On December 29, 2022 Biocytogen Pharmaceuticals (Beijing) Co., Ltd. ("Biocytogen", HKEX: 02315) reported official launch of its fully human heavy chain antibody platform, RenNano (Press release, Biocytogen, DEC 29, 2022, View Source [SID1234625668]). RenNano is the third member of the RenMice family, joining RenMab and RenLite. Together, Biocytogen’s three RenMice platforms allow for the streamlined discovery and development of fully human monoclonal antibodies, bispecific/multispecific antibodies and single-domain antibodies (sdAbs, or nanobodies).

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While humans and mice generate antibodies that require heavy and light chain pairing to be functional, camels and sharks generate heavy-chain-only antibodies (HCAb), meaning their variable domains (VHH or sdAb) can function without pairing with the light chain. Owing to their nanometer-level size and small molecular weight, sdAbs have superior permeability, thus can cross the blood-brain barrier and infiltrate solid tumor tissues. In addition, the longer CDR3 region enables sdAbs to detect the otherwise hidden epitopes of GPCRs and other challenging targets. Since sdAbs have a simple structure, they are ideal building blocks for assembling bispecific/multispecific antibodies and CAR cell therapies.

While nanobodies have its unique advantages, animals that naturally produce HCAbs, such as camels, are difficult to be widely used for the preparation of monoclonal antibodies because they are large, having a long breeding cycle and few offspring. Meanwhile, humanization is required to develop camelid antibody sequences into drugs, which further increases the complexity and time of drug development.

Therefore, Biocytogen developed RenNano mouse that was engineered to produce HCAbs by modifying the constant region of the fully human RenMab model. Compared with other existing HCAb platforms, the in situ replacement of the mouse genes with the complete human heavy chain variable genes makes the RenNano mouse one of the most comprehensive fully human antibody platforms in the world. SdAb sequences generated from RenNano mice have the highest possible diversity, and do not require antibody humanization, which saves time and cost, and reduces risk of failure during later stages of drug development. Additionally, compared with camelids or other natural HCAb-producing species, mice are easier to breed and immunize. Our in-house studies show that immunization of RenNano mice can generate HCAbs with diverse CDR3 sequences that recognize a variety of epitopes. These HCAbs can recognize antigens with nM-level affinity independent of light chains. Moreover, antibodies derived from RenNano mice are capable of exerting biological functions both in vitro and in vivo. They are highly hydrophilic and have favorable developability characteristics.

The successful development of the RenNano platform expands Biocytogen’s capabilities of antibody discovery and broadens the applications of our antibody library. We welcome global partners to realize the full potential of our RenMice platforms and derived antibodies and bring benefit to the patients.

About RenMice

RenMice, i.e., RenMab, RenLite and RenNano mice, which have proprietary intellectual property rights, were developed by Biocytogen over the course of 5 years using size-unlimited, precise chromosome engineering technology (SUPCE). RenMice is one of the top 3 fully human antibody mice made by in situ replacement technology globally. All RenMice members contain full human heavy chain VDJ loci replaced in situ. Regarding antibody κ light chains, RenMab mouse contains full human VJ loci replaced in situ and RenLite mouse contains a single human VJ locus replaced in situ. RenNano mouse has modified heavy chain constant regions to generate functional HCAbs.

RenMice can generate robust immune response and produce fully human antibodies with great diversity, specificity, affinity and druggability. Using RenMice, Biocytogen has built 6 fully human antibody discovery platforms, covering various types of targets and modalities such as monoclonal antibody (RenMab), bispecific antibody and bispecific ADC (RenLite), nanobody (RenNano), TCR-mimic antibody for intracellular targets (HLA/RenMice, i.e., MHC humanized RenMice), and antibody platform against GPCR and other challenging targets (RenMice knockouts).

RenMice has been recognized by top biopharmaceutical companies around the world, including Merck KGaA, Xencor, BeiGene, Innovent, etc.

On December 29, 2022 Qilu Pharmaceutical reported the latest progress being made with several clinical studies involving its innovative bifunctional antibody, QL1706, at several international and Chinese academic conferences, including the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2022 Annual Meeting, the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting, the Chinese Society of Clinical Oncology (CSCO) 2022 Annual Meeting, and the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2022 Asia Congress (Press release, Qilu Pharmaceutical, DEC 29, 2022, View Source [SID1234625667]).

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Antibodies targeting programmed death receptor 1 and its ligand (PD-1/PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been widely used in clinical practices to treat a variety of advanced tumors. However, some combinations of dual immune checkpoint inhibitors (ICIs) limit the maximum clinical benefits for patients due to greater toxicity. QL1706 is an innovative combination of anti-PD-1 monoclonal antibody and anti-CTLA-4 monoclonal antibody, developed on the MabPair technology platform. QL1706 has significant advantages in terms of proportional allocation between CTLA-4 IgG1 and PD-1 IgG4 antibodies and flexibility in the selection of the Fc backbone. QL1706 introduces mutations onto the heavy chain of CTLA-4 antibodies, so CTLA-4 IgG1 has a shorter elimination half-life than PD-1 IgG4 (4-5 days and 6-9 days, respectively), resulting in shorter patient exposure to CTLA-4 antibodies. QL1706 bifunctional antibody combines the activity of both PD-1 and CTLA-4 antibodies, while helping to attenuate the toxicity caused by CTLA-4 antibodies.

At AACR (Free AACR Whitepaper)’s annual meetings in 2021 and 2022, Qilu Pharmaceutical reported the results of the Phase Ia/Ib studies of QL1706 for advanced solid tumors in a poster presentation (abstract numbers: CT119, CT520). In the phase Ia study, a dose of 0.3-10.0 mg/kg (intravenous, every 3 weeks for a cycle) was used in a 3+3 dose escalation study; and 5.0 mg/kg and 7.5 mg/kg were used as extension doses. In the QL1706 10 mg/kg dose group, two cases of dose-limiting toxicity (DLT) occurred, including one case of grade-3 thrombocytopenia with grade-1 gingival bleeding and one case of grade-4 immunomodulatory nephritis, based on which the final recommended dose (RP2D) in phase 2 was determined to be 5 mg/kg. As of September 30, 2021, among a total of 518 patients enrolled in phase Ia and Ib, the incidence of treatment-related adverse events (TRAEs) was 72.2%, and the incidence of grade-3 TRAEs or above was 13.5%. The most common TRAEs with an incidence greater than 10% were rashes (17.6%), pruritus (12.5%), and hypothyroidism (11.6%).

At the ASCO (Free ASCO Whitepaper) 2022 Meeting, Qilu Pharmaceutical announced the results of the study of QL1706 for the treatment of patients with advanced nasopharyngeal cancer (abstract no. 6034) and cervical cancer (abstract no. 5535) in a poster presentation. As of the data cut-off date, 110 patients with nasopharyngeal cancer were enrolled in Phase Ia/Ib studies, of whom 71.8% had received second-line therapy or above, and 43.6% immunotherapy. Objective response was achieved in 24.5% of the patients, with a confirmed ORR of 39.1% (9/23) and 38.5% (15/39) among patients who had received first- and second-line therapies or above without immunotherapy, respectively. After a median follow-up of 7.7 months, the median progression-free survival (PFS) was 2.0 months (95% CI 1.4-2.9), the 6-month PFS rate was 47.4% while median overall survival (OS) data was not yet available.

In the phase Ib study, 53 patients with cervical cancer were enrolled, 83% of whom had squamous carcinoma and 17% adenocarcinoma; and 62% and 38% had received first- and second-line (or above) treatment, respectively. As of the data cut-off date, 34.0% of the patients were still receiving QL1706 treatment, and 60.3% had witnessed reduction in target lesions. One (2%) patient achieved complete response (CR) and 14 (26%) partial response (PR), with a confirmed ORR of 28% and a disease control rate of 55%. The median follow-up was 5.6 months, with a median PFS of 4.2 months and a 6-month PFS rate of 37%. Median OS was not achieved.

At the CSCO 2022 meeting, Qilu Pharmaceutical announced in a poster presentation the results of the phase II clinical study of QL1706 in combination with chemotherapy with or without bevacizumab in first-line treatment of recurrent or metastatic cervical cancer (paper number: 12865). Among the 57 patients with recurrent or metastatic cervical cancer enrolled, 30 were treated with QL1706 in combination with chemotherapy and QL1706 in combination with chemotherapy plus bevacizumab, with an overall ORR of 77.2% and DCR of 98.2%. Among them, the ORR and DCR of the group treated with QL1706 in combination with chemotherapy were 74.1% and 100.0%, respectively; and QL1706 in combination with chemotherapy plus bevacizumab 80.0% and 96.7%, respectively. As of the data cut-off date, median PFS and median OS were not achieved. Based on the results of this study, a phase III clinical study (NCT05446883) designed to evaluate the efficacy and safety of QL1706 in combination with paclitaxel-cisplatin/carboplatin with or without bevacizumab in the first-line treatment of recurrent or metastatic cervical cancer has now been conducted.

At the recent ESMO (Free ESMO Whitepaper) Asia Congresss, Qilu Pharmaceutical announced in a poster presentation the results of the Phase II clinical study of QL1706 in combination with chemotherapy with or without bevacizumab for the treatment of patients with advanced EGFR wild-type and EGFR mutant non-small cell lung cancer (abstract numbers: 622 and 637).

As various studies on QL1706 progress, its clinical layout have been covered for several major disease areas including lung cancer, gastrointestinal tumors, gynecological tumors, head and neck tumors and urological tumors. In addition to first-line treatment for cervical cancer, QL1706 will also be researched in more phase III clinical studies on first-line treatment and adjuvant therapy for non-small cell lung cancer and liver cancer, which is expected to create a new landscape of immunotherapy, providing more treatment options for patients and more possibilities for unmet clinical needs.

As previously reported, on September 20, 2022, Sesen Bio, Inc., a Delaware corporation ("Sesen Bio"), Seahawk Merger Sub, Inc., a Delaware corporation and a wholly-owned subsidiary of Sesen Bio ("Merger Sub"), and CARISMA Therapeutics Inc., a Delaware corporation ("Carisma"), entered into an Agreement and Plan of Merger and Reorganization (the "Merger Agreement"), pursuant to which, among other things, and subject to the satisfaction or waiver of certain conditions set forth in the Merger Agreement, Merger Sub will merge with and into Carisma, with Carisma continuing as a wholly-owned subsidiary of Sesen Bio and the surviving corporation of the merger (the "Merger") (Filing, 8-K, Sesen Bio, DEC 29, 2022, View Source [SID1234625666]). The Merger Agreement is filed as Exhibit 2.1 to Sesen Bio’s Current Report on Form 8-K filed on September 21, 2022 (the "September Form 8-K"). The material terms of the Merger Agreement were described in Item 1.01 of the September Form 8-K and are incorporated by reference herein.

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On December 29, 2022, Sesen Bio, Merger Sub and Carisma entered into the First Amendment to the Merger Agreement (the "Amendment"). The Amendment amends the Merger Agreement to, among other things, (i) reduce the minimum net cash of Sesen Bio required at the closing of the Merger from $100 million to $75 million, and (ii) increase the one-time special cash dividend to be paid to Sesen Bio stockholders from up to $25 million to the amount of cash available after Sesen Bio meets the $75 million net cash minimum.

In addition, as part of the Amendment, the parties agreed to revise the form of contingent rights agreement (the "CVR Agreement") to include the proceeds from any sale of Sesen Bio’s non-cash assets (net of customary deductions) to the contingent value right ("CVR") to be distributed by way of dividend to holders of Sesen Bio common stock on the record date. The contingent payments under the CVR Agreement, if they become due, will be payable to a rights agent for subsequent distribution to the holders of the CVRs. In the event that no such proceeds are received, holders of the CVRs will not receive any payment pursuant to the CVR Agreement. There can be no assurance that any cash payment will be made or that any holders of CVRs will receive any amounts with respect thereto.

As previously disclosed, the right to the contingent payments contemplated by the CVR Agreement is a contractual right only and will not be transferable, except in the limited circumstances specified in the CVR Agreement. The CVRs will not be evidenced by a certificate or any other instrument and will not be registered with the Securities and Exchange Commission. The CVRs will not have any voting or dividend rights and will not represent any equity or ownership interest in Sesen Bio or any of its affiliates. No interest will accrue on any amounts payable in respect of the CVRs.

The foregoing descriptions of the Amendment and the CVR Agreement do not purport to describe all of the terms of such agreements and are qualified by reference to the Amendment, which is attached as Exhibit 2.1 hereto and incorporated herein by reference, and the form CVR Agreement attached thereto.

On December 29, 2022 Rain Therapeutics Inc. ("Rain") (NasdaqGS: RAIN), (Rain), a late-stage biotechnology company developing precision oncology therapeutics with a lead product candidate, milademetan, an oral, small molecule inhibitor of the MDM2-p53 complex that reactivates p53, reported that it will change its name to Rain Oncology Inc. effective tomorrow, December 30, 2022, to better reflect the company’s focus on addressing unmet needs for cancer patients through precision oncology (Press release, Rain Therapeutics, DEC 29, 2022, View Source [SID1234625665]).

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"Our Company has always kept a steadfast focus on patients with cancer in an enduring passion to develop new precision oncology strategies. We felt it appropriate for our name to reflect that intent. As we enter the new year, now is the perfect time to launch Rain Oncology Inc. to reflect this unwavering mission," said Avanish Vellanki, Chief Executive Officer.

In connection with the name change, Rain will have a new corporate website at www.rainoncology.com. No action is required from current stockholders in connection with the name change. The company’s common stock will continue to be listed on The Nasdaq Global Select Market and the CUSIP will not change. The number of outstanding shares of the company’s common stock is not affected by the name change. The company’s ticker symbol "RAIN" will remain the same.

On December 29, 2022 Outlook Therapeutics, Inc. (Nasdaq: OTLK), a biopharmaceutical company working to develop and launch the first FDA-approved ophthalmic formulation of bevacizumab for use in retinal indications, reported its financial results for its fiscal year ended September 30, 2022, and provided recent corporate highlights (Press release, Outlook Therapeutics, DEC 29, 2022, View Source [SID1234625664]).

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Recent Corporate Highlights

Closed on approximately $50 million net proceeds from two new financings to support pre-launch activities through anticipated approval of ONS-5010 in third calendar quarter 2023.
Approximately $25 million registered direct equity offering priced at-the-market under Nasdaq rules.
Approximately $30 million net proceeds from issuance of an unsecured convertible promissory note with an initial conversion price of $2.00.
Received validation of Marketing Authorization Application (MAA) by the European Medicines Agency (EMA) for ONS-5010/ LYTENAVA (bevacizumab-vikg).
Announced that the FDA accepted its Biologics License Application (BLA) for ONS-5010 / LYTENAVA (bevacizumab-vikg) for the treatment of wet AMD and set a PDUFA goal date of August 29, 2023.
Entered into a strategic commercialization agreement with AmerisourceBergen, a global healthcare company and leader in specialty pharmaceutical distribution and services who will provide third-party logistics (3PL) services and distribution, as well as medical information and pharmacovigilance services in the United States.
Strengthened Board of Directors with appointment of Julia Haller, MD, one of the country’s most accomplished professionals in ophthalmic education, research and clinical ophthalmic practice.
"Our fiscal year 2022 laid a solid foundation for what we believe will be a transformational 2023. We are driving our commercialization planning towards expected launch with the accepted FDA filing of our BLA for ONS-5010 and PDUFA date set for August 29, 2023, and review of our MAA in the EU underway with a decision date expected in early 2024. We believe that ONS-5010 has the potential to be a game-changer for patients and physicians in the retina community, and we now have the necessary capital to support these efforts. We remain steadfast in our mission to enhance the standard of care in the retinal anti-VEGF space," commented C. Russell Trenary III, President and Chief Executive Officer of Outlook Therapeutics. "On behalf of the entire team, I would like to thank all stakeholders for their continued support and look forward to what we believe will be an exciting future for Outlook Therapeutics."

Upcoming Anticipated Milestones

Continued progress with ongoing pre-launch commercial preparations in anticipation of potential approval for ONS-5010 in 2023;
PDUFA goal date of August 29, 2023; and
Estimated decision date from the EMA’s Committee for Medicinal Products for Human Use (CHMP) on the Company’s submitted MAA in EU for ONS-5010 expected in early 2024.
ONS-5010 / LYTENAVA (bevacizumab-vikg) Pre-Launch Commercial Planning Underway

According to GlobalData, the use of unapproved repackaged IV bevacizumab from compounding pharmacies is estimated to account for approximately 50% of all wet AMD injections in the United States each year. Globally, the nine major markets account for an estimated $13.1 billion market for anti-VEGF drugs to treat retina diseases.

In anticipation of potential FDA marketing approval in 2023, Outlook Therapeutics has begun commercial launch planning, including best-in-class partnerships with FUJIFILM Diosynth Biotechnologies for drug substance, and with drug product manufacturer Aji Bio-pharma Services for the finished drug product.

Outlook Therapeutics is actively building out its sales and commercial team, and in September 2022, Outlook Therapeutics entered into a strategic commercialization agreement with AmerisourceBergen in preparation for the anticipated commercial launch in the United States of ONS-5010. As Outlook Therapeutics moves toward a potential launch in the United States, AmerisourceBergen’s commercialization support will expand to include additional services. Through the agreement with AmerisourceBergen, Outlook Therapeutics expects to significantly increase market access and efficient distribution of ONS-5010, if approved by the FDA. Moreover, working with AmerisourceBergen will help to provide Outlook Therapeutics with an accelerated pathway to deliver a high-quality customer experience to retina specialists. To bring ONS-5010 to market in a way that benefits all stakeholders – patients, clinicians, and payors – Outlook Therapeutics has also been in collaborative discussions with payors and the retina community.

Outlook Therapeutics is also developing registration documents on a parallel path for approvals in Europe and submitted them in December 2022. The formal review process of the MAA by the EMA’s CHMP is now set to begin with an estimated decision date expected in early 2024 and is also exploring a relationship with AmerisourceBergen to support the launch of ONS-5010 in international markets. AmerisourceBergen expanded its global distribution capabilities in 2021 with the acquisition of Alliance Healthcare, a leading wholesaler of healthcare products in Europe. Additionally, Outlook Therapeutics continues to explore potential strategic commercialization partners, such as the current partnership with Syntone Biopharma JV in China.

In addition to the clinical development program evaluating ONS-5010 for wet AMD, Outlook Therapeutics has received agreements from the FDA on three Special Protocol Assessments (SPAs) for three additional registration clinical trials. These SPAs cover the protocols for a planned registration clinical trial evaluating ONS-5010 to treat branch retinal vein occlusion (BRVO), NORSE FOUR, and two planned registration clinical trials evaluating the drug candidate for the treatment of diabetic macular edema (DME), NORSE FIVE and NORSE SIX.

ONS-5010 / LYTENAVA (bevacizumab-vikg) Development Updates

As previously announced, if ONS-5010 receives FDA approval, Outlook Therapeutics plans to submit a supplementary application (sBLA) for approval to provide the product in a pre-filled, silicone oil liquid-free syringe that meets the FDA’s strict specifications for ophthalmic use. To support the anticipated submission of this sBLA, Outlook Therapeutics is conducting its NORSE SEVEN clinical trial to compare the safety of ONS-5010 in vials versus pre-filled syringes. NORSE SEVEN is expected to enroll approximately 120 subjects with visual impairment due to retinal disorders. Patients will be treated for three months; the enrollment of patients in the arm of the study receiving ONS-5010 in vials has already been completed.

Financial Highlights for the 2022 Fiscal Year Ended September 30, 2022

For the fiscal year ended September 30, 2022, Outlook Therapeutics reported a net loss attributable to common stockholders of $66.1 million, or $0.31 per basic and diluted share, compared to a net loss attributable to common stockholders of $53.2 million, or $0.35 per basic and diluted share, for fiscal 2021.

At September 30, 2022, Outlook Therapeutics had cash and cash equivalents of $17.4 million.

Subsequent to September 30, 2022, the Company closed a registered direct equity offering priced at-the-market under Nasdaq rules, resulting in aggregate gross proceeds of approximately $25.0 million. Additionally, the Company closed on an unsecured convertible promissory note (the "Note") with a face amount of $31.8 million and net proceeds of approximately $30.0 million after original issue discount and after deducting the Lender’s transaction costs covered by the Company in connection with the issuance. The combined proceeds from the Note and the registered direct offering are expected to provide funding through the anticipated FDA approval of ONS-5010 in the third calendar quarter of 2023.

About ONS-5010 / LYTENAVA (bevacizumab-vikg)

ONS-5010 is an investigational ophthalmic formulation of bevacizumab under development as an intravitreal injection for the treatment of wet AMD and other retinal diseases. Because no currently approved ophthalmic formulations of bevacizumab are available, clinicians wishing to treat retinal patients with bevacizumab have had to use unapproved repackaged IV bevacizumab provided by compounding pharmacies, products that have known risks of contamination and inconsistent potency and availability. If approved, ONS-5010 can replace the need to use unapproved repackaged oncologic IV bevacizumab from compounding pharmacies for the treatment of wet AMD.

Bevacizumab-vikg is a recombinant humanized monoclonal antibody (mAb) that selectively binds with high affinity to all isoforms of human vascular endothelial growth factor (VEGF) and neutralizes VEGF’s biologic activity through a steric blocking of the binding of VEGF to its receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2) on the surface of endothelial cells. Following intravitreal injection, the binding of bevacizumab-vikg to VEGF prevents the interaction of VEGF with its receptors on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation in the retina.