On October 7, 2021 Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, reported that preclinical data at the virtual AACR (Free AACR Whitepaper)-NCI-EORTC Molecular Targets Conference for RLY-2608, the first allosteric, pan-mutant (H1047X, E542X and E545X) and isoform-selective PI3Kα inhibitor (Press release, Relay Therapeutics, OCT 7, 2021, View Source [SID1234591018]).

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The data presented at the conference show that in preclinical models, RLY-2608 preferentially binds mutant PI3Kα at a novel allosteric site discovered by the Dynamo platform. Scientists at Relay Therapeutics solved the full-length structure of PI3Kα, performed long time-scale molecular dynamic simulations to elucidate differences in motion between wild-type (WT) and mutant PI3Kα, and leveraged these insights to enable the design of RLY-2608. In biochemical and cellular assays, RLY-2608 inhibited the three major classes of PI3Kα oncogenic mutations (H1047X, E542X and E545X) while sparing WT PI3Kα. The data further suggest that RLY-2608 is also highly selective against other PI3K family members and exquisitely selective across the kinome. The data suggest that projected clinically relevant doses of RLY-2608 achieved tumor regression in PIK3CA mutant in vivo xenograft models representing H1047R and E545K mutations with significantly reduced impact on glucose metabolism compared to non-mutant selective active site inhibitors. In higher species, dosing of RLY-2608 resulted in exposures exceeding 90% inhibition of mutant PI3Kα in cells without resulting in elevated glucose levels or histopathological changes associated with dysregulation of glucose metabolism that are seen with non-mutant selective inhibitors.

These results support advancement of RLY-2608 into clinical development as a differentiated mechanism of mutant PI3Kα inhibition with the first-in-human study anticipated to start in the first half of 2022. RLY-2608 is the lead program of multiple preclinical efforts at Relay Therapeutics to discover and develop mutant selective inhibitors of PI3Kα.

RLY-2608 has the potential to address over 100,000 patients per year in the United States, one of the largest patient populations for a precision oncology medicine. Selectivity for all three mutation hot spots (H1047X, E542X and E545X) has the potential to effectively double the addressable patient population compared to selectivity for only H1047X.

"The data shared today provide another proof point that we’re developing what we believe to be the first known pan-mutant selective allosteric inhibitor of PI3Kα," said Don Bergstrom, M.D., Ph.D., executive vice president of R&D at Relay Therapeutics. "We believe RLY-2608 has the potential to address a significant unmet medical need in a large population and have validated our approach for developing mutant selective inhibitors of PI3Kα. RLY-2608 is only the start of our PI3Kα efforts, and by leveraging our Dynamo platform, we plan to build a franchise around this target for the long-term."

Conference Call Information
Relay Therapeutics will host a live webcast and conference call tomorrow, October 8, beginning at 12:30 pm E.T. to discuss the results of this presentation and the RLY-4008 presentation tomorrow. To access the live call, please dial (833) 540-1168 (domestic) or (929) 517-0359 (international) and refer to conference ID 4657916. A webcast of the conference call will be available under "News and Presentations" in the Media & Investors section of Relay Therapeutics’ website at View Source The archived webcast will be available on Relay Therapeutics’ website approximately two hours after the conference call and will be available for 30 days following the call.

The data presentation from the AACR (Free AACR Whitepaper)-NCI-EORTC Molecular Targets Conference is also available on the Relay Therapeutics website under "Publications/Presentations" near the bottom of View Source

About RLY-2608
RLY-2608 is the lead program of multiple preclinical efforts to discover and develop mutant selective inhibitors of PI3Kα. PI3Kα is the most frequently mutated kinase in all cancers, with oncogenic mutations detected in about 13% of patients with solid tumors. Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus WT PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. The Dynamo platform enabled the discovery of RLY-2608, the first known allosteric, pan-mutant (H1047X, E542X and E545X), and isoform-selective PI3Kα inhibitor designed to overcome these limitations. Relay Therapeutics solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of RLY-2608. RLY-2608 is on path to initiate a first-in-human clinical trial in the first half of 2022, subject to submission of an investigational new drug application and acceptance by the FDA.

On October 7, 2021, Allogene Therapeutics, Inc. ("Allogene") reported that, following a report of a chromosomal abnormality in ALLO-501A chimeric antigen receptor ("CAR") T cells in a patient treated in its ALPHA2 study, the U.S. Food and Drug Administration ("FDA") has placed a hold on Allogene’s cli nical trials (Press release, Cellectis, OCT 7, 2021, View Source [SID1234591014]).

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The clinical hold follows Allogene’s notification to the FDA of a chromosomal abnormality in an ALPHA2 study patient which was detected in a bone marrow biopsy undertaken to assess pancytopenia (low blood counts). Allogene reported that an investigation is underway to further characterize the observed abnormality, including any clinical relevance, evidence of clonal expansion or potential relationship to gene editing. Allogene reported that it expects to provide additional updates in the coming weeks following consultation with the FDA. The FDA continues to actively review the end of Phase 1 materials submitted by Allogene in anticipation for an ALLO-501A pivotal Phase 2 trial.

The single case involves a patient with Stage IV transformed follicular lymphoma and a type of genetic rearrangement, known as c-myc rearrangement, whose cancer was refractory to two prior lines of immune-chemotherapy and additional radiation therapy. The patient could not receive an autologous anti-CD19 CAR T cell therapy due to manufacturing failure associated with inadequate expansion of autologous CAR T cells.

Following infusion of ALLO-501A, the patient experienced Grade 1 cytokine release syndrome and Grade 2 immune effector cell-associated neurotoxicity syndrome, which required a course of high dose steroid therapy. The patient subsequently developed progressive pancytopenia and a bone marrow biopsy showed aplastic anemia and the presence of ALLO-501A CAR T cells with the chromosomal abnormality. Early translational data showed that the CAR T cells expanded, peaking on Day 28, and undergoing contraction thereafter. The patient had a partial response to ALLO-501A and subsequently underwent allogeneic stem cell transplantation. Prolonged cytopenia requiring rescue stem cell transplantation has been reported in autologous CAR T therapies.

On October 7, 2021 Apollo Endosurgery, Inc. ("Apollo") (NASDAQ:APEN), a global leader in less invasive medical devices for gastrointestinal and bariatric procedures, reported that preliminary unaudited financial results and corporate updates for the third quarter ended September 30, 2021, including anticipated revenue in the range of $16.0 million to $16.4 million and anticipated revenue growth in the range of 25% to 28% compared to third quarter 2020 (Press release, Apollo Endosurgery, OCT 7, 2021, View Source [SID1234591010]).

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Preliminary, Unaudited Third Quarter 2021 Financial Results

"We continue to successfully deliver against the priorities that we committed to early this year: specifically, to energize our business and drive near-term growth while laying the foundation for additional large-scale opportunities," said Chas McKhann, president and CEO. "Our recent De Novo 510(k) classification request for Apollo ESG and Apollo REVISE is an important, critical milestone for the company, and I am extremely proud of the work our clinical and regulatory teams have done to get us to this point. We believe we are well-positioned to become a leader in therapeutic endoscopy through continued execution on both our commercial and clinical initiatives. I’m excited about the bright future ahead for Apollo."

Anticipated revenue growth in the third quarter was led by the company’s endoscopic suturing (ESS) portfolio, which grew between 31% and 33% over the same period in 2020, highlighting continued demand for Apollo’s OverStitch and X-Tack products across a range of patient indications. Anticipated intragastric balloon (IGB) revenue increased by 19% to 21% despite a stronger-than-expected rebound in elective procedures for the ORBERA balloon in the prior year third quarter.

Apollo estimates that it had approximately $28 million in cash, cash equivalents, and restricted cash at September 30, 2021.

The company expects to announce third quarter final financial and operating results on November 1, 2021, after market close.

De Novo 510(k) Classification Request Submitted for Apollo ESG and Apollo REVISE

Apollo announced that it has submitted a De Novo classification request to the U.S. Food and Drug Administration (FDA) seeking 510(k) classification and clearance for the Apollo ESG and Apollo REVISE devices, which consist of the OverStitch Endoscopic Suturing System and related components (e.g., tissue helix, sutures, cinches). Apollo ESG is intended for use in the endoscopic sleeve gastroplasty procedure for weight loss and Apollo REVISE is intended for use in revision of bariatric surgery procedures. This submission follows recent announcements made during the Surgical Disruptive Technologies Summit by the principal investigators of the MERIT study (Multi-Center ESG Randomized Interventional Trial), that, based upon a preliminary analysis, the trial had met its primary endpoints for safety and efficacy.

The De Novo Classification Process is available to medical devices of low-to-moderate risk that do not have a legally marketed predicate device. Actual timing for the De Novo 510(k) process varies. The company currently expects a decision from the FDA within approximately 12 months.

2021 Financial Outlook

Based on results in the first three quarters of 2021, the company is updating its revenue guidance for the full year 2021 to between $63 and $64 million, which represents growth of 50% to 52% over 2020.

Apollo continues to monitor the potential and uncertain impact of the ongoing COVID-19 pandemic. Should hospitals or outpatient centers where the company’s procedures are performed experience continued or additional surges in cases and need to defer elective procedures to preserve capacity for COVID-19 patients, the company’s ability to achieve these financial projections could be adversely affected.

About the MERIT Study

The MERIT study (NCT03406975, FDA IDE G190189) is a multi-center, prospective randomized clinical trial evaluating the safety and effectiveness of the ESG procedure, a minimally invasive, endoscopic weight loss procedure performed with Apollo Endosurgery’s OverStitch Endoscopic Suturing System compared to a medically monitored regimen of diet and healthy lifestyle. The co-principal investigators are Dr. Erik Wilson, University of Texas at Houston (Houston, TX), and Dr. Barham Abu Dayyeh, Mayo Clinic, (Rochester, MN) under a collaborative research agreement sponsored by Apollo Endosurgery. The study’s primary efficacy endpoint is to achieve at least 25% excess body weight loss (%EBWL) at 12 months and at least 15% EBWL vs. control at 12 months, and the primary safety endpoint is a serious adverse event rate of less than 5%. Additionally, patients undergoing ESG are being evaluated for improvement in hypertension and type 2 diabetes at 24 months.

The MERIT study investigators submitted an abstract to the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO). The company anticipates that the MERIT investigators will present the study’s primary efficacy and safety endpoints in a global, virtual session entitled the "Top 10 Papers at IFSO" on Friday, October 22, 2021. The company anticipates that the full MERIT study results, including patient follow-up to two years, will be published in the first half of 2022.

On October 7, 2021 Plexium Inc., (Plexium), a biotech company focused on discovering and developing protein degrading therapeutics directed towards historically challenging drug targets, reported that company management will present and host one-on-one meetings at the Solebury Trout/BMO Fall Private Company Showcase 2021 (Press release, Plexium, OCT 7, 2021, View Source [SID1234591009]). The company will present on Thursday, October 14th, 2021 at 9:40 am ET.

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On October 7, 2021 Servier, a global independent pharmaceutical Group, and Guangdong Maijinjia Biotechnologies (MJJ Biotech), owner of a proprietary Technology platform, acquired from Ranger Biotechnologies (Ranger), which uses short highly modified oligonucleotides (Blockmirs) to upregulate protein expression, reported that they have entered into a Collaboration and Exclusive License Option Agreement to develop a novel therapy for treating rare neurodegenerative diseases (Press release, Servier, OCT 7, 2021, View Source;utm_medium=rss&utm_campaign=neurodegenerative-diseases-servier-enter-into-a-new-research-collaboration [SID1234591007]).

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Under the collaboration agreement, the Blockmir Technology provided by MJJ Biotech will be used to develop antisense oligonucleotides (ASOs) that specifically block selected miRNA binding sites on the mRNA of a non-disclosed target to upregulate its protein level. This innovative strategy could provide a new therapeutic solution for incurable rare neurological diseases.

Upon selection of active Blockmir candidates for IND qualification done with the collaboration of Ranger, Servier has the option to license, develop and commercialize novel therapeutic products based on this technology. MJJ Biotech will receive up to 35 million euros for option fee, and in development and regulatory as well as first commercial sale milestone payments. Specific financial terms are not disclosed.

"This collaboration is a unique opportunity to partner with an experienced and recognized player in the field of antisense oligonucleotide Blockmirs to help us design and optimize ASOs by gaining access to models, technology, and experience that complements our own capabilities in order to provide patients suffering from neurodegenerative diseases with innovative therapeutic solutions", stated Johannes Krupp, Research Program Director Neurology, at Servier.

"We are very pleased to enter into this partnership with Servier and see it as an important validation of the progress that has been made by MJJ Biotech since its founding in 2019. Servier is a major pharmaceutical company with immense experience in neurodegenerative disease and we will surely benefit from this collaboration in multiple ways. We are also confident that the collaboration will prove valuable to Servier and provide new avenues for treatment of rare neurodegenerative disease", stated Thorleif Møller, Chief Scientific Officer at MJJ Biotech.

Servier has been involved in neuroscience for several decades and focuses its research on neurodegenerative diseases. Servier is particularly interested in targeted movement disorders, such as Parkinson’s disease, amyotrophic lateral sclerosis and spinocerebellar ataxias, many of which are characterized by the abnormal accumulation of certain proteins.