On August 26, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported its 2022 interim results (Press release, Ascentage Pharma, AUG 26, 2022, View Source [SID1234618710]). During the reporting period, Ascentage Pharma remained steadfastly committed to its strategy of global innovation and made remarkable progress in clinical development and commercialization. Highlighting these results, Ascentage Pharma reported the first half-year sales and the accelerating commercialization of its first approved product, olverembatinib.

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During the reporting period, Ascentage Pharma achieved steady improvement to its cash flow. As of June 30, 2022, the company’s cash and bank balances were RMB1,698 million, which remained relatively constant when compared with the cash and bank balances as of December 31, 2021. Meanwhile, the company’s revenue for the six months ended June 30, 2022 substantially increased by 636.9%, from the same period last year, to RMB95.76 million. This increase in revenue was mainly attributable to the sales of olverembatinib, commercialization license fee income of patented IP and service income from customers. It is worth noting that since its approval in last November till the end of June 2022, olverembatinib has already realized an accumulated invoiced sales revenue amount of RMB95.93 million (unaudited, inclusive of value added tax).

Accelerated the commercialization of olverembatinib while continued to explore the drug’s therapeutic potential

Olverembatinib, the first and only drug approved for the treatment of chronic myeloid leukemia (CML) harboring the T315I mutation in China and Ascentage Pharma’s core asset that was designated a National Major New Drug Development and Manufacturing Program, effectively ended of the lack of treatment options for patients with CML harboring the T315I mutation, therefore has enormous clinical value. Since being approved till the end of June 2022, olverembatinib has realized an accumulated invoiced sales revenue amount of RMB95.93 million (unaudited, inclusive of value added tax).

To date, Ascentage Pharma has built a commercial organization possessing a wealth of experience in hematology and entered into a strategic collaboration with Innovent Biologics to jointly commercialize olverembatinib in China. In the months since its approval till June 2022, olverembatinib has been included by 34 government-backed local supplementary insurance programs in 10 provinces, substantially expanding the drug’s accessibility to patients. Meanwhile, olverembatinib was included into the Chinese Society of Clinical Oncology (CSCO) Guidelines and the China Anti-Cancer Association’s (CACA) 2022 Guidelines for the Holistic Integrative Management of Cancers, thus provided clinicians the necessary guidance in their practices. As a China-developed novel drug with clear global best-in-class potentials, olverembatinib is bringing clinical benefits to a growing number of patients around the world.

In partnership with Tanner Pharma, a global pharmaceutical services provider of specialty access solutions, Ascentage Pharma launched an innovative Named Patient Program (NPP) similar to the early access programs seen in the city of Boao in Hainan province, to allow Tanner to supply olverembatinib to healthcare providers on a named patient basis in countries where the drug is not commercially available. The NPP plans to cover more than 130 countries and regions around the world.

In July 2022, the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) accepted and granted Priority Review designation to a New Drug Application (NDA) that will support the full approval of olverembatinib in patients with chronic-phase chronic myeloid leukemia (CML-CP) who are resistant and/or intolerant of first- and second-generation tyrosine kinase inhibitors (TKIs). Following the conditional approval for olverembatinib in 2021, this marks another milestone development that would expedite olverembatinib’s journey to a broader population of patients with CML in China.

Currently, Ascentage Pharma is actively advancing the clinical development of olverembatinib globally. During the reporting period, olverembatinib was cleared by Health Canada to enter a Phase Ib study in patients with refractory CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), making it Ascentage Pharma’s first clinical study in Canada. Prior to this, olverembatinib had already been cleared to enter clinical trials in the US.

In addition to hematologic indications, the company is also exploring olverembatinib’s clinical utility in other therapeutic areas. At the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, Ascentage Pharma released the first dataset of olverembatinib in patients with gastrointestinal stromal tumor (GIST). These results showed promising antitumor activity in patients with TKI-resistant succinate dehydrogenase- (SDH-) deficient GIST with a clinical benefit rate (CBR) of 83.3%.

Furthermore, a new preclinical study discovered olverembatinib’s therapeutic potential as an alternative treatment for patients with moderate to severe COVID-19 infections. These preclinical data have already been published by the EMBO Molecular Medicine, a renowned scientific journal affiliated to the European Molecular Biology Organization (EMBO).

These studies demonstrated olverembatinib’s therapeutic potential and differentiated clinical utility in a wide range of therapeutic areas. With expected further expansion of its indications, olverembatinib will benefit a broad patient population globally.

Executing the strategy of global innovation as a pioneer for the industry

In the first half of 2022, Ascentage Pharma continued to increase its investment in innovation, with the research and development expenses increased by 7.5% year on year, to RMB341 million. Pressing ahead with its global clinical development programs, nine of Ascentage Pharma’s candidate drugs have already entered the clinical stage, currently being evaluated in more than 50 Phase I/II clinical studies in China, the US, and Australia. Meanwhile, Ascentage Pharma has further strengthened its intellectual property portfolio, paving the way for its accelerating research and development. As of June 30, 2022, the company holds 205 issued patents and more than 600 patent applications globally, among of which, 148 patents were issued overseas.

During the reporting period, Ascentage Pharma made rapid progress with its momentous clinical development programs covering an array of therapeutic areas. In addition to the company’s apoptosis-targeting assets and kinase inhibitors, Ascentage Pharma has also made strides with the development of candidate drugs targeting other novel targets, including its embryonic ectoderm development (EED) protein inhibitor that has attracted widespread interest from the research community. The EED inhibitor, APG-5918, was cleared by the US Food and Drug Administration (FDA) to enter a first-in-human study evaluating the safety, pharmacokinetics, and efficacy of APG-5918 in patients with advanced solid tumors and hematologic malignancies, and the IND for APG-5918 has already been accepted by the CDE in China. As the first China-developed EED inhibitor entering clinical development, APG-5918 underlines Ascentage Pharma’s capabilities in discovering and developing first-in-class/best-in-class novel assets.

While making strides with its global innovation, Ascentage Pharma was granted two Fast-Track designations and two Rare Pediatric Disease designations by the US FDA, and a total of 16 Orphan Drug designations by the US FDA and the EMA of the EU, a record number for any Chinese biopharmaceutical company.

Multiple highly differentiated clinical programs are steadily approaching fruition

As a global leader in the development of apoptosis-targeted drugs, Ascentage Pharma has presented the clinical data of its investigational assets at multiple international scientific congresses showcasing the first-in-class and best-in-class potential of these assets.

A Phase II pivotal study of lisaftoclax (APG-2575), the first China-developed Bcl-2 selective inhibitor entering clinical development and a key member of the company’s apoptosis-targeted pipeline, for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL) was approved by the CDE at the end of 2021 and dosed its first patients in March 2022, making lisaftoclax the second Bcl-2 selective inhibitor entering pivotal trials globally. To date, lisaftoclax is being investigated in a total of 19 studies globally for the treatment of multiple hematologic malignancies and solid tumors, and has shown promising therapeutic potentials.

During the reporting period, Ascentage Pharma announced the updated data of lisaftoclax in Chinese patients with R/R CLL/SLL at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting. These data showed an objective response rate (ORR) of 67.4% and favorable tolerability. In terms of safety, most adverse events were manageable, no dose-limiting toxicity (DLT) was observed at the maximum dose of 800mg, and the risk of clinical tumor lysis syndrome (TLS) in patients on daily dose ramp-up was minimal.

Furthermore, Phase I data of lisaftoclax in Chinese patients with relapsed/refractory non-Hodgkin lymphoma (r/r NHL) were released at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress. These data showed, lisaftoclax was well tolerated at doses of up to 800 mg/day, without evidence of TLS, and has antitumor activity in a range of relapsed/refractory hematologic malignancies such as CLL/SLL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and T-cell NHL. In the 11 efficacy evaluable patients with CLL (all of whom were heavily pretreated and had failed prior therapies such as chemoimmunotherapies and Bruton’s tyrosine kinase [BTK] inhibitors, and the majority had at least one type of adverse prognostic factors such as 17p deletion/TP53 mutation), there were 8 efficacy evaluable patients in cohorts received 200 mg or higher doses, including 3 complete responses (CRs) and 4 partial responses (PRs), thus demonstrating an ORR of 87.5%. There is a growing body of evidence signifying the global best-in-class potential of lisaftoclax.

While at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting, Ascentage Pharma reported the updated clinical data of alrizomadlin (APG-115), a MDM2-p53 inhibitor that is also a key asset in the company’s apoptosis-targeted pipeline, in combination with pembrolizumab. These data validated the antitumor efficacy of the combination therapy in patients with immuno-oncologic- (I-O) drug-resistant or recurrent melanoma, including two CRs, an ORR of 11% and a disease control rate (DCR) of 57%. The study also observed promising clinical benefit to patients with malignant peripheral nerve sheath tumor (MPNST), demonstrated by a DCR of 50%. MPNST is a rare pediatric type of sarcoma lacking effective treatment options. These results provide additional evidence validating the synergy and the first-in-class potential of MDM2-p53 inhibitors plus immuno-oncologic drugs.

Also at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting, Ascentage Pharma released the first dataset from the Phase I study of the company’s novel FAK inhibitor and third-generation ALK/ROS1 TKI, APG-2449, in patients with second-generation TKI-resistant ALK/ROS1+ non-small-cell lung cancer (NSCLC) or mesothelioma. According to these results, 4 of the 14 ALK+ patients resistant to second-generation TKIs achieved PRs, 10 TKI-naïve patients achieved an ORR of 80%, at a DCR of 100%. APG-2449 is the first China-developed third-generation ALK inhibitor. The candidate drug’s clinical progress is a manifestation of Ascentage Pharma’s R&D capabilities in the field of solid tumors.

Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma, said, "In the first half of 2022, Ascentage Pharma made solid progress in both commercialization and clinical development, successfully navigated the challenging circumstances posted by the COVID-19 pandemic. The rapid and successful commercialization of olverembatinib, the first and only third-generation BCR-ABL inhibitor, in the months after the NDA approval, has led to substantial revenue growth, allowing us to maintain a healthy cash flow that is essential to the company’s long-term development.

While forging ahead with the commercialization of olverembatinib in China, we launched a global NPP to offer patient access to olverembatinib in areas where the drug is not yet commercially available, in efforts to meet the unmet medical needs of patients from around the world. The NPP highlights olverembatinib’s differentiated clinical value and serves as a very important prelude to the drug’s future global launch. To our surprise, we discovered olverembatinib’s therapeutic potential as an alternative treatment for COVID-19 infections, and we plan to further evaluate the drug in clinical settings.

Executing on our strategy of global innovation, we presented the latest research data and clinical results of lead assets including olverembatinib, lisaftoclax, alrizomadlin, and APG-2449, at multiple international congresses such as the ASCO (Free ASCO Whitepaper), EHA (Free EHA Whitepaper), and AACR (Free AACR Whitepaper) annual meetings. These data readouts are indicative of our rich portfolio and promising clinical programs that are steadily approaching the point of fruition.

As a company focused on original pharmaceutical innovation, we will continue to expand the accessibility, advance the indication expansion and global clinical development of olverembatinib, while pressing ahead with the development programs of other investigational assets. We will remain steadfastly committed to global innovation and the mission of addressing unmet clinical needs in China and around the world, to create additional value for our investors and bring much needed novel therapies to our patients as soon as possible."

On August 26, 2022 Incyte (Nasdaq:INCY) reported that the U.S. Food and Drug Administration (FDA) has approved Pemazyre (pemigatinib), a selective fibroblast growth factor receptor (FGFR) inhibitor, for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement (Press release, Incyte, AUG 26, 2022, View Source [SID1234618709]). MLNs with FGFR1 rearrangement are extremely rare and aggressive blood cancers that may impact less than 1 in 100,000 people in the United States1.

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"The approval of Pemazyre represents an important treatment advancement for people living with MLNs with FGFR1 rearrangement who currently have limited treatment options"

"The approval of Pemazyre represents an important treatment advancement for people living with MLNs with FGFR1 rearrangement who currently have limited treatment options," said Hervé Hoppenot, Chief Executive Officer, Incyte. "These are complex hematologic malignancies with a range of presentations, and this approval highlights Incyte’s continued leadership and commitment to advancing care for patients with rare blood cancers."

A patient with an MLN with FGFR1 rearrangement may present with bone marrow involvement with a chronic myeloid malignancy (such as myeloproliferative neoplasm [MPN], myelodysplastic syndrome/MPN) or a blast phase malignancy (such as B- or T-cell acute lymphoblastic leukemia/lymphoma, acute myeloid leukemia or mixed phenotype acute leukemia). Bone marrow involvement may or may not be accompanied by extramedullary disease (EMD); some patients may present with EMD only. MLNs with FGFR1 rearrangement are caused by chromosomal translocations involving the FGFR1 gene, with various partner genes resulting in constitutive activation of the FGFR1 receptor tyrosine kinase, impacting cell differentiation, proliferation and survival2. Patients often relapse because existing first-line therapies sometimes fail to induce durable clinical and cytogenetic responses.

The FDA approval was based on data from the Phase 2 FIGHT-203 study, a multicenter open-label, single-arm trial that evaluated the safety and efficacy of Pemazyre in 28 patients with relapsed or refractory MLNs with FGFR1 rearrangement. Patients could have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or after a disease modifying therapy or were not a candidate for allo-HSCT or other disease modifying therapies.

Study participants included patients with documented MLNs with an 8p11 translocation on conventional cytogenetics and/or an FGFR1 rearrangement on break-apart FISH testing. (An FDA-approved test for detection of FGFR1 rearrangement in patients with relapsed or refractory MLNs is not available.)
In patients with chronic phase in the marrow with or without EMD (N = 18), the complete response (CR) rate was 78% (14/18; 95% CI 52, 94). The median time to response of CR was 104 days (range, 44 to 435 days). The median duration of CR was not reached (range, 1+ to 988+ days).
In patients with blast phase in the marrow with or without EMD (N = 4), two patients achieved a CR (duration: 1+ and 94 days).
In patients with EMD only (N = 3), one patient achieved a CR (duration: 64+ days).
For all patients (N = 28 including three patients without evidence of morphologic disease) the complete cytogenetic response rate was 79% (22/28; 95% CI: 59, 92).
The most common (≥ 20%) adverse reactions were hyperphosphatemia (74%), nail toxicity (62%), alopecia (59%), stomatitis (53%), diarrhea (50%), dry eye (50%), fatigue (44%), rash (35%), abdominal pain (35%), anemia (35%), constipation (32%), dry mouth (32%), epistaxis (29%), retinal pigment epithelial detachment (26%), extremity pain (26%), decreased appetite (24%), dry skin (24%), dyspepsia (24%), back pain (24%), nausea (21%), blurred vision (21%), peripheral edema (21%) and dizziness (21%).

"In patients with relapsed or refractory MLNs with FGFR1 rearrangement treated with Pemazyre in FIGHT-203, the high rate of complete response and complete cytogenetic response in patients with chronic phase disease and the high rate of complete cytogenetic response in patients with blast phase disease is clinically meaningful, especially in light of the lack of these specific responses with existing first-line treatments," said Dr. Srdan Verstovsek, M.D., Ph.D., Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, and principal investigator for the FIGHT-203 study.

The supplemental New Drug Application (sNDA) for Pemazyre for the treatment of adults with relapsed or refractory MLNs with FGFR1 rearrangement was reviewed by the FDA under Priority Review. The FDA grants Priority Review to medicines that may offer a major advance in treatment where none currently exists. The designation shortens the review period to six months compared to 10 months for Standard Review.

Incyte established its leadership in rare blood cancers more than 10 years ago with the development of the first JAK inhibitor approved by the FDA for the treatment of certain patients with myelofibrosis and polycythemia vera. Incyte continues to research additional pathways to address rare blood cancers through its LIMBER (Leadership In MPNs Beyond Ruxolitinib) clinical development program, designed to evaluate multiple therapies and investigational strategies to improve and expand treatments for patients living with MPNs and other related hematologic malignancies and conditions.

Incyte is committed to supporting patients and removing barriers to access medicines. Eligible patients in the U.S. who are prescribed Pemazyre have access to IncyteCARES (Connecting to Access, Reimbursement, Education and Support), a comprehensive program offering personalized patient support, including financial assistance and ongoing education and additional resources. More information about IncyteCARES is available by visiting www.incytecares.com or calling 1-855-452-5234.

About FIGHT-203
FIGHT-203 is a Phase 2, multicenter trial that enrolled patients 18 years and older with myeloid/lymphoid neoplasms (MLNs) with a fibroblast growth factor receptor 1 (FGFR1) rearrangement. Sponsored by Incyte, the study evaluated the safety and efficacy of pemigatinib for the treatment of adults with MLNs with FGFR1 rearrangement. Patients received pemigatinib 13.5 mg once daily in 21-day cycles, either on a continuous schedule (the approved recommended starting dosage for use in patients with MLNs with FGFR1 rearrangement) or as an intermittent schedule (14 days on, 7 days off, an unapproved dosage regimen in MLN with FGFR1 rearrangement). Pemigatinib was administered until disease progression or unacceptable toxicity or until patients were able to receive allo-HSCT. For more information about the study, please visit View Source

About Pemazyre (pemigatinib)
Pemazyre, a fibroblast growth factor receptor (FGFR) inhibitor, is the first targeted treatment approved for use in the United States for treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement.

Pemazyre is also indicated for the treatment of adults with relapsed or refractory previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response (DOR). Continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Ocular Toxicity
Retinal Pigment Epithelial Detachment (RPED): PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED.

Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE. Modify the dose or permanently discontinue PEMAZYRE as recommended in the prescribing information for PEMAZYRE.

Dry Eye: Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

Hyperphosphatemia and Soft Tissue Mineralization
PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE. Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.

Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is >5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia as recommended in the prescribing information.

Embryo-Fetal Toxicity
Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.

Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

Adverse Reactions: Cholangiocarcinoma
Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE (n=146). Serious adverse reactions in ≥2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in ≥1% of patients included intestinal obstruction and acute kidney injury.

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE. Adverse reactions requiring dosage interruption in ≥1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.

Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE. Adverse reactions requiring dosage reductions in ≥1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 0.5% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N = 635]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

In cholangiocarcinoma (n=146) the most common adverse reactions (incidence ≥20%) were hyperphosphatemia (60%), alopecia (49%), diarrhea (47%), nail toxicity (43%), fatigue (42%), dysgeusia (40%), nausea (40%), constipation (35%), stomatitis (35%), dry eye (35%), dry mouth (34%), decreased appetite (33%), vomiting (27%), arthralgia (25%), abdominal pain (23%), hypophosphatemia (23%), back pain (20%), and dry skin (20%).

Adverse Reactions: Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement

Serious adverse reactions occurred in 53% of patients receiving PEMAZYRE at all dosages (n=34). Serious adverse reactions in > 5% of patients included acute kidney injury. Fatal adverse reactions occurred in 9% of patients who received PEMAZYRE, including acute kidney injury, multiple organ dysfunction syndrome, and malignant neoplasm progression, occurring in one patient each.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received PEMAZYRE at all dosages. Adverse reactions requiring permanent discontinuation included cardiac failure, multiple organ dysfunction syndrome, blood alkaline phosphatase increase, and calciphylaxis. In patients who started treatment on the recommended dosage (n = 20), adverse reactions requiring dosage interruption of PEMAZYRE occurred in 80% of patients. Adverse reactions which required dosage interruption in > 2 patients treated at the recommended dosage included nail toxicities (20%) and hyperphosphatemia (15%).

Dose reductions of PEMAZYRE due to an adverse reaction occurred in 80% of patients who started treatment on the recommended dosage. Adverse reactions requiring dose reductions occurring in > 2 patients were nail toxicities (20%), hyperphosphatemia (20%), and alopecia (15%).

The most common (≥ 20%) adverse reactions were hyperphosphatemia (74%), nail toxicity (62%), alopecia (59%), stomatitis (53%), diarrhea (50%), dry eye (50%), fatigue (44%), rash (35%), abdominal pain (35%), anemia (35%), constipation (32%), dry mouth (32%), epistaxis (29%), retinal pigment epithelial detachment (26%), extremity pain (26%), decreased appetite (24%), dry skin (24%), dyspepsia (24%), back pain (24%), nausea (21%), blurred vision (21%), peripheral edema (21%), and dizziness (21%).

Drug Interactions

Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce the dose of PEMAZYRE if concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.

Special Populations
Advise lactating women not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Reduce the recommended dose of PEMAZYRE for patients with severe renal impairment as described in the prescribing information.

Reduce the recommended dose of PEMAZYRE for patients with severe hepatic impairment as described in the prescribing information.

On August 26, 2022 Inhibikase Therapeutics, Inc. (Nasdaq: IKT) (Inhibikase), a clinical-stage pharmaceutical company developing protein kinase inhibitor therapeutics to modify the course of Parkinson’s disease, Parkinson’s-related disorders and other diseases of the Abelson Tyrosine Kinases, reported that the U.S. Food and Drug Administration (FDA) has reviewed its Investigational New Drug (IND) application for IkT-001Pro for the treatment of Chronic Myelogenous Leukemia (CML) and issued a Study May Procced (SMP) letter (Press release, Inhibikase Therapeutics, AUG 26, 2022, View Source [SID1234618707]).

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IkT-001Pro is a prodrug formulation of imatinib mesylate and has been developed to improve the safety of the first FDA-approved Abelson (Abl) kinase inhibitor, imatinib (marketed as Gleevec). Imatinib is commonly taken for hematological and gastrointestinal cancers that arise from Abl kinase mutations found in the bone marrow or for gastrointestinal cancers that occur from c-Kit and/or PDGFRa/b mutations in the stomach; c-Kit, PDGFRa/b and Abl are all members of the Abelson Tyrosine Kinase protein family. IkT-001Pro has the potential to be a safer alternative for patients and may improve the number of patients that reach and sustain major and/or complete cytogenetic responses in stable-phase CML. In preclinical studies, IkT-001Pro was shown to be as much as 3.4 times safer than imatinib in non-human primates, reducing burdensome gastrointestinal side effects that occur following oral administration. Imatinib delivered as IkT-001Pro was granted Orphan Drug Designation for stable-phase CML in September, 2018.

"We are excited to have received the SMP letter from the FDA for IkT-001Pro for CML. This represents the first program to emerge from our novel prodrug platform, which aims to improve the safety and tolerability of approved and novel therapeutics," commented Milton H. Werner, Ph.D., President and Chief Executive Officer. "Based on preclinical studies, we believe that IkT-001Pro has the potential to significantly improve the safety profile of oral imatinib, which may enhance patient adherence and quality of life, potentially leading to better rates of complete cytogenetic response. We look forward to initiating a bioequivalence study in the second half of 2022."

IkT-001Pro will be evaluated in a single ascending dose bioequivalence study and will enroll approximately 64 male and female healthy volunteers aged 25 to 55 who will receive IkT-001Pro at one of four doses. The study is designed to evaluate the safety profile of IkT-001Pro as well as identify a dose with a similar systemic exposure and pharmacokinetic profile compared to 400 mg imatinib mesylate at 96 hours post administration. Following this study, Inhibikase will conduct a superiority study comparing the selected dose of IkT-001Pro to 400 mg imatinib mesylate, the current standard-of-care for stable-phase Chronic Myelogenous Leukemia and evaluate the adverse event profile and patient reported outcomes as a measure of superiority over standard-of-care.

About Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML)1 is a slowly progressing cancer that affects the blood and bone marrow. In CML, a genetic change takes place in immature myeloid cells — the cells that make most types of white blood cells. This change creates an abnormal gene product called BCR-ABL which transforms the cell into a CML cell. Leukemia cells increasingly grow and divide in an unregulated manner, eventually spilling out of the bone marrow and circulating in the body via the bloodstream. Because they proliferate in an uncontrolled manner, the excessive production of myeloid cells acts like a liquid tumor. In time, the cells can also settle in other parts of the body, including the spleen. CML is a form of slow-growing leukemia that can change into a fast-growing form of acute leukemia that is difficult to treat.

On August 26, 2022 Indi Molecular reported that it has been granted U.S. Patent 11,414,460 entitled "KRAS-Specific Cyclic Peptides, Compositions, and Methods of Using and Making" along with Institute for Systems Biology (Press release, Indi Molecular, AUG 26, 2022, View Source [SID1234618706]). The patent claims cover compositions and methods for making and using cyclic peptide that selectively binds K-Ras G12D.

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"Given the frequency with which KRAS mutations are found in tumors, inhibition of this protein provides a potentially promising avenue for treatment of cancer," said Albert A. Luderer, Ph.D., chief executive and co-founder, Indi Molecular. "KRAS mutations are present in up to 30% of all tumors, including as many as 90% of pancreatic cancers."

Indi Molecular’s KRAS program builds on the synthetic platform developed by Indi Molecular and California Institute for Technology on protein catalyzed capture agents. James Heath, Ph.D., president and professor at Institute for Systems Biology, is the lead inventor of the KRAS and PCC technology. Heath is also a co-founder of Indi Molecular and serves as a board member and as a senior consultant for research and development.

"This composition of matter patent covers compounds, compositions, and methods involving cyclic peptides that can bind to KRAS (G12D) oncogenic protein. This is the third issued patent in the KRAS family of patents. The granted patent provides further evidence of the potential use of cyclic peptides in our oncology programs" said Sherri Candelario, Ph.D., vice president of intellectual property, Indi Molecular.

On August 26, 2022 Biomea Fusion, Inc. (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported the presentation of two posters at the 19th International Myeloma Society (IMS) Annual Meeting, which took place August 25-27, 2022 in Los Angeles, California (Press release, Biomea Fusion, AUG 26, 2022, View Source [SID1234618704]). Both poster presentations can be viewed on Biomea’s website at View Source

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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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"Our team has continued to accumulate novel scientific evidence demonstrating compelling preclinical activity of BMF-219 as a potential first-in-class and best-in-class menin inhibitor across a spectrum of tumor types where menin is known to play a critical role. To that end, we are pleased to present additional preclinical data at the IMS Annual Meeting that support the expansion of our ongoing COVALENT-101 clinical trial to enroll patients with DLBCL and MM. We look forward to seeing how BMF-219’s preclinical effect translates to patient benefit in the clinical setting," said Thomas Butler, CEO, Chairman of the Board and Co-Founder of Biomea.

Poster Presentation Details:

Poster P-107: Anti-tumor activity of covalent menin inhibitor, BMF-219, in High-Grade B-Cell Lymphoma and Multiple Myeloma Preclinical Models

Abstract Text:
Introduction

Menin is a scaffold protein that interacts with various transcriptional regulators and partner proteins to promote tumorigenesis in a context-dependent manner. Menin drives oncogenic signaling by regulating expression of genes such as HOXA9 and MEIS1 and is also known to play a key role in MYC-mediated transcriptional activities. BMF-219 is a highly selective, potent, orally bioavailable, small molecule covalent inhibitor of menin. We previously reported the ability of BMF-219 to modulate MYC expression and exhibit high potency against Double HIT Lymphoma (DHL) DLBCL (Diffuse Large B Cell Lymphoma) preclinical models.

Methods
In the current study we demonstrate the anti-tumor activity of BMF-219 in multiple myeloma (MM), and Double/Triple Hit Lymphoma (DHL/THL) and Double Expressor Lymphoma (DEL) high-grade B-cell lymphomas (HGBCL) preclinical models harboring various mutational backgrounds. Additionally, we provide mechanistic evidence for direct inhibition of menin protein, in cell line models representing MM, DHL and DEL.

Results

BMF-219 exhibited high potency in THL and DEL cell lines (IC50 = 0.27 μM and 0.37 μM, respectively), achieving >90% growth inhibition as single agent. BMF-219 was multi-fold more potent and exerted dramatically greater growth inhibition compared to clinical reversible menin inhibitors in all DLBCL cell lines tested, including an expanded panel of DHL cell lines. In ex vivo studies, an R-CHOP refractory THL patient sample and an R-EPOCH refractory MYC-amplified DLBCL patient sample were highly sensitive to BMF-219 treatment (IC50 = 0.15 μM and 0.2 μM, respectively) and demonstrated complete growth inhibition at 1 μM exposure. In contrast, two clinical reversible menin inhibitors demonstrated much lower potency (IC50 = ~1 μM to >10 μM). MM cell lines harboring mutations in TP53, KRAS and NRAS were all sensitive to BMF-219 with growth inhibition IC50 values in the range of 0.25 μM to 0.5 μM and achieved 100% inhibition at 1 μM. Notably, BMF-219 demonstrated single-agent efficacy (IC50 = 0.1 μM to 0.3 μM) against a panel of newly diagnosed and R/R ex vivo MM samples, including a p53-deleted clinical profile. Mechanistically, BMF-219 induced a reduction in menin protein levels, the direct target of this covalent inhibitor. The dose-dependent reduction in menin protein across the collection of MM and DLBCL cell lines with varying cytogenetic and mutational backgrounds will be discussed. Analysis of additional proteins modulated by BMF-219 in these cell line models will also be addressed.

Conclusions:

Collectively, our data demonstrate the novel and robust anti-tumor activity of BMF-219 in HGBCL and MM preclinical models that represent categories of high unmet need. BMF-219 exhibits multi-fold higher potency and complete growth inhibition in these preclinical models compared to clinical reversible menin inhibitors, demonstrating its unique anti-tumor potential in these cancers.

Poster P-269: COVALENT-101: A Phase 1 study of BMF-219, a novel oral covalent menin inhibitor, in patients with relapsed/refractory (R/R) acute leukemia, diffuse large B-cell lymphoma, and multiple myeloma

Abstract Text:
Introduction

Trial in Progress
Background: Menin, a protein involved in transcriptional regulation, impacting cell cycle control, apoptosis, and DNA damage repair, plays a direct role in oncogenic signaling in multiple cancers. Inhibition of menin is a novel approach to cancer treatment. Preclinical data of BMF-219, a highly selective, orally bioavailable, small-molecule covalent inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling in vitro and in vivo. BMF-219 exhibited a strong anti-proliferative effect on various menin-dependent acute myeloid leukemia (AML) cell lines, diffuse large B-cell lymphoma (DLBCL) lines representing Double/Triple Hit Lymphoma (DHL/THL) & Double Expressor Lymphoma (DEL), and MM cell lines with diverse mutational backgrounds. BMF-219 also showed high potency ex vivo in patient samples from MLL-rearranged and NPM1-mutant AML, THL and MYC-amplified DLBCL, and bone marrow mononuclear cells from treatment-naive and R/R MM.

Methods
COVALENT-101 (BF-MNN-101; NCT05153330) is a prospective, open-label, multi-cohort, non-randomized, multicenter Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of once daily oral BMF-219 in patients with R/R acute leukemia (AL), DLBCL, and MM who have received or are ineligible for standard therapy. Utilizing an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts independently for each indication until 1 subject experiences either a ≥ Grade 2 related adverse event or dose limiting toxicity (DLT). At that point, the cohort will switch to a classical "3 + 3" design. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts for each indication will enroll patients to obtain further safety and efficacy data.

Patients with R/R AL who have failed or are ineligible for any standard therapies, R/R DLBCL following ≥ 2 but ≤ 5 prior therapies, and R/R MM who have received ≥ 3 therapies are eligible. Patients must have ECOG PS ≤ 2, and adequate organ function. Key exclusion criteria include known CNS disease involvement, prior menin inhibitor therapy, and clinically significant cardiovascular disease.

Results
The primary objective is to determine independently for each cohort/indication the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and assessment of its antitumor activity based on best overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and time to progression (TTP) per disease specific response criteria as assessed by the investigator. Food-effect studies will be performed in DLBCL and MM patients at certain dose levels.

Conclusions
Enrollment in COVALENT-101 commenced in January 2022.