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Aileron Therapeutics Announces Proof-of-Concept Clinical Data from Ongoing ALRN-6924 Phase 1b Trial Presented in Late-Breaking Presentation at the EORTC-NCI-AACR Annual Symposium

On October 24, 2020 Aileron Therapeutics (Nasdaq: ALRN) reported new positive clinical data from its ongoing Phase 1b trial demonstrating clinical proof of concept that treatment with ALRN-6924 prior to second-line topotecan administration resulted in a protective effect against severe anemia, thrombocytopenia and neutropenia in patients with p53-mutated small cell lung cancer (SCLC) (Press release, Aileron Therapeutics, OCT 24, 2020, View Source [SID1234568952]). The results are being featured today in a late-breaking poster presentation entitled, "Prevention of Chemotherapy-induced Myelosuppression in SCLC Patients Treated with Dual MDM2/MDMX Inhibitor ALRN-6924" (online here) at the 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Annual (ENA 2020) Symposium on Molecular Targets and Cancer Therapeutics.

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Chemotherapy, the backbone of treatment for millions of cancer patients, is unselective, meaning it cannot distinguish between cancer cells and healthy cells. As a result, chemotherapy destroys both cancer cells and rapidly dividing healthy cells, such as bone marrow cells, hair follicle cells and skin cells, among others. ALRN-6924 is the first and only chemoprotective therapy in clinical development that utilizes a biomarker strategy. Specifically, ALRN-6924 is a cell-permeating peptide drug designed to work intracellularly, activating wild-type p53 to selectively shield healthy cells from chemotherapy in patients who harbor p53-mutant tumors, approximately 50% of all cancer patients, without interrupting chemotherapy’s targeting of cancer cells.

"These proof-of-concept results for ALRN-6924 bring us a major step closer toward our goal of creating a new paradigm of proactive prevention of chemotherapy-induced side effects to address a significant unmet need among cancer patients," said Manuel Aivado, M.D., Ph.D., President and CEO of Aileron. "As a medical oncologist, I appreciate that physicians need assurance that a chemoprotective agent will not reduce the efficacy of chemotherapy or promote tumor growth. Designed to shield only healthy, non-p53-mutated cells and leave p53-mutated cancer cells fully vulnerable to chemotherapy, we believe ALRN-6924 provides that assurance. With ALRN-6924, we believe we have the potential to ultimately bring chemoprotection to patients across a broad set of cancer types, improving their quality of life and enhancing their anti-cancer response to chemotherapy."

Dr. Vojislav Vukovic, M.D., Ph.D., Chief Medical Officer at Aileron, commented, "We are extremely pleased to have achieved clinical proof of concept in our ongoing Phase 1b trial. ALRN-6924 has demonstrated the ability to protect very sick patients with SCLC against severe and life-threatening toxicities and side effects that are associated with a chemotherapy that is known to be highly toxic to the bone marrow. Importantly, we now have validation to expand clinical development into other types of p53-mutated cancers and chemotherapies and pursue our long-term vision to bring chemoprotection to all patients with p53-mutated cancers regardless of cancer type or chemotherapy."

Data Highlights

As of August 31, 2020, the data cut-off for this data presentation, a total of 26 adult patients were enrolled in the dose optimization part of the ALRN-6924 Phase 1b trial, evaluating treatment with ALRN-6924 given 24 hours prior to chemotherapy. 18 patients were enrolled across three ALRN-6924 dose levels (1.2 mg/kg, 0.6 mg/kg and 0.3 mg/kg) and an additional eight (8) patients were enrolled in a 0.3 mg/kg expansion cohort. 25 of these patients were evaluable per the trial protocol. ALRN-6924 was administered 24 hours before each dose of topotecan. Topotecan (1.5 mg/m2) was administered on days 1 through 5 of every 21-day treatment cycle. In the trial, toxicities were evaluated using the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Per the Phase 1b trial protocol, patients were not permitted to receive prophylactic G-CSF treatment in cycle 1.

Across all ALRN-6924 dose levels, Grade 3/4 anemia, Grade 3/4 thrombocytopenia and Grade 4 neutropenia (defined as <500/µL) were limited to 24%, 36% and 48% of patients, respectively. In the topotecan plus placebo arm of a recent third-party randomized Phase 2 trial in SCLC patients receiving topotecan (n=28), Grade 3/4 anemia, Grade 3/4 thrombocytopenia and Grade 4 neutropenia were reported in 63%, 70% and 76% of patients, respectively (Hart et al., ASCO (Free ASCO Whitepaper) 2019). In the ALRN-6924 trial, while chemoprotection effects were observed across all ALRN-6924 dose levels, the 0.3 mg/kg dose level showed the most robust chemoprotection results, with Grade 3/4 anemia, Grade 3/4 thrombocytopenia and Grade 4 neutropenia limited to 21%, 36% and 43% of patients, respectively. Additionally, none of the patients on ALRN-6924 experienced febrile neutropenia. In the topotecan plus placebo arm of the recent third-party randomized Phase 2 trial in SCLC patients receiving topotecan (n=29), febrile neutropenia was observed in 17% of patients (Hart et al., ASCO (Free ASCO Whitepaper) 2019). None of the patients treated at the 0.3 mg/kg ALRN-6924 dose level had hematological serious adverse events (SAEs) and only one patient (7%) received one red blood cell transfusion and one platelet transfusion1. In the topotecan plus placebo arm of the recent third-party randomized Phase 2 trial, 41% and 31% of SCLC patients received red blood cell and platelet transfusions, respectively (Hart et al., ASCO (Free ASCO Whitepaper) 2019). At the 0.3 mg/kg ALRN-6924 dose level, no patients required erythropoiesis-stimulating agents, and seven patients (50%) required G-CSF treatment.

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1 Finding followed EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium Late-Breaking Abstract submission.

ALRN-6924 (given 24h prior to chemotherapy) Phase 1b Trial
Bone Marrow-Related Key Toxicity Findings
Adverse Events (AEs)* NCI CTCAE ≥ Grade 3
Third Party
Randomized Phase 2
Trial in SCLC
Historical Control‡

Toxicity ALRN-6924
0.3 mg/kg +
Topotecan
N (%)
N=14 ALRN-6924
(All Dose Levels)
Topotecan
N (%)
N=25
Placebo
+ Topotecan
N (%)
N=28
All AEs 13 (93) 24 (96) 27 (96)
Anemia 3 (21) 6 (24) 17 (61)
Thrombocytopenia 5 (36) 9 (36) 16 (57)
Neutropenia 11 (79) 22 (88) 24 (86)
Febrile Neutropenia 0 0 5 (17) †

Neutropenia
Grade 4 6 (43)** 12 (48)** 21 (76)
*AEs based on laboratory values, as applicable
**For cycle 1 and for all treatment cycles
‡ Hart et al. ASCO (Free ASCO Whitepaper) 2019
† Febrile neutropenia reported for 29 patients

"Chemotherapy-induced toxicities historically have been viewed by the medical community as an unfortunate yet unavoidable reality associated with effective chemotherapeutics. With therapeutic advancements like ALRN-6924, I believe there is a potential to dramatically evolve that mindset," said Bojan Zaric, M.D., Ph.D., Head of Clinical Research, Head of Lung Cancer Clinic, Institute for Pulmonary Diseases of Vojvodina, Serbia, and Principal Investigator of the ALRN-6924 Phase 1b trial.

Dr. Zaric continued, "These Phase 1b data provide early yet important insights into ALRN-6924’s unique activity among chemoprotective agents in development, as well as potential advantages over the current standard of care therapies to address bone marrow toxicities. The findings suggest a strong potential for ALRN-6924 to protect patients undergoing chemotherapy against severe anemia, thrombocytopenia and neutropenia."

Enrollment in the dose optimization part of the Phase 1b trial (ALRN-6924 administered 24 hours before topotecan) is complete, and monitoring is ongoing with four of the evaluable patients continuing treatment past the data cut-off date.

Upcoming Milestones

Aileron continues to enroll patients in a schedule optimization part of the Phase 1b trial intended to determine whether ALRN-6924 given six hours prior to topotecan ("6h-schedule part") could be an alternative dosing schedule that could provide patients and healthcare providers with additional flexibility of when to administer ALRN-6924 before topotecan. The company expects to report final data from the Phase 1b trial, including data from the 6h-schedule part, in the first quarter of 2021.

In addition, in the fourth quarter of 2020, Aileron plans to initiate a clinical study of ALRN-6924 in healthy volunteers to characterize the time to onset, and the magnitude and duration of cell cycle arrest in human bone marrow relative to ALRN-6924 administration. Subject to the results of the healthy volunteer study and the final data from the Phase 1b trial, Aileron expects to initiate a non-small cell lung cancer program beginning with a Phase 1b trial in the fourth quarter of 2021 and a development program in a gastrointestinal cancer indication at a later point in time. Aileron does not currently plan to conduct additional development of ALRN-6924 in patients with SCLC.

"We designed a robust Phase 1b trial to enable us to evaluate multiple dose levels and schedules of ALRN-6924," said Dr. Vukovic. "We anticipate garnering additional insights from the alternative six-hour dosing schedule part of the Phase 1b SCLC trial and the healthy volunteer study that could provide a strong foundation for regulatory discussions around a registration program for ALRN-6924 in non-small cell lung cancer patients who are receiving platinum-based chemotherapy."

Conference Call and Webcast

Aileron will host a conference call and webcast on Monday, Oct. 26, 2020 at 8:30 a.m. ET to discuss the Phase 1b data and the company’s clinical development strategy to expand its chemoprotection research to multiple p53-mutated cancers and chemotherapies. To access the conference call, investors are invited to dial 877-705-6003 (domestic) or +1 201-493-6725 (international). The conference ID number is 13712133. A live audio webcast can be accessed by visiting the investor relations section of Aileron’s website at View Source The webcast will be archived on Aileron’s site for one year.

How ALRN-6924 Is Designed to Protect Healthy Cells from Chemotherapy

ALRN-6924 is being developed by Aileron as a novel chemoprotective medicine to selectively protect healthy cells in patients with cancers that harbor p53 mutations to reduce or eliminate chemotherapy-induced side effects.

Chemotherapy preferentially acts on cells that are cycling or undergoing the process of cell division. In cancer cells, the cell cycle is unchecked, which leads to uncontrolled cell proliferation, a hallmark of cancer. Certain types of healthy cells also naturally need to cycle, such as bone marrow cells, hair follicle cells, skin cells, and cells lining the oral cavity and the gastrointestinal tract. As a result, chemotherapy targets and kills both cycling healthy cells and cycling cancer cells. This, in turn, can lead to a spectrum of chemotherapy-induced side effects, from unpleasant to life-threatening and fatal.

ALRN-6924, an investigational first-in-class MDM2/MDMX dual inhibitor, is administered prior to chemotherapy to patients with p53-mutant cancers. ALRN-6924 is designed to activate normal p53 protein in patients’ healthy cells, temporarily and reversibly pausing cell cycling to selectively shield the patients’ healthy cells from chemotherapy. The protection is limited to healthy cells, as ALRN-6924 cannot work in p53-mutated cancer cells given that p53 has lost its function in those cells. Therefore, cancer cells continue to cycle uninterrupted and remain fully susceptible to destruction by
chemotherapy.

Entry into a Material Definitive Agreement

On October 23, 2020, Plus Therapeutics, Inc. (the "Company") reported that it entered into an Equity Distribution Agreement (the "Distribution Agreement") with Canaccord Genuity LLC (the "Agent"), pursuant to which the Company may issue and sell, from time to time, shares of its common stock having an aggregate offering price of up to $10,000,000 (the "Shares"), depending on market demand, with the Agent acting as an agent for sales (Filing, 8-K, PLUS THERAPEUTICS, OCT 23, 2020, View Source [SID1234572295]). Sales of the Shares may be made by any method permitted by law deemed to be an "at the market offering" as defined in Rule 415(a)(4) of the Securities Act of 1933, as amended (the "Securities Act"), including, without limitation, sales made directly on or through the NASDAQ Capital Market. The Agent will use its commercially reasonable efforts to sell the Shares requested by the Company to be sold on its behalf, consistent with the Agent’s normal trading and sales practices, under the terms and subject to the conditions set forth in the Distribution Agreement. The Company has no obligation to sell any of the Shares. The Company may instruct the Agent not to sell the Shares if the sales cannot be effected at or above the price designated by the Company from time to time and the Company may at any time suspend sales pursuant to the Distribution Agreement.

The Company will pay the Agent a commission of up to 3.0% of the gross proceeds from the sale of Shares by the Agent under the Distribution Agreement. The Company has also agreed to reimburse the Agent for its reasonable documented out-of-pocket expenses, including fees and disbursements of its counsel, in the amount of $50,000. In addition, the Company has agreed to provide customary indemnification rights to the Agent.

The Offering will terminate upon the earlier of (1) the issuance and sale of all shares of the Company’s common stock subject to the Distribution Agreement, or (2) the termination of the Distribution Agreement as permitted therein, including by either party at any time without liability of any party.

Any sales of Shares under the Distribution Agreement will be made pursuant to the Company’s Registration Statement on Form S-3 (File No. 333-249410), including the related prospectus, filed with the Securities and Exchange Commission (the "SEC") on October 9, 2020 and declared effective on October 19, 2020, as supplemented by the prospectus supplement dated October 23, 2020, and any applicable additional prospectus supplements related to the Offering that form a part of the Registration Statement. The aggregate market value of Shares eligible for sale in the Offering and under the Distribution Agreement will be subject to the limitations of General Instruction I.B.6 of Form S-3, to the extent required under such instruction. The prospectus supplement filed with the SEC on October 23, 2020 is only offering Shares having an aggregate offering price of $4,960,000 million. The Company will be required to file another prospectus supplement in the event it determines to offer more than $4,960,000 million of Shares in accordance with the terms of the Distribution Agreement, to the extent then permitted under General Instruction I.B.6 of Form S-3. The Company intends to use the net proceeds from this offering for general corporate purposes and for working capital.

The foregoing description of the Distribution Agreement does not purport to be complete and is qualified in its entirety by reference to the Distribution Agreement, which is filed as Exhibit 1.1 to this report and is incorporated herein by reference. A copy of the legal opinion of Pillsbury Winthrop Shaw Pittman LLP regarding the legality of the issuance and sale of the Shares is filed as Exhibit 5.1 to this report and is incorporated by reference herein.

Novel manufacturing process design enables hotlab manufacturing scale-up

On October 23, 2020 Quirem Medical reported a first clinical QuiremSpheres patient procedure took place with a patient dose prepared using a novel hotlab manufacturing process design, developed together with VANDERWILT Techniques (Press release, Quirem Medical, OCT 23, 2020, View Source [SID1234571203]). The new process improves radiation safety for the hotlab operators and limits the production time, preparing for further scaling-up of the production of QuiremScout and QuiremSpheres. QuiremScout is an innovative product for screening liver cancer patients before they are treated with QuiremSpheres. QuiremSpheres is a CE-marked medical device indicated for treatment of unresectable liver tumors.

"Quirem Medical and VANDERWILT Techniques have a long-standing strategic partnership during which VANDERWILT has proven to be instrumental in the optimization of the hotlab processing steps. The effectuation of this latest process innovation, including bespoke instruments and tooling, is a new milestone. It supports our hotlab operators in their daily operations, minimizing processing time while reducing dose exposure significantly." says Stuart Koelewijn, Hotlab Operations Manager of Quirem Medical BV.

"We see a strongly increasing demand for our products throughout Europe and beyond. VANDERWILT has proven to be a reliable and innovative partner to us, while we are constantly improving our internal processes to match the increasing demand and to prepare for the global expansion of our business." says Jan Sigger, CEO of Quirem Medical BV.

INTELGENX ANNOUNCES SECOND TRANCHE CLOSING OF PRIVATE PLACEMENT

On October 23, 2020 IntelGenx Technologies Corp. (TSX-V:IGX) (OTCQX:IGXT) (the "Company" or "IntelGenx") reported that it has closed a private placement (the "Offering") to certain investors in the United States of U.S.$532,000 principal amount of 8% convertible notes due October 15, 2024 (the "Notes") (Press release, IntelGenx, OCT 23, 2020, View Source [SID1234569224]). The Notes will bear interest at a rate of 8% per annum, payable quarterly, and will be convertible into shares of common stock of the Company (the "Shares") beginning 6 months after their issuance at a price of U.S.$0.18 per Share. The Offering represents a second tranche of the Notes. As previously announced, the Company closed an offering of an additional $1.2 million of Notes on October 15, 2020.

The Company intends to use the proceeds of the Offering for working capital purposes.

In connection with the Offering, the Company paid to an agent a cash commission of approximately U.S.$37,000 in the aggregate and issued non-transferable warrants to the agent (the "Agent’s Warrants"), entitling the holder to purchase 212,800 common shares at a price of U.S.$0.18 per Share until October 15, 2022.

The TSX Venture Exchange (the "TSXV") has conditionally approved the listing of the Shares issuable upon conversion of the Notes, as well as the Shares issuable upon exercise of the Agent’s Warrants. Listing on the TSXV will be subject to the Company fulfilling all of the listing requirements of the TSXV within 15 days of the closing of the Offering.

This press release does not constitute an offer to sell, or a solicitation of an offer to buy, securities in any jurisdiction where not permitted by law. Any securities described in this announcement have not been registered under the United States Securities Act of 1933, as amended (the "U.S. Securities Act"), or any state securities laws, and may not be offered or sold in the United States, or to, or for the account or benefit of a "U.S. person" as defined in Regulation S under the U.S. Securities Act, except in transactions exempt from, or not subject to, registration under the U.S. Securities Act and applicable state securities laws.

The Notes were distributed pursuant to the prospectus exemption of section 12 of the Securities Act (Québec) for distribution of securities to persons established outside Québec.

EORTC SPECTA platform identifies genetic alterations in rare cancers for potential targeted therapies

On 23 October 2020 In the virtual 32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) symposium on Molecular Targets and Cancer Therapeutics, Dr Marie Morfouace PhD, EORTC Translational Scientist, reported that it will present results of study using EORTC SPECTA, a molecular and biological research platform (Press release, EORTC, OCT 23, 2020, View Source [SID1234568964]). The platform detected genetic alterations in rare cancers, which could be potential targets for therapy.

Rare cancers can include more than 300 different types of cancers and may affect all organs. Even though they represent 20% of all adult cancers, they account for more than 30% of cancer mortality. They are clearly under-represented in clinical research programmes, especially in research programmes exploring genomic alterations of cancer.

The EORTC and EURACAN developed a collaborative clinical research project called "Arcagen." This project aims to recruit 1,000 patients with rare cancer and perform a molecular profiling, using the Foundation Medicine tests. This feasibility study presents results from 87 patients from three French sites were analysed.

Forty-one patients were diagnosed with sarcoma, 9 with ovarian Yolk Sac Tumour (YST), 14 with rare head and neck cancers and 13 with thymic cancer. Male to female ratio was almost 1:1 (38 male and 35 female) and the median age at diagnosis was 48 years (range 28–85).

89% of patients had reportable genomic alterations. The most common alterations were linked to the cell cycle regulation, in particular in sarcoma and rare head and neck tumours (TP53, RB1 as well as CDKN2A/B deletions or MDM2 amplification). Multiple single-nucleotide variants (SNVs) were detected in the RAS/RAF family, and could be of notable interest in the YST and thymic tumours. The TMB status was globally low across all samples with a median of 3 Must/MB (range).

Only 5.1% of tumours had mutations that were directly targetable with approved agents: NTRK fusion (n = 1; sarcoma), EGFR 20 insertion (n = 1; head and neck tumour) and FGFR fusion/amplification (n = 2; sarcoma). However, regarding global action ability (independently of disease type), we could recommend a targeted treatment for 39% of the patient population (n = 30) such as CDK4/6 inhibitors, RTKI, PARPi, mTOR inhibitors, and immune checkpoint inhibitors.

The pilot study highlights a need for specific research on rare cancers to find driver alterations and develop adequate therapies and the feasibility of enrolling patients with rare cancers. Prospective recruitment is ongoing for this project. The possibility of liquid biopsy was added to optimize the success rate for molecular analysis for all patients. When failure occurs on the tumor tissue molecular analysis, a blood draw can be performed and analysed using the FoundationOne Liquid CDx.

Marie Morfouace says "The pilot study shows that comprehensive molecular characterization of rare tumors is important , since the molecular landscape of these tumors is much less known than more common cancers. The data shows that fewer actionable targets and therapeutic options are available to patients with rare adult cancers vs more common cancers (60% vs 25%), and highlight the need for research on rare cancers."

"The EORTC SPECTA platform is important in enabling research is this scientific, technical, operational, and geographic scope. Reliable multi-test, multi-tumour, multi-country research needs a level of harmonisation and control that can only happen with the use of a large research platform such as SPECTA," says Dr Vassilis Golfinopoulos MD, EORTC HQ director. "Acknowledging that development scientific knowledge needs large-scale collaboration, EORTC promptly makes SPECTA available for ARCAGEN and other suitable research initiative."

This study conducted with the support of a grant from Roche.

32nd EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics, 24-25 October 2020, Virtual conference

Poster presentation
Abstract number: 123
Arcagen: Molecular profiling of rare cancer patients – analysis of the pilot study (87 patients)

Morfouace1, I. Ray-Coquard2, N. Girard3, A. Stevovic1, I. Treilleux2, P. Meeus2, S. Aust2, A. Floquet4, S. Croce4, M. Seckl5, J. Gietema6, M. Caplin7, C. de la Fouchardiere2, L. Licitra8, H. Kapiteijn9, S. Piperno Neumann3, A. Idbaih10, J.Y. Blay2, On behalf of EURACAN.

1EORTC, TRU, Brussel, Belgium; 2Centre Léon Bérard, Lyon, France; 3Institut Curie, na, Paris, France; 4Institut Bergonié, Bordeaux, France; 5Imperial College, London, United Kingdom; 6University Medical Centre, Groningen, Netherlands; 7Royal Free London NHS Trust, London, United Kingdom; 8Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 9Leiden University Medical Centre, Leiden, Netherlands; 10Sorbonne Université and AP-HP, Paris, France