On October 12, 2021BridgeBio Pharma, Inc. (Nasdaq: BBIO), a commercial-stage biopharmaceutical company that focuses on genetic diseases and cancers, reported that meaningful progress in its KRAS cancer portfolio, new programs in gene therapy, and advancements in cardiorenal and early-stage Mendelian programs at its second annual R&D Day today (Press release, BridgeBio, OCT 12, 2021, View Source [SID1234591107]). BridgeBio will also discuss how it is broadening the scope of its R&D engine with the launch of its new early-stage research institute, BridgeBioX.

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BridgeBio’s R&D Day will feature presentations by Neil Kumar, Ph.D., BridgeBio founder and CEO; Richard Scheller, Ph.D., chairman of R&D at BridgeBio; Charles Homcy, M.D., chairman of pharmaceuticals at BridgeBio; Uma Sinha, Ph.D., chief scientific officer at BridgeBio; and scientists and physicians leading BridgeBio’s drug discovery and development programs.

BridgeBio has more than 30 programs in its pipeline for patients living with genetic diseases and genetically-driven cancers. Fourteen of those programs are being advanced in the clinic or commercial setting, and earlier this year BridgeBio received its first two U.S. Food and Drug Administration (FDA) drug approvals.

R&D Day pipeline news and updates:

BridgeBio Precision Oncology

KRAS inhibitors for KRAS cancers: BridgeBio announces its discovery of next-generation G12C dual inhibitors, the first-known compounds that directly bind and inhibit KRAS in both its active (GTP bound) and inactive (GDP bound) conformations driven by insights from its molecular dynamics platform. This unique mechanism of action (MOA) is differentiated in preclinical models from first generation compounds, which only bind inactive KRAS. RAS is one of the most well-known oncogenic drivers with approximately 30% of all cancers being driven by RAS mutations, including large proportions of lung, colorectal and pancreatic tumors.
In preclinical models, BridgeBio compounds showed rapid and complete modification of active (GTP bound) KRAS, which is not observed with first generation compounds. BridgeBio compounds were shown to be >500 fold more potent in inhibiting KRAS:RAF effector binding and more potent at inhibiting downstream signaling than first generation inhibitors.
In cellular resistance models, BridgeBio’s dual KRAS inhibitors were shown to be >35x more potent at blocking the emergence of resistance clones than first generation inhibitors, suggesting the potential for more durable efficacy in the clinic.
PI3Ka:RAS breaker: The company will discuss the discovery of multiple PI3Ka:RAS breakers, a potential therapeutic approach developed to block RAS driven PI3Kα activation with the potential to avoid adverse effects on glucose metabolism that limit the potential of PI3Ka kinase inhibitors.
BridgeBio will also announce its novel G12D inhibitor research program.
BridgeBio expects to select a RAS development candidate in 2022.
BridgeBio Gene Therapy

BBP-818 – New adeno-associated virus (AAV) gene therapy program for classic galactosemia (severe GALT deficiency): Classic galactosemia, which is caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT), affects approximately 7,000 patients in the United States and the European Union. Studies in more than 500 patients with galactosemia have shown that despite early detection and strict adherence to diet, children with ≤1% of GALT enzyme levels may experience language delay, speech defects, learning disabilities, cognitive impairment, osteopenia, and in females, primary ovarian insufficiency.
BBP-818 is designed to enable production of the GALT enzyme and to enable the body’s natural ability to metabolize galactose. Preclinical studies in a mouse model of classic galactosemia have shown that BridgeBio’s BBP-818 therapy restored up to 72% of wild-type levels of GALT enzyme in the brain following a single dose.
In addition to the GALT program, BridgeBio Gene Therapy is advancing clinical candidates for Canavan disease and congenital adrenal hyperplasia (CAH), and a preclinical program for TMC1 hearing loss. BridgeBio will also announce at R&D Day preclinical gene therapy programs targeting tuberous sclerosis, cystinuria, and a genetic dilated cardiomyopathy, as well as collaborations to identify and characterize next generation capsids with tropism for the central nervous system and kidney.
BridgeBio Cardiorenal

BBP-711 – Glycolate oxidase (GO) inhibitor for hyperoxaluria: BridgeBio will share preliminary Phase 1 data in which BBP-711 was well-tolerated and resulted in maximal increases in plasma glycolate exceeding those achieved by any GO-targeting agents reported in healthy adult volunteers. At steady state in multiple ascending dose cohorts, BBP-711 treatment resulted in plasma glycolate concentrations comparable to case reports of individuals with germline HAO1 knockout, the gene encoding GO, suggesting complete inhibition.
BBP-711 is being developed for the treatment of primary hyperoxaluria type 1 (PH1) and hyperoxaluria caused by hepatic overproduction of oxalate in recurrent kidney stone formers. A full readout of Phase 1 data in healthy adult volunteers is expected in 2022, to be followed by initiation of a Phase 2/3 trial in PH1 and a Phase 2 proof-of-concept trial in recurrent kidney stone formers.
Acoramidis (AG10) – TTR stabilizer for transthyretin amyloid cardiomyopathy (ATTR-CM): BridgeBio will cover the company’s most significant near-term catalysts with a focus on upcoming topline results for acoramidis. Topline results from Part A of the Phase 3 ATTRibute-CM trial are expected in late 2021 and from Part B in 2023. The primary endpoint at Part A is the change from baseline in a 6-minute walk distance (6MWD) in trial participants receiving acoramidis or placebo after 12 months. If the change from baseline in 6MWD in Part A is highly statistically significant, BridgeBio expects to submit an application for regulatory approval of acoramidis in 2022 to the FDA. ATTR is a rare heart condition with a progressive and debilitating impact on quality of life likely affecting more than 400,000 patients worldwide.
Encaleret – Calcium-sensing receptor (CaSR) inhibitor for autosomal dominant hypocalcemia type 1 (ADH1): BridgeBio will review updated Phase 2b data for encaleret, which was originally shared in an oral presentation at the American Society of Bone and Mineral Research (ASBMR) 2021 Annual Meeting. Within five days of individualized dose titration in 13 participants, encaleret normalized mean blood calcium levels and 24-hour urine calcium excretion. Achieving simultaneous blood and urine calcium normalization is a challenge for patients with ADH1 due to the limitations of current standard-of-care. Encaleret could be the first approved therapy for ADH1, a condition caused by gain of function variants in the CaSR gene estimated to be carried by 12,000 individuals in the United States alone. BridgeBio plans to engage with regulatory health authorities to discuss the design of a Phase 3 registrational trial in patients with ADH1.
BridgeBioX

BridgeBio will announce BridgeBioX, the company’s new early research discovery engine with a dedicated lab at Stanford University. BridgeBio created BridgeBioX to test earlier scientific hypotheses in discovery research and target large, complex genetic diseases with high unmet need. BridgeBio’s creation comes with cutting edge tools in genetics and molecular biology, along with expanded capabilities across modalities with the goal of advancing therapies rapidly. The research lab was created to foster collaboration between industry and academia, and to build a culture driven by intellectual curiosity and a dedication to patient impact.
BridgeBio Mendelian

BBP-418 – Glycosylation substrate for limb-girdle muscular dystrophy type 2i (LGMD2i): BridgeBio will review Phase 1 data in which BBP-418 was shown to be well-tolerated in healthy volunteers. The Phase 2 trial was initiated in patients with LGMD2i in the first quarter of 2021. With approximately 7,000 patients with potentially treatable mutations, LGMD2i is an inherited recessive muscular dystrophy caused by mutation of fukutin-related protein. A Phase 2 data readout is expected in 2022.
BBP-589 – Recombinant collagen for recessive dystrophic epidermolysis bullosa (RDEB): BridgeBio will discuss BBP-589, the only potential systemic treatment option being developed for patients with RDEB. BBP-589 was previously shown to be well-tolerated in Phase 1 with dose-dependent increase in C7 skin deposition. RDEB is a Mendelian disease that has devastating effects on patients due to the epidermis separating from the dermis and causes blistering, tearing and scarring of the skin, along with severe pain and itching. In the United States, RDEB has a prevalence of approximately 2,000 patients. Phase 2 data are expected in the first half of 2022.
BridgeBio’s R&D Day will be held today from 8:30 am ET – 11:00 am ET and it will be webcast, with a link available in the event calendar on BridgeBio’s investor website, View Source A replay of the webcast will be available for one year following the event.

To register for BridgeBio’s R&D Day, please sign up here.

Agenda:

Welcome and introduction – Grace Rauh, vice president of marketing and communications, BridgeBio
Genetic basis of disease – Richard Scheller, Ph.D., chairman of R&D, BridgeBio
BridgeBio’s endless summer – Neil Kumar, Ph.D., founder and CEO, BridgeBio
Precision cardiorenal introduction – Cameron Turtle, D.Phil., chief strategy officer, BridgeBio
Acoramidis: TTR stabilizer for ATTR – Jonathan Fox, M.D., Ph.D., chief medical officer, BridgeBio Cardiorenal
Encaleret: Calcium sensing receptor (CaSR) inhibitor for autosomal dominant hypocalcemia type 1 (ADH1) – Mary Scott Roberts, M.D., senior director of clinical development, BridgeBio Cardiorenal
Gene therapy platform – Eric David, M.D., J.D., CEO, BridgeBio Gene Therapy
Mendelian programs: Primary hyperoxaluria type 1 (PH1), limb-girdle muscular dystrophy type 2i (LGMD2i), recessive dystrophic epidermolysis bullosa (rDEB) – Uma Sinha, Ph.D., chief scientific officer, BridgeBio
Precision oncology programs: KRAS, SHP2 – Eli Wallace, Ph.D., chief scientific officer, BridgeBio Oncology
BridgeBioX – Charles Homcy, M.D., chairman of pharmaceuticals, BridgeBio
Q&A

On October 11, 2021, Poseida Therapeutics, Inc. (the "Company"), and Takeda Pharmaceuticals USA, Inc. ("Takeda") reported that entered into a collaboration and license agreement (the "Collaboration Agreement"), pursuant to which the Company granted to Takeda a worldwide exclusive license under the Company’s piggyBac, Cas-CLOVER, biodegradable DNA and RNA nanoparticle delivery technology and other proprietary genetic engineering platforms to research, develop, manufacture and commercialize gene therapy products for certain indications, including Hemophilia A (Filing, 8-K, Poseida Therapeutics, OCT 12, 2021, View Source [SID1234591106]). The parties will collaborate to initially develop up to six in vivo gene therapy programs and Takeda also has an option to add two additional programs to the collaboration. The Company is obligated to lead research activities up to candidate selection, after which Takeda is obligated to assume responsibility for further development and commercialization of each program.

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Under the Collaboration Agreement, Takeda is obligated to make an upfront payment to the Company of $45.0 million. Takeda is also obligated to provide funding for all collaboration program development costs; provided that the Company is obligated to perform certain platform development activities at its own cost. Under the Collaboration Agreement, the Company is eligible to receive upfront and preclinical milestone payments that could potentially exceed $125.0 million in the aggregate if preclinical milestones for all six programs are achieved. The Company is also eligible to receive future clinical development, regulatory and commercial milestone payments of $435.0 million in the aggregate per target, with a total potential deal value over the course of the collaboration of up to $2.7 billion, if milestones for all six programs are achieved and up to $3.6 billion if the milestones related to the two optional programs are also achieved. The Company is entitled to receive tiered royalty payments on net sales in the mid-single to low double digits, subject to certain standard reductions and offsets. Royalties will be payable, on a product-by-product and country-by-country basis, until the latest of the expiration of the licensed patents covering such product in such country, ten years from first commercial sale of such product in such country, or expiration of regulatory exclusivity for such product in such country.

Either party may terminate the Collaboration Agreement in the event of an uncured material breach of the other party, in the case of insolvency of the other party or in the event the other party makes certain challenges to the patents of such party. Takeda may terminate the Collaboration Agreement for convenience upon prior written notice or in the event of a safety concern immediately upon written notice.

On October 12, 2021 Bicycle Therapeutics plc (Nasdaq: BCYC), a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported that it has commenced an underwritten public offering of $125,000,000 of American Depositary Shares ("ADSs"), each representing one ordinary share (Press release, Bicycle Therapeutics, OCT 12, 2021, View Source [SID1234591105]). All of the ADSs in the proposed offering will be sold by Bicycle. In connection with the offering, Bicycle intends to grant the underwriters in the offering a 30-day option to purchase up to an additional $18,750,000 of ADSs. The proposed offering is subject to market and other conditions, and there can be no assurance as to whether or when the proposed offering may be completed, or as to the actual size or terms of the offering.

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Bicycle plans to use the net proceeds from the offering to advance its proprietary product pipeline and for other research and development, as well as for general corporate purposes.

Goldman Sachs & Co. LLC, Morgan Stanley and SVB Leerink are acting as joint book-running managers for the proposed offering. JMP Securities is acting as co-manager for the proposed offering.

The proposed offering is being made pursuant to a "shelf" registration statement on Form S-3 that was filed by Bicycle with the Securities and Exchange Commission ("SEC") and automatically became effective upon filing. A preliminary prospectus supplement and accompanying prospectus relating to and describing the terms of the offering have been filed with the SEC and are available on the SEC’s website at www.sec.gov. Copies of the preliminary prospectus supplement, final prospectus supplement and accompanying prospectus, when available, may be obtained from: Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, New York 10282, telephone: 1-866-471-2526, or by email at [email protected]; Morgan Stanley & Co. LLC, Attention: Prospectus Department, 180 Varick Street, 2nd Floor, New York, NY 10014, or by email at [email protected]; or SVB Leerink LLC, Attention: Syndicate Department, 53 State Street, 40th Floor, Boston, MA 02109, by telephone at (800) 808-7525, ext. 6105.

This press release shall not constitute an offer to sell, or a solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On October 12, 2021 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported updated results from the Company’s ongoing Phase 1 CARBON trial evaluating the safety and efficacy of CTX110, its wholly-owned allogeneic CAR-T cell therapy targeting CD19+ B-cell malignancies (Press release, CRISPR Therapeutics, OCT 12, 2021, View Source [SID1234591103]).

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"We are excited to share positive data from our CARBON trial, which show that CTX110 could offer patients with large B-cell lymphomas an immediately available ‘off-the-shelf’ therapy with efficacy similar to autologous CAR-T and a differentiated safety profile," said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. "Furthermore, we have the potential to improve upon already observed efficacy with a consolidation dosing strategy. Based on these encouraging results, we are planning to expand CARBON into a potentially registrational trial in the first quarter of 2022."

CARBON Trial Overview

The Phase 1 CARBON trial is an open-label, multicenter clinical trial evaluating the safety and efficacy of CTX110 in adult patients with relapsed or refractory B-cell CD19+ malignancies who have received at least two prior lines of therapy. To date, enrollment has been focused on patients with the most aggressive disease presentations, including diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), high-grade double- or triple-hit lymphomas, and transformed follicular lymphoma. The majority of patients had Stage IV lymphoma and were refractory to their last line of therapy before entering the trial. Nine patients received prior autologous stem cell transplant. Patients who received prior autologous CAR-T therapy were not eligible.

As of the August 26, 2021 data cutoff, 30 patients with large B-cell lymphoma (LBCL) had been enrolled, of which 26 patients had received CTX110 with at least 28 days of follow-up and are included in the analysis. Only one enrolled patient did not receive CTX110. Three patients at the time of the data cut had less than 28 days of follow-up and were not evaluable for this analysis.

Patients were infused with a single CTX110 infusion following three days of a standard lymphodepletion regimen consisting of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day). Patients could

be re-dosed with CTX110 following disease progression. The primary endpoints include safety as measured by the incidence of dose limiting toxicities (DLTs) and overall response rate (ORR). Key secondary endpoints include complete response (CR) rate, duration of response and overall survival.

Additional details may be found at clinicaltrials.gov, using identifier: NCT04035434.

Safety

CTX110 was well tolerated across all dose levels. The adverse events of interest for all evaluable patients are shown in the table below.

There were no cases of Graft versus Host Disease (GvHD) and no infusion reactions to either lymphodepleting chemotherapy or CTX110.

All cases of cytokine release syndrome (CRS) were Grade 1 or 2 per the American Society for Transplantation and Cellular Therapy (ASTCT) criteria and either required no specific intervention or resolved following standard CRS management. Neither the frequency nor severity of CRS has increased in patients who were re-dosed with CTX110.

The only case of Grade 3 or higher immune effector cell-associated neurotoxicity syndrome (ICANS) was in the patient with concurrent HHV-6 encephalitis who was previously disclosed. There have been no cases of ICANS in any other patients treated at Dose Level (DL3) through Dose Level (DL4).

Only two patients experienced Grade 3 or higher infections: the previously discussed patient with HHV-6 encephalitis, and one patient who developed pseudomonal sepsis that resolved in four days.

The emerging safety profile of CTX110 is positively differentiated from autologous CAR-T therapies that show high frequencies of severe CRS and ICANS, and from other allogeneic CAR-T therapies that require more toxic lymphodepletion regimens and can result in prolonged immunosuppression and increased risk of serious infections.

Clinical Activity

Data are shown below for the 26 patients that received CTX110 and had at least 28 days of follow-up. The ORR and CR rates for patients treated at DL2 and above are shown both on an intent-to-treat (ITT) and modified ITT (mITT) basis. ITT includes all enrolled patients (n=24 at DL2 and above) whereas mITT includes only those patients who received an infusion of CTX110 (n=23 at DL2 and above). Dose-dependent responses and durable complete responses were seen with CTX110. Disease assessment was performed by investigator review according to the 2014 Lugano response criteria.

A single dose of CTX110 at DL2 and above resulted in a 58% ORR and 38% CR rate on an ITT basis.
+
Responses were seen in a variety of patients, including patients who had refractory disease, bulky disease, or who had progressed after prior autologous stem cell transplant.

The data demonstrate the potential for CTX110 to produce durable remissions, as evidenced by a 21% six-month CR rate (4 of the 9 patients who achieved CR at Day 28, remained in CR at 6 months; 5 patients had not reached their 6-month evaluation point), which is in the range of durable remissions observed with approved autologous CAR-T therapies on an ITT basis.

The data provide a strong rationale that consolidation dosing can improve on an already competitive profile for CTX110.

Based on this safety and efficacy profile, the Company plans to expand into a potential registrational trial that incorporates consolidation dosing in Q1 2022. In parallel, the Company continues to advance the rest of its immuno-oncology portfolio and scale its manufacturing capabilities in its new state-of-the-art manufacturing facility in Framingham, Massachusetts.

Conference Call and Webcast

To access the conference call, please dial +1 (866) 952-8559 (domestic) or +1 (785) 424-1743 (international) and reference the conference ID "CRISPR."

A live webcast of the event will be available on the "Events & Presentations" page in the Investors section of the Company’s website at View Source A webcast replay will be available on the CRISPR Therapeutics website after the event and will be archived for 14 days.

About CTX110

CTX110, a wholly owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR-T investigational therapy targeting Cluster of Differentiation 19, or CD19. CTX110 is being investigated in the ongoing CARBON trial.

About CARBON

The ongoing Phase 1 single-arm, multi-center, open label clinical trial, CARBON, is designed to assess the safety and efficacy of several dose levels of CTX110 for the treatment of relapsed or refractory B-cell malignancies.

On October 12, 2021 Veracyte, Inc. (Nasdaq: VCYT) reported that it will release its financial results for the third quarter of 2021 after the close of market on Tuesday, November 9 (Press release, Veracyte, OCT 12, 2021, View Source [SID1234591102]). Company management will host a conference call and webcast to discuss financial results and provide a general business update at 4:30 p.m. Eastern Time on the same day.

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The conference call will be webcast live from the company’s website and will be available via the following link: View Source A webcast replay will be available following conclusion of the live broadcast and will be accessible on the company’s website at View Source