the "Common Stock") at an exercise price per share of $1.50, with an expiration date of December 31, 2024 (the "First Warrant"), and (2) a warrant to purchase up to 4,609,400 shares of Common Stock at an exercise price per share of $2.50, with an expiration date of December 31, 2025 (the "Second Warrant" and, together with the First Warrant, the "Warrants"). The Warrants are exercisable for cash at any time prior to the applicable expiration date, may be net exercised in certain circumstances, and will be automatically net exercised in connection with a change of control of the Company if the value ascribed to the consideration to be paid for one share of Common Stock in such change of control is greater than the applicable exercise price. The number of shares issuable upon exercise of the Warrants and the exercise prices of the Warrants are subject to adjustment by reason of stock dividends, splits, recapitalizations, reclassifications and the like. If Tempus acquires any shares of Common Stock directly from the Company other than by exercising the Warrants (any such shares, "Non-Warrant Shares"), then the total number of shares issuable upon exercise of the Warrants will be reduced by the Non-Warrant Shares on a share-for-share basis, proportionally between the First Warrant and the Second Warrant based on how many shares are then underlying the Warrants. The Company agreed to register the resale of the shares underlying the Warrants by filing a registration statement with the U.S. Securities and Exchange Commission (the "SEC") within 30 calendar days of the issuance date of the Warrants.

Under the Tempus Agreement, Tempus agreed to certain customary standstill restrictions that apply (a) whenever Tempus (together with its affiliates) owns at least 9,218,800 shares of Common Stock until the parties’ exclusivity obligations expire or terminate under the Tempus Agreement and (b) from the Effective Date through the first anniversary of the Effective Date, to the extent the parties’ exclusivity obligations expire or terminate under the Tempus Agreement and Tempus (together with its affiliates) owns at least 5% of the outstanding shares of Common Stock. These standstill restrictions are subject to suspension in certain cases set forth in the Tempus Agreement. In addition, the Company has agreed to notify Tempus in certain circumstances if the Company is pursuing a change of control transaction for the Company.

With respect to any shares it acquires from exercising the Warrants, Tempus also agreed to certain voting commitments under the Tempus Agreement. These voting commitments require Tempus to vote any shares it acquires from exercising the Warrants in accordance with the recommendations of the majority of the Company’s board of directors, and generally apply to director nominations for any meeting of the Company’s stockholders occurring on or before December 31, 2025, various compensation-related matters, and ratification of auditors. These voting commitments terminate on the later of (i) when the parties’ exclusivity obligations expire or terminate under the Tempus Agreement and (ii) the first anniversary of the Effective Date.

Either party may terminate the Tempus Agreement upon the other party’s material breach or insolvency, if the other party assigns the agreement to a competitor of the terminating party, if there are certain materially adverse changes to certain of the other party’s licenses, permits or certifications or if the other party or its personnel have any materially adverse personal or professional conflicts of interest, subject to certain notice periods. After the first anniversary of the Effective Date, either party may terminate the Tempus Agreement for convenience upon 18 months’ prior written notice. Tempus may terminate the agreement if the Company does not achieve the Second Milestone by a specified date.

The foregoing summary of the Tempus Agreement is qualified in its entirety by reference to the full text of the Tempus Agreement, a copy of which is attached to this report as Exhibit 10.1, which is incorporated herein by reference.

The foregoing summary of the Warrants is qualified in its entirety by reference to the full text of (i) the First Warrant, a copy of which is attached to this report as Exhibit 4.1, which is incorporated herein by reference, and (ii) the Second Warrant, a copy of which is attached to this report as Exhibit 4.2, which is incorporated herein by reference.

On November 24, 2021 Pyrotech (Beijing) Biotechnology Co., Ltd ("Pyrotech Therapeutics"), a company dedicated to developing revolutionary innovative drugs for inflammation and cancer, reported that their independently developed small molecule innate immune agonist PTT-936, with a completely new mechanism of action, has been approved by the U.S. Food and Drug Administration (FDA) for clinical research (Press release, Pyrotech, NOV 24, 2023, View Source [SID1234643789]). This marks the company’s first innovative drug to enter clinical evaluation in the United States.

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PTT-936 is a novel alpha-protein kinase 1 (ALPK1) small molecule agonist that activates the body’s immune system to attack tumors. ALPK1, as a new innate immune receptor, can recognize the small molecule ADP-heptose derived from bacteria and activate the body’s immune response. In 2018, Dr. Feng Shao, a co-founder of Pyrotech Therapeutics, reported this discovery in the journal "Nature" (Zhou et al., Nature 2018). Preclinical studies have shown that activating ALPK1 can efficiently induce anti-tumor immunity. Based on this insight, Pyrotech Therapeutics developed the novel ALPK1 agonist PTT-936.

Preclinical studies have demonstrated that PTT-936, either as a monotherapy or in combination with immune checkpoint inhibitors, exhibits excellent anti-tumor activity. Compared to other innate immune agonists with different mechanisms, PTT-936 has a potentially larger therapeutic window. As a small molecule agonist based on a completely new target and mechanism, PTT-936 is expected to circumvent the safety and efficacy issues limiting the utility of existing innate immune agonists and thereby offer a new treatment option for cancer patients.

On November 24, 2023 Theolytics, a biotechnology company harnessing viruses to combat disease, reported pre-clinical data on its lead oncolytic adenovirus – THEO-260 at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) annual meeting, which was held from Friday October 20, 2023, to Tuesday, October 24, 2023, in Madrid, Spain (Press release, Theolytics, NOV 24, 2023, View Source [SID1234638013]).

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ASCO Abstract

Title: Development of an oncolytic virus for the treatment of high grade serous

ovarian cancer and other stromal rich tumours

LINK to abstract

The data presented supports the progression of oncolytic adenovirus THEO-260 to first in human clinical trials. The results show THEO-260 is highly efficacious in killing cancer cells and cancer associated fibroblasts in fresh ovarian cancer patient tumour samples. Cancer associated fibroblasts in stromal rich tumours are a barrier to the effectiveness of many cancer treatments. The destruction of cancer associated fibroblasts, in addition to cancer cells, is a potentially exciting and differentiating feature of Theolytics’ virotherapy. To date, neither chemotherapy, nor immunotherapeutic approaches have been able to demonstrate a similar level of clearance of cancer associated fibroblasts pre-clinically, potentially positioning THEO-260 as a breakthrough in the oncolytic virus field.

Miriam Bazan-Peregrino, VP Translational Development at Theolytics who presented the data at ESMO (Free ESMO Whitepaper) 2023 said, "In pre-clinical models THEO-260 shows antitumour efficacy, with complete responses. The therapy demonstrates high selectivity and was shown to be safe in immunocompetent mouse models. The genetic and temperature stability of THEO-260 has been confirmed and is currently being GMP manufactured at high yields. Together, these data support the development of this promising new therapy, which we hope will create a step-change in the treatment of Platinum Resistant Ovarian Cancer."

On November 24, 2023 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China has accepted the New Drug Application (NDA) for GFH925 (IBI351) and granted GFH925 with Priority Review designation, for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation who have received at least one systemic therapy (Press release, GenFleet Therapeutics, NOV 24, 2023, View Source [SID1234637961]). It’s the first China-developed KRAS G12C inhibitor that has its NDA submission accepted and granted with Priority Review Designation by NMPA. GFH925 also received Breakthrough Therapy Designations this year for treating advanced KRAS G12C-mutant NSCLC that have received at least one systemic therapy and colorectal carcinoma (CRC) patients who have received at least two systemic therapies.

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The Priority Review designation is based on the results from a single-arm registrational Phase II study of GFH925 monotherapy treating advanced KRAS G12C-mutant NSCLC patients who failed or was intolerant of standard-of-care treatment in China (NCT05005234). The results will be presented at the upcoming European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia Congress 2023.

The results of GFH925 from a Phase I trial was updated in an oral presentation at the 2023 AACR (Free AACR Whitepaper) Annual Meeting. As of data cutoff date (February 10, 2023), of the 67 evaluable NSCLC patients, 41 achieved partial response (PR), with investigator assessed ORR 61.2% and DCR 92.5%. Of 30 patients with NSCLC treated at 600mg BID (the recommended phase 2 dose), better efficacy signal was observed, with investigator assessed ORR 66.7% (confirmed ORR 53.3%) and DCR 96.7%.

In combating NSCLC, the multi-center trial of GFH925 and ERBITUX (cetuximab, EGFR inhibitor) has progressed into phase II study in Europe with favorable safety and encouraging efficacy and numerous patients were observed with partial response. The trial is led by led by Professor Rafael Rosell, a world-renowned expert in particular in the field of lung cancer, and partial responses were observed among advanced KRAS G12C-mutant patients. In China, Innovent is also exploring the potential of IBI351(GFH925) in combination therapies for previously untreated advanced NSCLC patients with KRAS G12C mutation; two Phase Ib studies of IBI351（GFH925）in combination with cetuximab and sintilimab (TYVYT, PD-1 inhibitor) respectively are currently ongoing.

"GFH925 is GenFleet’s first NDA-stage product and becomes China’s first KRAS G12C inhibitor that receives NDA acceptance and Priority Review Designation. That demonstrates GFH925’s encouraging safety and efficacy in treating advanced NSCLC, and its potential in commercialization in the future. Meanwhile, GenFleet’s combination study of GFH925 and cetuximab treating NSCLC in 1st line also progressed smoothly in Europe with preliminary results of good safety and efficacy. GenFleet will promote the advancement of more multiple-regional studies in monotherapy and combination therapies and we look forward to positive progress of this study and other studies of GFH925 conducted by Innovent." stated Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.

KRAS mutation as the ‘undruggable’ target for decades has become one of the most popular directions for clinical development recently. IBI351 is a novel, irreversible covalent inhibitor of KRAS G12C mutation. IBI351 monotherapy demonstrated favorable safety and promising activity in KRAS G12C mutated advanced NSCLC. We look forward to the NDA approval of this novel drug to benefit more NSCLC patients with KRAS G12C mutation soon." stated Professor Yi-Long Wu from Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital.

GFH925 is also the first domestic KRAS G12C inhibitor that received CDE Breakthrough Therapy Designation as monotherapy for previously treated KRAS G12C mutant CRC patients. According to the preliminary data of GFH925 monotherapy treating CRC at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting, favorable safety/tolerability and promising antitumor activity of GFH925 monotherapy were observed among patients. As of data cutoff date (Feb 16, 2023), a total of 54 metastatic colorectal cancer patients were included for analysis; of 42 evaluable subjects at 600mg BID, ORR was 42.9% (18/42), confirmed ORR was 31.0% (13/42), DCR was 88.1% (37/42).

About KRAS G12C Mutated Non-small Cell Lung Cancer

Lung cancer is one of the malignancies with the highest incidence and mortality worldwide, among which non-small cell lung cancer (NSCLC) is the most common pathological type, accounting for about 85% of all lung cancers. KRAS mutations are common driver gene mutations in NSCLC, most of which occur in lung adenocarcinoma. KRAS mutations rarely co-exist with driver mutations such as EGFR and ALK, and patients with advanced NSCLC with KRAS G12C mutations are often unable to benefit from the multiple drugs already on the market that target these mutations or rearrangements. After the progress of first-line standard treatment in this population, there are limited second-line treatment options with low effective rate and poor prognosis.

About GFH925（IBI351）

RAS protein family can be divided into KRAS, HRAS and NRAS categories. KRAS mutation are detected in nearly 90% of pancreatic cancer, 30-40% of colon cancer, and 15-20% lung cancer patients. The occurrence of KRAS G12C mutation subset is more frequently observed than those with ALK, ROS1, RET and TRK 1/2/3 mutations combined.

Discovered by GenFleet Therapeutics, GFH925 (Innovent R&D code: IBI351) is a novel, orally active, potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRAS G12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of GFH925 towards G12C. Subsequently, GFH925 effectively inhibits the downstream signal pathway to induce tumor cells’ apoptosis and cell cycle arrest.

In September 2021, Innovent and GenFleet Therapeutics entered into an exclusive license agreement for the development and commercialization of GFH925 in China (including mainland China, Hong Kong, Macau and Taiwan) with additional option-in rights for global development and commercialization.

On November 24, 2023 Circio Holding ASA (OSE: CRNA), a biotechnology company developing novel circular RNA and immunotherapy medicines, reported that the European Patent Office (EPO) board of appeal has moved to revoke the EU Patent 3140320 "Peptide vaccine comprising mutant RAS peptide and chemotherapeutic agent" during proceedings held on 22 November 2023 (Press release, Circio, NOV 24, 2023, View Source [SID1234637959]).

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EU Patent 3140320 is a method of use patent covering the combination of TG01 with the chemotherapeutic gemcitabine (and similar agents) in pancreatic cancer. The EPO board of appeal ruled that the patent should be revoked due to a lack of sufficient inventive step based on prior publications relating to TG01 clinical studies. Method of use patents are known to be challenging to uphold due to mandatory public disclosures surrounding trial design and treatment regimen. The EPO ruling applies only in European countries.

Dr. Lubor Gaal, Chief Financial Officer of Circio Holding ASA, said: "We are disappointed by and disagree with the EPO´s ruling to revoke our TG01/gemcitabine patent for pancreatic cancer. However, this chemotherapy combination was discontinued in 2019, and the ruling has no impact on ongoing clinical studies where TG01 is being tested with novel immunotherapies and in other cancer forms outside of this patent. Moreover, TG01 remains covered by orphan drug designations in pancreatic cancer and data protection as a biologic in both the EU and USA, which provides market protection for up to 12 years."