On April 4, 2023 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:HCM; HKEX:13) reported that it has consulted the China National Medical Products Administration ("NMPA") and reached an agreement to initiate the registration phase of the ongoing Phase II trial of HMPL-453 for intrahepatic cholangiocarcinoma ("IHCC") patients with fibroblast growth factor receptors ("FGFR") 2 fusion (Press release, Hutchison China MediTech, APR 4, 2023, View Source [SID1234629797]). If positive, the data from the registration phase may be used to support a future New Drug Application ("NDA") filing. The first patient received their first dose in March 2023.

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In addition, it also reached an agreement to initiate the registration phase of the ongoing Phase II trial of savolitinib for gastric cancer patients with mesenchymal–epithelial transition ("MET") amplification following NMPA consultation. If positive, the data from the registration phase may be used to support a future NDA filing. The first patient also received their first dose in March 2023.

The study of HMPL-453 is a single-arm, multi-center, open-label, Phase II registration study to evaluate the efficacy, safety and pharmacokinetic of HMPL-453 in treating advanced IHCC patients with FGFR2 fusion. Primary endpoint is objective response rate ("ORR"). Secondary endpoints include progression-free survival ("PFS"), disease control rate (DCR), duration of response (DoR) and overall survival (OS). The study is expected to enroll approximately 90 additional patients. Additional details may be found at clinicaltrials.gov using identifier NCT04353375.

The study of savolitinib is a single-arm, multi-center, open-label, Phase II registration study to evaluate the efficacy, safety and tolerability of savolitinib in treating gastric cancer and esophagogastric junction adenocarcinoma patients with MET amplification. Primary endpoint is ORR evaluated by the Independent Review Committee (IRC) (RECIST 1.1). Secondary endpoints include PFS and incidence of various adverse events (AE). The study is expected to enroll approximately 60 additional patients. Further details may be found at clinicaltrials.gov using identifier NCT04923932.

About HMPL‑453
HMPL‑453 is a novel, highly selective and potent inhibitor targeting FGFR 1, 2 and 3. Aberrant FGFR signaling has been found to be a driving force in tumor growth (through tissue growth and repair), promotion of angiogenesis and resistance to anti-tumor therapies. Abnormal FGFR gene alterations are believed to be the drivers of tumor cell proliferation in several solid tumor settings.

HUTCHMED currently retain all rights to HMPL-453 worldwide.

About IHCC with FGFR2 Fusion
IHCC is one of the subtypes of primary liver cancer. In China, an estimated 61,900 newly diagnosed IHCC occurred in 2015 and the overall IHCC incidence increased by 9.2% per year between 2006 and 2015.[i] FGFR2 fusion has been reported to have a prevalence of 10-15% in IHCC patients.[ii] [iii]

About savolitinib
Savolitinib is an oral, potent and highly selective MET tyrosine kinase inhibitor that has demonstrated clinical activity in advanced solid tumors. Іt blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression.

Savolitinib is marketed in China under the brand name ORPATHYS for the treatment of patients with non-small cell lung cancer ("NSCLC") with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. Іt is currently under clinical development for multiple tumor types, including lung, kidney and gastric cancers, as a single treatment and in combination with other medicines. Starting on March 1, 2023, ORPATHYS was included in the National Reimbursement Drug List (NRDL) for the treatment of locally advanced or metastatic NSCLC adult patients with MET exon 14-skipping alterations who have progressed after or unable to tolerate platinum-based chemotherapy.

Іn 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize savolitinib. Joint development of savolitinib in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of savolitinib in China. AstraZeneca is responsible for the commercialization of savolitinib in China and worldwide. Sales of savolitinib are recognized by AstraZeneca.

About Gastric Cancer with MET Amplification
MET-driven gastric cancer has a very poor prognosis.[iv] The ongoing registration trial follows multiple Phase II studies that have been conducted in Asia to study ORPATHYS in MET-driven gastric cancer patients, including VIKTORY.3 VIKTORY is an investigator initiated Phase II umbrella study in gastric cancer in South Korea in which a total of 715 patients were successfully sequenced into molecular-driven patient groups, including those with MET amplified gastric cancer. Patients whose tumors harbor MET amplification were treated with ORPATHYS monotherapy.

It is estimated that MET amplification accounts for approximately 4-6% of gastric cancer patients.[v],[vi] The annual incidence of MET amplification gastric cancer is estimated to be approximately 24,000 in China.

On April 4, 2023 Heidelberg Pharma AG (FSE: HPHA) reported that it will present data from preclinical studies at this year’s American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting that provide positive evidence of the efficacy and tolerability of the company’s proprietary ATAC technology (Press release, Heidelberg Pharma, APR 4, 2023, View Source [SID1234629796]). Heidelberg Pharma is active in cancer research and works with antibody drug conjugates (ADCs) that use the toxin Amanitin as payload. The meeting will be held in Orlando, Florida, USA, from 14th to 19th April 2023.

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Details of the poster presentation:

Subcutaneous dosing increases the therapeutic index of Amatoxin-based ADCs

Abstract number:

1523, Section 14

Session:

Antibody Drug Conjugates

Date and time:

17th April 2023, 9:00 am – 12:30 pm ET (03:00 – 06:30 pm CEST)

Presenter:

Dr. Kristin Decker

Link to the abstract:

View Source!/10828/presentation/2645

The study investigated how the pharmacokinetics, tolerability and efficacy of different ATACs are affected by the route of administration (subcutaneous versus intravenous). While intravenous dosing is the common administration method for marketed ADCs, subcutaneous dosing in general has pharmacokinetic advantages and is preferable for patients. Subcutaneous (s.c.) dosing of ATACs was shown to result in prolonged half-life and lower maximal serum levels in preclinical models compared with intravenous (i.v.) administration. Both factors resulted in improved tolerability of the ATACs. At the same time, antitumor efficacy in a xenograft model using human cancer cell lines was comparable after s.c. or i.v. administration.

The improved tolerability combined with consistent efficacy resulted in an improved therapeutic index of the candidate HDP-103. The present study demonstrates that s.c. dosing not only refines the pharmacokinetic distribution of ATACs but also can improve the therapeutic index. Thus, s.c. dosing may represent a promising route of administration for ATACs in humans as well.

Details of the poster presentation:

Amanitin-based ADCs targeting Guanylyl cyclase C (GCC) as novel therapeutic modality for treatment of colorectal cancer

Abstract number:

2636, Section 13

Session:

Antibody Technologies

Date and time:

17th April 2023, 1:30 – 5:00 pm ET (07:30 – 11:00 pm CEST)

Presenter:

Alexandra Braun

Link to the abstract:

View Source!/10828/presentation/2173

The poster presentation will cover preclinical data on ATACs targeting GCC (guanylyl cyclase C). This surface protein is overexpressed in many gastrointestinal tumors, and most notably in colorectal cancer. Due to its specific expression profile, GCC represents an exceptionally tumor-specific target. ATACs directed against GCC possess high antitumor activity and inhibit tumor growth in preclinical models even at low concentrations after single or multiple dose treatment. The favorable safety profile due to the good tolerability of these ATACs confirms that they may represent a promising new therapeutic option against colorectal cancer.

Poster presentations can be found from 18th April 2023, on the company website in the "Research & Development > Scientific Posters" section.

On April 4, 2023 Cellectis (Euronext Growth: ALCLS – NASDAQ: CLLS) (the "Company"), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies reported that the Company entered into the warrant agreement (the "Warrant Agreement") and finalized the related ancillary documents required under the credit facility with the European Investment Bank ("EIB") (the "Finance Contract") for up to €40 million previously announced on December 28, 2022 (Press release, Cellectis, APR 4, 2023, View Source [SID1234629790]). The Company also announced the drawdown of the first tranche of €20 million ("Tranche A") under the Finance Contract, expected to be disbursed by the EIB in early April 2023. The Company plans to use the proceeds of Tranche A towards the development of its pipeline of allogeneic CAR T-cell product candidates: UCART22, UCART20x22, UCART123 and UCARTCS1.

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The disbursement of Tranche A is subject to, among other conditions, (i) the issuance of a specified number of warrants to the benefit of EIB (the "Tranche A Warrants") and (ii) the completion of certain clinical development milestone by a Cellectis’ licensee, and, as of the date of this press release, each of (i) and (ii) has been satisfied. In particular, on March 28, 2023, the Company issued 2,799,188 Tranche A Warrants to EIB, in accordance with the terms of the 11th resolution of the shareholders’ meeting held on June 28, 2022 and articles L. 228-91 and seq. of the French Commercial Code, representing 5.0% of the Company’s outstanding share capital as at their issuance date. The exercise price of the Tranche A Warrants is equal to €1.92, corresponding to 99% of the volume-weighted average price of the Company’s ordinary shares over the last 3 trading days preceding the decision of the board of directors of the Company to issue the Tranche A Warrants.

Tranche A will mature six years from its disbursement date. Interest on Tranche A shall be paid in kind, shall be capitalized annually by increasing the principal amount of Tranche A, and shall accrue at a rate equal to 8% per annum.

Prepayment events under the Finance Contract: Tranche A may, in certain circumstances, be prepaid, in whole or in part, for a prepayment fee, either at the election of the Company or as a result of EIB’s demand following certain prepayment events, including a change of control or change in senior management of the Company.

Subject to certain terms and conditions, upon the occurrence of customary events of default (e.g., payment default, misrepresentations in representations included in the Finance Contract, and cross defaults, among others), EIB may demand immediate repayment by the Company of all or part of the outstanding amount and/or cancel the undisbursed tranches.

Terms and Conditions of the EIB Warrants: As described above, in connection with the Finance Contract, the Company agreed to issue warrants to EIB as a condition to the funding of each tranche under the Finance Contract.

The number of warrants to be issued to EIB under the Finance Contract (the "EIB Warrants") is or will be determined as follows: (i) with respect to Tranche A, 2,799,188 Tranche A Warrants representing 5.0% of the Company’s outstanding share capital as indicated above; (ii) with respect to a second tranche of €15 million ("Tranche B"), (a) if the sum of cash injections through the issuance of new ordinary shares or other securities subordinated to the Finance Contract and upfront and milestone payments in connection with existing or new partnerships between October 31, 2022 and the Tranche B disbursement exceeds €42,500,000, an aggregate number of warrants equal to 15,000,000 divided by the product of the average price of the Company’s ordinary shares over the five trading days before the issuance date (the "5-Day AP") multiplied by 4.0 and (b) otherwise, an aggregate number of warrants equal to 15,000,000 divided by the product of the 5-Day AP multiplied by 3.75; and (iii) with respect to a third tranche of €5 million ("Tranche C"), (a) if the sum of cash injections through the issuance of new ordinary shares or other securities subordinated to the Finance Contract and upfront and milestone payments in connection with existing or new partnerships between October 31, 2022 and the Tranche C disbursement exceeds €70,000,000, an aggregate number of warrants equal to 5,000,000 divided by product of the 5-Day AP multiplied by 4.75; and (b) otherwise, an aggregate number of warrants equal to 5,000,000 divided by the product of the 5-Day AP multiplied by 4.25.

Each EIB Warrant will entitle EIB to one ordinary share of the Company in exchange for the exercise price (subject to applicable adjustments and anti-dilution provisions). The EIB Warrants will have an exercise price per share equal to 99% of the weighted average price per share of the Company over the last three trading days prior to their issuance. The EIB Warrants with respect to Tranche B and Tranche C are only issuable if the Company elects to drawdown such tranches.

The EIB Warrants expire on the twentieth anniversary of their issuance date, at which time such unexercised EIB Warrants will be automatically deemed null and void. Any outstanding EIB Warrant will become exercisable following the earliest to occur of (i) a change of control event, (ii) the maturity date of Tranche A, (iii) a public take-over bid approved by the Company’s board of directors, (iv) a sale of all or substantially all of certain assets of Cellectis and its subsidiaries, (v) a debt repayment event (i.e. any mandatory repayment pursuant to the Finance Contract or any voluntary payment more than 75% of any Tranche) in respect of one or more Tranches, , or (vi) the receipt of a written demand for repayment from EB in connection with an event of default under the Finance Agreement (each an "Exercise Event").

Following any Exercise Event and until expiration of the applicable EIB Warrants, EIB may exercice a put option by which EIB may require the Company to repurchase all or part of the then-exercisable but not yet exercised EIB Warrants. The exercise of such put option would be at the fair market value of the EIB Warrants, subject to a cap equal to the aggregate principal amount disbursed by EIB pursuant to the Finance Contract at the time of the put option, reduced by certain repaid amounts, at the time of exercice of the put option.

Furthermore, in the case of any public take-over bid from a third party or a sale of all outstanding shares of the Company to any person or group of persons acting in concert, the Company shall, subject to certain conditions including the sale by certain shareholders of all of their shares and other securities, be entitled to repurchase all, but not less than all, of the EIB Warrants, at a price equal to the greater of (a) 0.3 times the amount disbursed by the EIB under the Finance Contract divided by the aggregate number of EIB Warrants issued (reduced by the number of exercised EIB Warrants), and (b) the fair market value of the EIB Warrants.

The Company has a right of first refusal to repurchase the EIB Warrants that are offered for sale to a third party under the same terms and conditions of such third party’s offer, provided that such right of first refusal does not apply if the contemplated sale occurs within the scope of a public take-over bid by a third party.

Subject to the right of first refusal and compliance with applicable securities laws, the EIB Warrants may be transferred following an Exercise Event, to certain affiliates of EIB, or otherwise with the prior written approval of the Company.

The Warrant Agreement provides for customary anti-dilution adjustments in connection with changes to the structure of the Company’s share capital.

In connection with the Warrant Agreement, the Company agreed to certain customary affirmative and negative undertakings. The negative undertakings include: restrictions on certain dispositions of assets by the Company and its subsidiaries and restrictions on the Company and its subsidiaries making specified restricted payments, including loan repayments, dividends and share repurchases.

The Warrant Agreement contains certain customary representations and warranties by the Company and is governed by French law.

Concomitantly with this press release, the Company filed a report with the U.S. Securities and Exchange Commission on Form 6-K, which further describes the Finance Contract and the Warrants Agreement: View Source

Caribou Biosciences, Inc. (Nasdaq: CRBU), a leading clinical-stage CRISPR genome-editing biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to CB-011, which is being developed for relapsed or refractory multiple myeloma (r/r MM) (Press release, Caribou Biosciences, APR 4, 2023, View Source [SID1234629789]). CB-011 is being evaluated in the company’s ongoing CaMMouflage Phase 1 clinical trial in patients with r/r MM.

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"Fast Track designation for CB-011 allows us instrumental interactions with the FDA as we progress our clinical development and regulatory plans for CB-011. This designation could not be more timely as we recently dosed our first patient in the CaMMouflage Phase 1 trial," said Syed Rizvi, MD, Caribou’s chief medical officer. "Our goal is to develop CB-011 as a readily available off-the-shelf treatment option for patients with relapsed or refractory multiple myeloma to overcome the need for apheresis or bridging therapy, variable quality and long manufacturing timelines, manufacturing failures, or the inability to bear the burden of treatments that require frequent dosing over several months."

Fast Track designation is designed to expedite the development and review processes for promising therapeutic candidates that may fill an unmet medical need. Clinical programs with Fast Track designation may benefit from early and frequent communication with the FDA throughout the regulatory review process and may also be eligible for Accelerated Approval and Priority Review if relevant criteria are met.

About CB-011

CB-011 is the second product candidate from Caribou’s allogeneic CAR-T cell therapy platform and is being evaluated in patients with relapsed or refractory multiple myeloma (r/r MM) in the CaMMouflage Phase 1 trial. CB-011 is an allogeneic anti-BCMA CAR-T cell therapy engineered using Cas12a chRDNA technology. CB-011 is the first allogeneic CAR-T cell therapy in the clinic, to Caribou’s knowledge, that is engineered to improve antitumor activity through an immune cloaking strategy with a B2M knockout and insertion of a B2M–HLA-E fusion protein to blunt immune-mediated rejection. Additional information on the CaMMouflage trial (NCT05722418) can be found at clinicaltrials.gov.

About Caribou’s Novel Next-Generation CRISPR Platform

CRISPR genome editing uses easily designed, modular biological tools to make DNA changes in living cells. There are two basic components of Class 2 CRISPR systems: the nuclease protein that cuts DNA and the RNA molecule(s) that guide the nuclease to generate a site-specific, double-stranded break, leading to an edit at the targeted genomic site. CRISPR systems have exhibited editing at unintended genomic sites, known as off-target editing, which may lead to harmful effects on cellular function and phenotype. In response to this challenge, Caribou has developed CRISPR hybrid RNA-DNA guides (chRDNAs; pronounced "chardonnays") that direct substantially more precise genome editing compared to all-RNA guides. Caribou is deploying the power of its Cas12a chRDNA technology to carry out high efficiency multiple edits, including multiplex gene insertions, to develop CRISPR-edited therapies.

On April 4, 2023 BioCryst Pharmaceuticals, Inc. (Nasdaq: BCRX) reported that the compensation committee of BioCryst’s board of directors granted six newly-hired employees stock options to purchase an aggregate of 124,300 shares, and restricted stock units (RSUs) covering an aggregate of 40,350 shares, of BioCryst common stock (Press release, BioCryst Pharmaceuticals, APR 4, 2023, View Source [SID1234629788]). The options and RSUs were granted as of March 31, 2023, as inducements material to each employee entering into employment with BioCryst. The options and RSUs were granted in accordance with Nasdaq Listing Rule 5635(c)(4).

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The options have an exercise price of $8.34 per share, which is equal to the closing price of BioCryst common stock on the grant date. The options and RSUs vest in four equal annual installments beginning on the one-year anniversary of the grant date, in each case subject to the new employee’s continued service with the company. Each stock option has a 10-year term. The options and RSUs are subject to the terms and conditions of BioCryst’s Inducement Equity Incentive Plan and a stock option agreement or restricted stock unit agreement, as applicable, covering the grant.