On May 15, 2022 Antengene Corporation Limited ("Antengene" SEHK: 6996.HK), a leading innovative, commercial-stage global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class therapeutics in hematology and oncology, reported that its first commercialized product, the oral XPO1 inhibitor XPOVIO (selinexor) approved for the treatment of relapsed/refractory multiple myeloma (R/R MM), has officially entered multiple hospitals, online-hospitals, and direct-to-patient (DTP) pharmacies in mainland China and widely prescribed in the country for the first time at Shanghai Jiaotong University School of Medicine Ruijin Hospital, Shanghai Jiaotong University School of Medicine Renji Hospital, Tongji Hospital of Tongji University, Shanghai Sixth People’s Hospital, Shanghai Jiaotong School of Medicine St. Luke’s Hospital, and the PLA Naval Medical Center (Press release, Antengene, MAY 15, 2022, View Source [SID1234614559]). By the end of May, selinexor will be expeditiously rolled out to approximately 600 hospitals and 105 DTPs in over 30 provinces, autonomous regions, and municipalities including Beijing, Shanghai, Guangdong, Jiangsu, Zhejiang, Henan, and Shandong, providing Chinese MM patients across the country with an easy to access to this new treatment option.

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Expeditious Launch of Novel Targeted Therapy for Unmet Cancer Need

Multiple myeloma (MM) is the second most common hematologic malignancy in China, accounting for approximately 10% of all hematologic malignancy incidences. The number of new diagnoses of MM has been rising year after year, thus presenting a rapidly growing medical need.[1] Strikingly, more patients are diagnosed at younger ages.

The prior standard of care for MM has been based on treatment with a combination of therapies including dexamethasone, proteosome inhibitors, immunomodulatory agents and an anti-CD38 monoclonal antibody. Despite the availability of these therapies, MM remains a hard-to-treat cancer. Most patients with MM experience at least one relapse,[2][3] with each relapse resulting in a shorter duration of response. In particular, those patients relapsed after third- or forth-line treatments have a poor prognosis and limited treatment options,[4][5] with a median progression-free survival (PFS) of only 3-6 months and an overall survival (OS) of about 6 months.

In July 2019, the U.S. Food and Drug Administration (FDA) approved a new drug application (NDA) for XPOVIO , the world’s first oral selective inhibitor of nuclear export protein-1 (XPO1) approved for combination use with low-dose dexamethasone for the treatment of patients with R/R MM who have received at least four prior therapies and whose disease is refractory to at least two proteosome inhibitors, at least two immunomodulatory agents and an anti-CD38 monoclonal antibody. Less than a year after that, the FDA granted approval for another indication for XPOVIO, as a monotherapy for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). In December 2020, XPOVIO obtained its third FDA-approved indication, for combination use with bortezomib and dexamethasone in treatment of adult patients with MM who previously received at least one prior therapy.

To address the urgent medical need of MM patients in China, Antengene raced against time and dedicated significant resources to bringing this novel drug to the country. On December 14, 2021, selinexor was approved through a priority review process by the China National Medical Products Administration (NMPA), for the treatment of adults with R/R MM who previously received treatment with at least three agents including a proteosome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

Prof. Xiaojun Huang, at Peking University People’s Hospital, commented, "R/R MM remains a major clinical challenge with limited treatment options for relapsed patients. I am glad that selinexor is available in China and can start benefiting Chinese patients right away. The introduction of this novel therapy represents a clinical breakthrough bringing the country one step closer to advanced targeted therapies that are already available to patients in developed countries."

Prof. Jianxiang Wang, at the Hematology Institute of the Chinese Academy of Medical Sciences, noted, "I am pleased that selinexor has entered clinical application and now being prescribed to Chinese patients in need. This innovative drug has demonstrated an impressive clinical profile in the MARCH study, including favourable safety and tolerability, and clear efficacy with an overall response rate (ORR) of 29.3% and a median OS of 13.2 months.[6] Moreover, this novel drug offers fast onset of actions and the convenience of once-weekly oral administration that simplifies the treatment regimen and spares patients from the ordeal of frequent injections."

Prof. Depei Wu, at the First Affiliated Hospital of Soochow University, said, "MM poses a growing threat to people’s health in China. To effectively treat this condition, it requires early diagnosis, early treatment and timely adjusted treatment plans. I am thrilled that selinexor is now available to patients in China. I believe this new therapy will offer multiple myeloma patients significantly deeper responses, longer survival, and improved prognosis."

Prof. Jun Ma, at the Harbin Institute of Hematology&Oncology, added, "selinexor has a novel mechanism of action that delivers synergistic effects in combination with a number of readily available agents indicated for multiple myeloma. I am confident that we will be able to gain deeper insight from our clinical experience with selinexor-based combination therapies, thus bringing greater clinical benefit to patients."

Prof. Yu Hu, at the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, remarked, "I am thrilled that selinexor can now be prescribed to patients in China. I believe this novel therapeutic offers a much-needed strategy that will bring renewed hope and improved health to many patients. I hope to see more novel medicines like selinexor, utilizing innovative mechanisms to bring new treatment options and potential curative care to patients, become available in China."

Integrated Distribution Channels, Coordinated Efforts to Fast Track Adoption

To make selinexor available to Chinese patients as swiftly as possible, Antengene has built world-class operations and commercial teams and established extensive strategic collaborations with Shanghai Pharmaceutical Lin-Gang Special Area Co., Ltd, the exclusive importer and national distributor of selinexor in China, and the provincial subsidiaries of Shanghai Pharmaceutical Co., Ltd, a Tier I distributor of selinexor in China, as well as a few other leaders in the across the product supply chain, such as DTP pharmacies under SPH Health Commerce Co., Ltd, the headquarters and provincial subsidiaries of SinoPharm Distribution Co., Ltd, China Resources Hunan Ruige Pharmaceutical Co., Ltd, Medbanks, LinkDoc, and Zhejiang INTYN Pharmacy Franchise Co., Ltd. Upon approval, Antengene promptly mobilized an internal team and external partners to secure supply chain readiness covering customs clearance, warehousing, quality assurance, distribution, and transportation. This coordinated effort paved the way for the rapid clinical application of selinexor across mainland China, hence benefiting many patients in need.

"Honoring our mission of Treating Patients Beyond Borders, we aim to leverage our global presence and extensive network of partners to commercialize practice-changing innovative therapies, and rapidly build out our distribution network to introduce high-quality innovative drugs to Chinese patients." said Dr. Jay Mei, Antengene’s Founder, Chairman and CEO. "To have selinexor entering clinical practice and widely prescribed and utilized in mainland China vastly expands the drug’s accessibility for patients. Committed to serving patients in need, our overseas teams are racing against time to secure the accessibility of this life-saving drug for patients in South Korea, Singapore and Australia, where selinexor was also granted approvals. Moving forward, we will continue to expand our distribution network to allow more patients to benefit from the important therapy."

Novel Mechanism with Broad Potential to be Combined with Other Therapies

Selinexor is the world’s first orally-available, selective inhibitor of the nuclear export protein XPO1. Selinexor promotes the intra-nuclear accumulation and activation of tumor suppressor proteins and growth regulating proteins, down-regulating the levels of multiple oncogenic proteins, and activating the glucocorticoid receptors (GR) pathway, ultimately resulting in antitumor effects.

Utilizing this innovative mechanism of action, selinexor has demonstrated combinatory potential with multiple therapeutic agents including dexamethasone, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), daratumumab, cyclophosphamide, adriamycin, and melphalan. To date, six selinexor-based regimens have received a total of 11 recommendations by numerous leading medical societies, including the National Cancer Care Network (NCCN) Guidelines, the Guidelines for the Diagnosis and Danagement of Multiple Myeloma in China, and the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Guidelines.

At present, Antengene is conducting a total of 10 clinical studies of selinexor in mainland China (3 are being jointly conducted by Antengene and Karyopharm Therapeutics Inc. [Nasdaq:KPTI]), including several late-stage clinical trials, for the treatment of a range of relapsed/refractory hematologic malignancies and advanced solid tumors such as relapsed/refractory multiple myeloma, relapsed/refractory diffused large B-cell lymphoma and indolent lymphoma, relapsed/refractory T and NK-cell lymphoma, and recurrent/metastatic cervical/endometrial/ovarian cancers.

Note: XPOVIO is a prescription drug that should only be used under doctors’ instructions. Should you need any advice on the use of this drug, please consult your local hospitals or pharmacies.

On May 15, 2022 Sanofi reported that Latest results from the Phase 3 IKEMA clinical trial evaluating Sarclisa (isatuximab) in combination with carfilzomib and dexamethasone (Kd) demonstrated a median progression free survival (mPFS) of 35.7 months (Hazard Ratio [HR] 0.58; 95% Confidence Interval [CI]: 25.8 to 44.0; n=179), compared to 19.2 months in patients treated with Kd alone (95% CI: 15.8 to 25.1; n=123), as evaluated by an Independent Review Committee (Press release, Sanofi, MAY 15, 2022, View Source [SID1234614557]). These results, presented at the Controversies in Multiple Myeloma World Congress, represent the longest mPFS among studies investigating a proteasome inhibitor backbone in the second-line setting for the treatment of relapsed multiple myeloma (MM). These data will also be presented at the European Society for Medical Oncology on May 19.

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Philippe Moreau, MD
Head of the Department of Hematology, University Hospital of Nantes, France
"The increase in progression free survival, observed consistently across all subgroups, when adding Sarclisa to carfilzomib and dexamethasone is remarkable in patients with relapsed multiple myeloma in a proteasome inhibitor combination. Relapse is common in multiple myeloma, creating the need for differentiated second-line treatments that provide patients a longer period of time without disease progression. This updated analysis reinforces the potential for Sarclisa to become a new standard of care for patients with relapsed multiple myeloma."

A PFS analysis following the U.S. Food and Drug Administration recommendations on censoring rules, as applied in the approved U.S. prescribing information, showed an mPFS of 41.7 months for Sarclisa added to Kd (Sarclisa combination therapy) compared to 20.8 months in patients treated with Kd alone (HR 0.59; 95% CI: 27.1 to Not Calculable [NC]).

Time to next treatment for patients treated with Sarclisa combination therapy was 44.9 months (HR 0.55; 95% CI: 31.6 to NC) versus those treated with Kd alone at 25 months (95% CI: 17.9 to 31.3). Time to next treatment measured the interval from the date of randomization1 to the date of commencement of the next line of therapy, thereby allowing for measurement of the period of therapeutic benefit.2

Peter C. Adamson, MD
Global Head of Oncology Clinical Development and Pediatric Innovation at Sanofi
"To observe progression free survival of more than three years in patients with relapsed multiple myeloma when Sarclisa was added to a proteasome inhibitor backbone of therapy is unprecedented and reinforces our confidence in Sarclisa as a potential best in class anti-CD38 antibody."

The safety and tolerability of Sarclisa observed in this analysis were consistent with the safety profile of Sarclisa in other clinical trials, with no new safety signals observed. For the Sarclisa combination therapy and Kd groups, the most common adverse events were infusion related reaction (45.8%, 3.3%), diarrhea (39.5%, 32%), hypertension (37.9%, 35.2%), upper respiratory tract infection (37.3%, 27%), fatigue (31.6%, 20.5%), dyspnoea (30.5%, 22.1%), pneumonia (27.1%, 21.3%), back pain (25.4%, 21.3%), insomnia (25.4%, 24.6%), and bronchitis (24.3%, 12.3%). Treatment exposure in the Sarclisa combination therapy arm was 30 weeks longer than in the control arm. Treatment emergent adverse events (TEAEs) of ≥ Grade 3 were reported in 83.6% of patients treated with Sarclisa combination therapy and in 73% of those treated with Kd alone. Serious TEAEs were higher in the Sarclisa combination therapy arm versus Kd alone (70.1% versus 59.8%). No difference was observed after exposure adjustment."

These results will be discussed with regulatory authorities at a future date.

About the IKEMA trial

The randomized, multi-center, open label Phase 3 IKEMA clinical trial enrolled 302 patients with relapsed MM across 69 centers spanning 16 countries. All study participants had received one to three prior anti-myeloma therapies. During the trial, Sarclisa was administered through an intravenous infusion at a dose of 10mg/kg once weekly for four weeks, then every other week for 28-day cycles in combination with carfilzomib twice weekly at the 20/56mg/m2 dose and dexamethasone at the standard dose for the duration of treatment. The primary endpoint of IKEMA was progression free survival. Secondary endpoints included overall response rate, the rate of complete response or better, the rate of very good partial response or better, rate of minimal residual disease-negativity, overall survival and safety.3

About Sarclisa

Sarclisa is a monoclonal antibody that targets a specific epitope on the CD38 receptor on multiple myeloma (MM) cells. It is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly and uniformly expressed on the surface of MM cells, making it a potential target for antibody-based therapeutics such as Sarclisa.

Based on the Phase 3 ICARIA-MM study, Sarclisa is approved in a number of countries, including the U.S. and EU, in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor. Based on the Phase 3 IKEMA study, Sarclisa is also approved in multiple countries in combination with carfilzomib and dexamethasone, including in the U.S. for the treatment of patients with RRMM who have received 1–3 prior lines of therapy and in the European Union for patients with MM who have received at least 1 prior therapy. In the U.S., the generic name for Sarclisa is isatuximab-irfc, with irfc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA).

Sarclisa continues to be evaluated in multiple ongoing Phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum. It is also under investigation for the treatment of other hematologic malignancies and solid tumors. The safety and efficacy of these additional uses have not been reviewed by any regulatory authority worldwide.

For more information on Sarclisa clinical trials, please visit www.clinicaltrials.gov.

About multiple myeloma

MM is the second most common hematologic malignancy,4 with more than 130,000 new diagnoses of MM worldwide yearly.5 Despite available treatments, MM remains an incurable malignancy and is associated with significant patient burden. Since MM does not have a cure, most patients will relapse. Relapsed MM is the term for when the cancer returns after treatment or a period of remission. Refractory MM refers to when the cancer does not respond or no longer responds to therapy.

On May 13, 2022 Outlook Therapeutics, Inc. (Nasdaq: OTLK), a pre-commercial biopharmaceutical company working to develop and launch the first FDA-approved ophthalmic formulation of bevacizumab for use in retinal indications, reported recent corporate highlights and financial results for its fiscal second quarter ended March 31, 2022 (Press release, Outlook Therapeutics, MAY 13, 2022, View Source [SID1234616059]).

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Recent Corporate Highlights

Successfully submitted a BLA for ONS-5010, an investigational therapy which, if approved, will be branded as LYTENAVA (bevacizumab-vikg), for the treatment of wet age-related macular degeneration (wet AMD);
Expanded commercial team with the appointment of Joel Prieve as Senior Vice President, Commercial Operations, in February 2022; and
Further expanded commercial team with appointment of Alicia Tozier as Senior Vice President, Marketing and Market Access, in March 2022.
"This past quarter was marked by the achievement of the most important milestone to date for Outlook Therapeutics – the submission of our BLA for ONS-5010. In anticipation of potentially providing an on-label, FDA-approved alternative for wet AMD patients in the United States, we are ramping up our pre-commercial launch activities. To support these efforts, we have continued to add to the expertise of our commercial team to build momentum among partners, payors and the retina community. We are focused on positioning ourselves to unlock the full potential of ONS-5010," commented C. Russell Trenary III, President and Chief Executive Officer of Outlook Therapeutics.

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

Outlook Therapeutics’ wet AMD clinical program for ONS-5010 consists of three completed clinical trials, NORSE ONE, NORSE TWO, and NORSE THREE. With the successful completion of these clinical trials, Outlook Therapeutics submitted its BLA under the Public Health Service Act (PHSA) 351(a) regulatory pathway in March 2022. If the BLA is approved, it is expected to result in 12 years of marketing exclusivity for ONS-5010 as the first and only ophthalmic formulation of bevacizumab approved by the FDA to treat wet AMD.

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 and the enrollment of patients in the arm of the study receiving ONS-5010 in vials has already been completed.

Pre-Launch Commercial Planning Underway

According to the National Eye Institute (NEI), use of unapproved repackaged IV bevacizumab from compounding pharmacies is estimated to account for at least 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 early 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 Biopharma Services for finished drug product. The Company also is actively building out its distribution and commercial team structures.

To bring ONS-5010 to market in a way that benefits all stakeholders – patients, clinicians and payors – Outlook Therapeutics has 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 expects to submit them in the fourth quarter of calendar 2022. Outlook Therapeutics continues to explore potential strategic commercialization partners, such as the current partnership with Syntone Biopharma JV in China. Outlook Therapeutics expects ONS-5010, if approved, to be a safe and cost-effective choice for patients, clinicians, and payors worldwide for retinal indications.

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.

Upcoming Anticipated Milestones

Receive PDUFA date from FDA;
Continued progress with ongoing pre-launch commercial preparations in anticipation of potential approval for ONS-5010 in early 2023; and
Completion in calendar 2022 of the NORSE SEVEN study evaluating Outlook Therapeutics’ vial delivery system versus a pre-filled syringe of ONS-5010.
Financial Highlights for the Fiscal Second Quarter Ended March 31, 2022

For the fiscal second quarter ended March 31, 2022, Outlook Therapeutics reported a net loss attributable to common stockholders of $19.7 million, or $0.09 per basic and diluted share, compared to a net loss attributable to common stockholders of $13.1 million, or $0.09 per basic and diluted share, for the same period last year.

At March 31, 2022, Outlook Therapeutics had cash and cash equivalents of $58.4 million, compared to $70.2 million at December 31, 2021. Outlook Therapeutics’ cash and cash equivalents on hand are expected to provide funding into the first calendar quarter of 2023.

"We believe Outlook Therapeutics is in a strong financial position," stated Lawrence A. Kenyon, Chief Financial Officer of Outlook Therapeutics. "We have successfully accessed capital via our ATM program and plan to continue using this financing option, subject to market conditions. Also, we have initiated discussions with the holders of our unsecured notes to extend the maturity of these notes until 2024 after we begin generating revenue from LYTENAVA, if approved. With these steps, we believe we have charted a path that would allow Outlook Therapeutics to launch LYTENAVA without the need to raise significant additional capital."

About ONS-5010 / LYTENAVA (bevacizumab-vikg)

ONS-5010 is an investigational ophthalmic formulation of bevacizumab under development to be administered 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 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.

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Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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