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Ascentage Pharma’s First Third-Generation BCR-ABL Inhibitor in China Olverembatinib (HQP1351) Recommended for Breakthrough Therapy Designation

On March 24, 2021 Ascentage Pharma, a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) has recommended the novel candidate drug olverembatinib (HQP1351) of Guangzhou Healthquest Pharma Co., Ltd, a wholly-owned subsidiary of Ascentage Pharma, for a Breakthrough Therapy Designation (BTD) for the treatment of patients with chronic-phase chronic myeloid leukemia (CP CML) resistant and/or intolerant to first- and second-generation tyrosine kinase inhibitors (TKIs) (Press release, Ascentage Pharma, MAR 24, 2021, View Source [SID1234633502]). This BTD recommendation marks another major development for olverembatinib following the Priority Review granted by the CDE in October 2020. The indication of BTD recommendation is an expansion from that of the Priority Review designation.

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According to the NMPA’s Provisions for Drug Registration (SAMR Order No. 27) and Working Procedures for Review of Breakthrough Therapeutics (No. 82 of 2020) implemented on July 1, 2020, the breakthrough therapy review policy is designed to promote the research and creation of drugs with apparent clinical advantages, which are intended for the prevention or treatment of serious life-threatening diseases or diseases which severely impact the qualify of life for which there is no existing treatment or where sufficient evidence indicates advantages of the novel drug over currently available treatment options. Drugs that have been granted the BTD are prioritized by the CDE in communications and exchange, and in receiving guidance to promote the drug development progress. Furthermore, BTD designated drugs will be eligible to the Priority Review status that will accelerate the review process at the stage of application for commercialization. In conclusion, this measure will effectively accelerate the development and review of drugs presenting significant clinical value or addressing urgent clinical needs.

CML is a hematologic malignancy of the white blood cells. Following the commercialization of BCR-ABL TKIs, the treatment of CML has been revamped. However, despite clinical benefits offered by the first-generation BCR-ABL inhibitor imatinib (GLEEVEC), and several second-generation TKIs, acquired resistance to TKIs remains a major challenge in the treatment of CML. BCR-ABL tyrosine kinase mutations represent a key mechanism of acquired drug resistance; T315I, which is the most common drug-resistant mutation, occurs in about 25% of patients with drug-resistant CML. Patients with T315I-mutant CML are resistant to both first- and second-generation BCR-ABL inhibitors, presenting an urgent unmet medical need for an effective new generation treatment.

Olverembatinib is a novel, orally active, potent third-generation BCR-ABL inhibitor designed to effectively target BCR-ABL mutants, including T315I, and the first China-developed third-generation BCR-ABL inhibitor targeting drug-resistant CML. In July 2019, olverembatinib was cleared by the US Food and Drug Administration (FDA) to enter a Phase Ib clinical study. In May 2020, olverembatinib was granted an Orphan Drug Designation and a Fast Track Designation by the FDA. In October 2020, olverembatinib was granted Priority Review by the CDE in China for the treatment of adult patients resistant to TKI and with T315I-mutant chronic phase CML or accelerated phase CML. In December 2020, clinical trial results of olverembatinib were selected for oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting for the third consecutive year. These data further demonstrated the favorable safety and promising efficacy profiles of olverembatinib.

"Acquired drug resistance to TKIs remains an urgent unmet medical need and a major challenge in the treatment of CML," commented Professor Xiaojun Huang, Director of the Institute of Hematology, Peking University, and the principal investigator of olverembatinib in China. "Currently, no third-generation TKI has been approved in China, and no TKIs approved overseas is expected to enter China anytime soon. Multiple studies of olverembatinib, a China-developed BCR-ABL TKI, have consistently demonstrated promising efficacy and favorable safety in patients with drug-resistant CML, signifying significant potential clinical benefit to the patient population. We hope this BDT will further accelerate the clinical development and the review process for olverembatinib, and ultimately allow patients to soon benefit from this novel therapeutic."

"Olverembatinib is our first candidate drug entering the NDA-stage, and it is expected to become the first approved third-generation BCR-ABL inhibitor in China," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "This BTD for olverembatinib for the treatment of patients with CP CML intolerant or resistant to first- and second-generation TKIs represents the strong recognition of olverembatinib’s therapeutic potential in addressing the unmet medical needs in the treatment of CML. Being granted this BTD will strengthen our communication with the CDE, and more importantly, pave the way for a Priority Review designation to the future NDA for this indication, thus accelerate the clinical development and the approval of olverembatinib in China, and help us to make olverembatinib available to patients as early as possible."

Sana Biotechnology Reports Fourth Quarter and 2020 Financial Results and Business Updates

On March 24, 2021 Sana Biotechnology, Inc. (NASDAQ: SANA), a company focused on creating and delivering engineered cells as medicines, reported financial results and business highlights for the fourth quarter and year ended December 31, 2020 (Press release, Sana Biotechnology, MAR 24, 2021, View Source [SID1234584003]).

"Engineering cells, whether done in vivo or ex vivo, has the potential to transform outcomes for patients across many diseases. We are excited about our significant progress in 2020 in turning this vision into a reality – continuing to build our scientific team, expanding our technology with key acquisitions and licenses, and generating important data across multiple platforms and programs," said Steve Harr, Sana’s President and Chief Executive Officer. "With the completion of our initial public offering in February, we have additional capital to execute our long-term vision of engineering cells to treat serious diseases such as cancer, various genetic disorders, type 1 diabetes, heart disease, and central nervous system diseases. We look forward to providing updates at multiple scientific conferences throughout the year and driving our multiple programs toward the clinic."

Recent Corporate Highlights

Hired key talent to our senior leadership team, including Ed Rebar, Ph.D., Chief Technology Officer, Terry Fry, M.D., Head of T Cell Therapeutics, and Ke Liu, M.D., Ph.D., Head of Regulatory Affairs & Strategy.
Entered into an exclusive license agreement with Washington University for certain intellectual property rights related to methods of generating, compositions of, and use of cells of endodermal lineage and beta cells.
Acquired Oscine Corp., a privately-held early stage biotechnology company developing glial progenitor cells focused on brain disorders to complement our broader ex vivo cell engineering platform.
Expanded our Board of Directors with the addition of Joshua Bilenker, M.D., former CEO of Loxo Oncology, Alise Reicin, M.D., CEO of Tectonic Therapeutic, and Michelle Seitz, CFA, Chairman and CEO of Russell Investments.
Entered into a non-exclusive license and development agreement with FUJIFILM Cellular Dynamics, Inc. (FCDI) for access to FCDI induced pluripotent stem cells (iPSCs).
Further strengthened our balance sheet with net proceeds of $626.6 million from the sale of 27 million shares of common stock in our initial public offering, bringing pro forma cash to over $1 billion as of February 28, 2021.
Fourth Quarter and 2020 Financial Results

GAAP Results

Cash Position: Cash, cash equivalents, and marketable securities as of December 31, 2020 were $412.0 million compared to $139.0 million as of December 31, 2019, an increase of $273.0 million. During the year ended December 31, 2020, Sana sold 27.2 million shares of its Series B convertible preferred stock at $16.00 per share for gross proceeds of $435.5 million.
Research and Development Expenses: Research and development expenses for the quarter and year ended December 31, 2020, inclusive of non-cash expenses, were $104.1 million and $257.9 million, respectively, compared to $39.3 million and $119.4 million for the same periods in 2019. The increases of $64.8 million and $138.5 million were primarily due to personnel-related expenses related to increased headcount to expand Sana’s research and development capabilities, costs for laboratory supplies and preclinical studies, and facility costs. The increase was also due to non-cash expenses for the increase in the estimated fair value of the success payment liabilities of $31.0 million and $70.2 million for the quarter and year ended December 31, 2020, respectively, and the increase in the estimated fair value of the contingent consideration of $33.8 million and $34.9 million for the quarter and year ended December 31, 2020, respectively. The increases in 2020 were offset by higher costs incurred in 2019 for the acquisition of technology. Research and development expense included stock-based compensation of $2.3 million and $4.9 million for the quarter and year ended December 31, 2020, respectively, and $0.4 million and $1.2 million for the same periods in 2019.
General and Administrative Expenses: General and administrative expenses for the quarter and year ended December 31, 2020, inclusive of non-cash expenses, were $9.2 million and $28.3 million, respectively, compared with $5.8 million and $21.8 million for the same periods in 2019. The increases of $3.4 million and $6.5 million for the quarter and year ended December 31, 2020, respectively, were primarily due to increased personnel-related expenses attributable to an increase in headcount to build our infrastructure, facility costs, and consulting fees.
Net Loss: Net loss for the quarter and year ended December 31, 2020 was $113.2 million, or $7.40 per share, and $285.3 million, or $21.92 per share, respectively. This compares to $43.0 million, or $4.94 per share, and $130.8 million, or $26.68 per share for the same periods in 2019.
Non-GAAP Measures

Non-GAAP Operating Cash Burn: Non-GAAP operating cash burn for the quarter and year ended December 31, 2020 was $37.8 million and $125.0 million, respectively, compared to $27.9 million and $76.2 million for the same periods in 2019. Non-GAAP operating cash burn is the decrease in cash, cash equivalents, and marketable securities excluding cash inflows from financing activities, cash outflows from business development activities, and the purchase of property and equipment.
Non-GAAP Research and Development Expenses: Non-GAAP research and development expenses for the quarter and year ended December 31, 2020 were $36.5 million and $123.0 million, respectively, and $28.3 million and $72.1 million for the same periods in 2019. Non-GAAP research and development expense excludes one-time costs to acquire technology and non-cash expenses related to the change in the estimated fair value of its contingent consideration and success payments.
Non-GAAP Net Loss: Non-GAAP net loss for the quarter and year ended December 31, 2020 was $45.5 million, or $2.98 per share, and $150.4 million, or $11.56 per share, respectively. This compares to $32.1 million, or $3.68 per share, and $83.5 million, or $17.04 per share, respectively, for the same periods in 2019. Non-GAAP net loss excludes one-time costs to acquire technology and non-cash expenses related to the change in the estimated fair value of its contingent consideration and success payments.
A discussion of non-GAAP measures, including a reconciliation of GAAP and non-GAAP measures, is presented below under "Non-GAAP Financial Measures."

HUTCHMED Enters Agreement to Divest Non-Core OTC Joint Venture for US$169 Million

On May 24, 2021 Hutchison China MediTech Limited ("HUTCHMED") (Nasdaq/AIM: HCM) reported that it has reached an agreement with GL Mountrose Investment Two Limited, a company controlled and managed by GL Capital Group ("GL Capital"), to sell its entire indirect interest in Hutchison Whampoa Guangzhou Baiyunshan Chinese Medicine Company Limited ("HBYS"), a non-core and non-consolidated over-the-counter ("OTC") drug joint venture business (Press release, Hutchison China MediTech, MAR 24, 2021, View Source [SID1234583629]).

"HUTCHMED’s focus is the discovery and development of novel therapies in oncology and immunology. Over the past 20 years, we have invested in establishing one of the leading innovation-driven, global biopharmaceutical companies based in China," said Simon To, Chairman of HUTCHMED. "The sale of our shares in HBYS, and exit from the OTC drug arena, will allow us to focus our organization and resources on our primary aim of accelerating investment in our Oncology/Immunology assets in China and beyond."

Jeffrey Li, Founder and Chief Executive Officer of GL Capital, said, "As a long-term shareholder and supporter of HUTCHMED, GL is pleased to acquire its share in one of the best-known OTC businesses in China. This transaction is in-line with GL’s strategy of building a leadership position in the OTC drug area to serve patients’ needs for self-medication and cost containment of their overall healthcare budget."

The aggregate amount to be received by HUTCHMED of approximately $169 million in cash represents about 22 times HBYS’ adjusted net profit attributable to HUTCHMED equity holders of $7.7 million in 20201. Of the proceeds, approximately $127 million is related to its shareholding in HBYS with the approximately $42 million balance related to distributions of the previously announced land compensation and prior year undistributed profits.

A deposit of $15.9 million is payable by GL Capital immediately following signing of the agreement which will be credited against the proceeds due on closing of the transaction. The transaction is subject to regulatory approval in China and is expected to close in mid-2021.

New Frontier in Oncology: Platelet Membrane-coated Nanoparticles Offer a Novel and Promising Platform for Treatment of Solid Organ Tumors

On March 24, 2021 Cello Therapeutics reported new study published in Nature Communications, has shown how their novel nano-sized formulation can inhibit tumor growth and metastasis in multiple mouse models of solid tumors [1]. Cancer remains one of the main causes of morbidity and mortality globally (Press release, Cello Therapeutics, MAR 24, 2021, View Source [SID1234577776]). Solid tumors, in particular, make up ~90% of all newly diagnosed cancer cases as well as cancer deaths [2]. Despite the potential for a surgical "cure," residual and metastatic diseases remain a significant issue. New treatment options such as immunotherapy are urgently needed to control and eliminate these tumors. Breast, colorectal, lung, and prostate cancers, in particular, account for nearly 50% of all new cancer cases in the United States and are responsible for almost 50% of all deaths due to cancer. As the second overall leading cause of death, cancer presents a pressing issue in healthcare affecting a significant portion of the US population.

Immunotherapy has emerged as an effective therapeutic approach against cancer that harnesses the power of immune cells and the body’s own immune system. Some recent approaches, including immune checkpoint inhibitors and adoptive transfer of chimeric antigen receptor (CAR) T cells, have shown considerable promise. However, each still has its disadvantages. For example, checkpoint inhibitors are oftentimes associated with severe systemic side effects and only benefit a subset of patients with tumors expressing specific receptors, while CAR T therapy has not fared well against solid tumors despite its success in hematological cancers. In particular, systemic administration of such immunotherapies can result in toxicities in the respiratory, GI, hepatic, pulmonary, endocrine, and neurological systems. To overcome such challenges, intratumoral injection is becoming more common as a mode of administration. The localization of immune-activating agents can help to kick start antitumor immunity while reducing their systemic exposure.

Cello Therapeutics combines immunotherapy and localized administration with an innovative approach. Taking cues from nature, Cello has developed a nanoparticle formulation that mimics platelets in their ability to bind to tumors and the tumor microenvironment. Platelets have been implicated in many disease pathologies, including tumor progression. Previous studies have shown that platelets naturally bind to both cancer cells and components of the tumor microenvironment. In addition, platelets have even been shown to facilitate metastasis by binding to circulating tumor cells and "hiding" them from detection.

Cello’s nanoparticles, which are approximately 1,000 times smaller than the width of a strand of human hair in size, are coated with membrane derived from natural platelets. This membrane coating enables the nanoparticles to bind and be retained at the tumor site much longer than fully synthetic nanoparticles, providing greater opportunity for encapsulated payloads to accomplish their intended effect.

In our recent publication in Nature Communications, Cello used these platelet membrane-coated nanoparticles loaded with an immune-stimulating molecule to treat models of colorectal and breast cancer. When administered locally via intratumoral injection, the nanoparticles, dubbed "PNP-R848 (Fig. 1)," exhibited an impressive antitumor immune response.

Transmission electron microscopy
Fig. 1. Transmission electron microscopy image of PNP-R848 (left). Scale bar = 50 nm. Final lyophilized and fill-finished formulation of PNP-R848 (right).

In the colorectal cancer model, PNP-R848 not only entirely eradicated the tumor, but it also induced a sustained long term immunity (Fig. 2). Mice that had been treated initially with PNP-R848 were rechallenged not once, but twice, with increasing tumor burdens. The mice were able to completely reject and kill these tumors without any additional PNP-R848 treatments, suggesting that treatment with PNP-R848 has the potential to prevent future recurrence of the cancer.

Survival Curve
Fig. 2. Survival curve of colorectal cancer-bearing mice after treatment with vehicle, free R848, PEG-NP-R848, or PNP-R848.

In an aggressive metastatic breast cancer model, administration of PNP-R848 was able to significantly inhibit tumor growth compared with free drug or drug loaded into purely synthetic particles. In addition, treatment with PNP-R848 was able to substantially reduce the number of metastatic nodes found in the mice, indicating that localized administration of PNP-R848 is able to induce a system-wide specific immune response against the tumor (Fig. 3).

Tumor Growth Inhibition
Fig. 3. Tumor growth inhibition (left) and quantification of metastatic nodes (right) in breast cancer-bearing mice after treatment with vehicle, free R848, PEG-NP-R848, or PNP-R848.

The nanoparticles are able to generate a superior antitumor immune effect compared to either free drug or PEGylated nanoparticles likely due to their enhanced retention at the tumor site. Upon injection, the PNP-R848 remains at the tumor site, where it is taken up by resident antigen presenting cells (APCs). Once taken up, the PNP-R848 releases its cargo, which activates the APCs. The activated APCs then migrate to the nearest lymph node, where they train other immune cells, called T cells, to recognize and fight the cancer. Some T cells return to the tumor site to battle the tumor, while others circulate and surveil in the body to eliminate any tumor cells that escaped from the original tumor site. The overall mechanism can be seen in Fig. 4.

Antitumor Mechanism
Fig. 4. Schematic representation of PNP-R848’s antitumor mechanism. I.T.: intratumoral, APCs: antigen presenting cells.

Combining the benefits of both manmade and natural materials, the development of therapeutic approaches based on the modification of synthetic nanoparticles with natural cell membranes represents an important advancement in the field of nanomedicine. The ability of PNP-R848 to retain at the tumor site and promote a specific and sustained systemic antitumor immune response is a promising step towards a generalizable cure for cancer.

Cello is currently scaling up manufacturing of PNP-R848 and evaluating its safety profile in preparation for clinical trials.

iTeos Reports Fourth Quarter and Full Year 2020 Financial Results and Provides Business Update

On March 24, 2021 iTeos Therapeutics, Inc. (Nasdaq: ITOS), a clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of highly differentiated immuno-oncology therapeutics for patients, reported financial results for the fourth quarter and full year ended December 31, 2020 and provided recent business highlights (Press release, iTeos Therapeutics, MAR 24, 2021, View Source [SID1234577161]).

"In 2020, we laid a strong foundation, growing our leadership team and completing an IPO in July that solidified our cash position to support our clinical trials and operations into the second half of 2023. We are making strong progress advancing the Phase 1/2a trials for our two lead clinical candidates, inupadenant, our adenosine A2A receptor antagonist, and EOS-448, our anti-TIGIT antibody. We look forward to reporting initial data for our TIGIT program at the upcoming AACR (Free AACR Whitepaper) Annual Meeting in April, followed by updated data from our expansion cohorts for inupadenant later this year," said Michel Detheux, PhD, president and chief executive officer of iTeos. "As we approach multiple near-term clinical milestones, we also continue to leverage our deep knowledge of the tumor microenvironment to perform rigorous preclinical evaluations to grow our pipeline of highly differentiated immuno-oncology therapeutics and expect to nominate an additional product candidate by year-end."

Program Highlights

Inupadenant (EOS-850): Designed as a highly selective small molecule insurmountable antagonist of the adenosine A2A receptor, or A2AR, to inhibit the adenosine pathway which is a key driver of immunosuppression in the tumor microenvironment across a broad range of tumors. Currently in a multi-arm Phase 1/2a clinical trial in adult patients with advanced solid tumors.

The company is currently enrolling patients in three distinct cohorts in its Phase 1/2a study as both a monotherapy and in combination. The initial cohort is evaluating inupadenant as a monotherapy in a basket of cancers, and the second cohort is evaluating the safety of inupadenant in combination with pembrolizumab in patients with solid tumors. The final cohort is evaluating inupadenant in combination with chemotherapy in patients with triple-negative breast cancer.
Updated single-agent data, including results from tumor biopsy analyses, and initial pembrolizumab combination data are expected to be reported later in 2021.
EOS-448: Antagonistic antibody specifically designed to target TIGIT (T-cell immunoreceptor with Ig and ITIM domains), a checkpoint with multiple mechanisms leading to immunosuppression. EOS-448 was also selected to engage the Fc gamma receptor, or FcγR, and enhance the anti-tumor response through a multifaceted immune modulatory mechanism. These mechanisms include the activation of macrophages and dendritic cells and the promotion of antibody-dependent cellular cytotoxicity, or ADCC, leading to the selective depletion of cells which express high levels of TIGIT including immunosuppressive regulatory T cells and exhausted T cells. Currently in a Phase 1/2a clinical trial in multiple advanced solid tumors.

Enrollment in the dose escalation portion of the study has now been completed. Following the determination of the recommended Phase 2 dose, the company expects to begin trials in mid-2021 to evaluate EOS-448 in combination with pembrolizumab, an anti-PD-1 antibody, in combination with inupadenant, and in other combinations in specific tumor types.
The company will present initial clinical and safety data as part of a late-breaking e-poster at the first session of the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held virtually April 10-15, 2021. The poster will go live on Saturday, April 10th at 8:30 a.m. ET, and company management will hold a call on Monday, April 12th at 8:00 a.m. ET to discuss the results.
Abstract Title: CT118 – Preliminary data from Phase I first-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows favorable tolerability profile and early signs of clinical activity in immune-resistant advanced cancers.
Abstract Number: IO-002-Abst-001
Preclinical programs: The company continues to progress research programs focused on additional targets that complement the mechanism of action of A2AR and TIGIT programs or address additional pathways of immunosuppression. The company is optimizing its screening and selection process to identify potential product candidates and expects to nominate an additional product candidate for Investigational New Drug-enabling studies before the end of 2021.

Upcoming Events

American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, April 10-15, 2021
Kempen Life Sciences Conference – European Immuno and Targeted Oncology, April 21, 2021
Jefferies Healthcare Conference, June 1-4, 2021
Fourth Quarter and Full Year 2020 Financial Results

Cash Position: The Company’s cash and cash equivalent position was $336.3 million as of December 31, 2020, as compared to $19.9 million as of December 31, 2019. Cash balance provides runway into second half of 2023.
Research and Development (R&D) Expenses: R&D expenses were $9.2 million for the quarter and $29.9 million for the full year ended December 31, 2020, as compared to $6.0 million for the fourth quarter and $19.2 million for the full year of 2019. The increase was primarily due to an increase in activities related to clinical trials for inupadenant and EOS-448.
General and Administrative (G&A) Expenses: G&A expenses were $5.7 million for the quarter and $15.3 million for the full year ended December 31, 2020, as compared to $2.3 million for the fourth quarter and $8.8 million for the full year of 2019. The increase in both periods was primarily due to increased headcount and professional fees associated with becoming a publicly traded company.
Net Loss: Net loss attributable to common shareholders was $14.9 million, or a net loss of $0.43 per basic and diluted share, for the quarter ended December 31, 2020, as compared to $6.6 million, or a net loss of $23.30 per basic and diluted share, for the fourth quarter of 2019. Net loss was $43.4 million, or a net loss of $2.88 per basic and diluted share, for the year ended December 31, 2020, as compared to $26.5 million, or a net loss of $130.85 per basic and diluted share, for the full year of 2019.