On December 11, 2023 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported the presentation of preclinical data from the Company’s highly differentiated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) program in an oral presentation at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, HotSpot Therapeutics, DEC 11, 2023, View Source [SID1234638463]).

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MALT1 is a component of the CARD11-BCL10-MALT1 (CBM) protein complex, which serves as a key regulator of NFkB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies, including Non-Hodgkin’s lymphoma, as well as other lymphomas and selected solid tumors. Leveraging our proprietary Smart Allostery platform, HotSpot has developed potential first-in-class small molecules designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NFkB pathway, while sparing MALT1’s protease function.

"MALT1’s therapeutic potential rests in the role of its scaffolding function to regulate the NFkB pathway, which is implicated in a broad range of hematological and solid tumors," said Geraldine Harriman, Co-Founder and Chief Scientific Officer of HotSpot. "Using our Smart Allostery platform, HotSpot has delivered a potential first-in-class allosteric inhibitor, HST-1021, that is designed to potently and selectively inhibit MALT1’s scaffolding function. HST-1021’s pharmacological attributes suggest therapeutic potential, as these preclinical data demonstrated in vivo tumor growth inhibition without any observed negative impact on other immune functions. We look forward to providing additional updates as we advance our program, as we plan to file an Investigational New Drug (IND) application for HST-1021 in 2024."

The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 inhibitor development candidate:

Using the Smart Allostery platform, HotSpot elucidated and drugged a natural hotspot on MALT1 that potently and selectively inhibited MALT1’s scaffolding function, while sparing MALT1’s protease function.
In several B-cell lymphoma xenograft models, HST-1021 demonstrated robust, dose-dependent tumor growth inhibition (TGI), including in both MALT1 protease-inhibitor sensitive ABC-DLBCL and MALT1 protease-resistant NFkB-driven DLBCL models.
In contrast to MALT1 protease inhibitors, HotSpot’s scaffolding inhibitor did not deplete Treg cells or suppress T-cell activation in vivo, which HotSpot believes supports the potential for clinical mitigation of the risk of autoimmune disease resulting from chronic MALT1 protease function inhibition and would allow for broad combination use.

On December 11, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers harboring ESR1 mutations, reported that results of its two Phase 2 Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) studies were published in Annals of Oncology, the peer-reviewed journal of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) and the Japanese Society of Medical Oncology (Press release, Sermonix Pharmaceuticals, DEC 11, 2023, View Source [SID1234638500]).

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The articles, published online and with open access in the December edition of the journal, are as follows:

Lasofoxifene versus fulvestrant for ER+/HER2- advanced breast cancer with an ESR1 mutation: Results from the randomized, phase 2 ELAINE 1 trial
Open-label, phase 2, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after progression on prior therapies: ELAINE 2
"These Phase 2 ELAINE studies ideally position Sermonix for the initiated global registrational ELAINE-3, Phase 3 study comparing lasofoxifene in combination with abemaciclib versus fulvestrant plus abemaciclib," said Dr. David Portman, Sermonix founder and chief executive officer. "We are excited to share the results of our recent studies in this prestigious journal and to continue our path toward potential approval and commercial development of our novel targeted endocrine therapy."

Top-line data for ELAINE-1, a study of postmenopausal women with locally advanced or metastatic estrogen receptor-positive (ER+)/HER2- breast cancer with an ESR1 mutation, were shared as an oral presentation at the 2022 ESMO (Free ESMO Whitepaper) Congress. The study demonstrated that lasofoxifene, a novel targeted and tissue-selective oral endocrine therapy that acts as an ER antagonist at the breast, numerically prolonged median progression-free survival (PFS) compared with fulvestrant (5.6 months vs. 3.7 months; P=0.138) in metastatic breast cancer patients with ESR1 mutations who had progressed taking a prior aromatase inhibitor (AI) and CDK4/6i, with a favorable safety profile. Also, 30.7% of patients on lasofoxifene achieved a PFS of 12 months compared to 14.1% on fulvestrant.

ELAINE-1 also demonstrated an objective response rate (ORR) of 13.3% for lasofoxifene compared to 2.9% for fulvestrant (P=0.124), and saw on lasofoxifene the first-ever known finding of a durable complete response – ongoing at 2.5 years – that could be characterized as complete clinical remission in a metastatic ER+/HER2- breast cancer patient with an ESR1 mutation after prior CDK4/6 inhibitor treatment and subsequent treatment with a single-agent hormonal therapy.

An exploratory ELAINE-1 analysis, shared in March 2023 at the International Society for the Study of Women’s Sexual Health (ISSWSH) Annual Meeting, found in patients presenting at baseline with moderate to severe vaginal and vulvar dryness/pain on a validated measurement scale that lasofoxifene numerically improved these symptoms compared to fulvestrant.

ELAINE-2 (NCT04432454), an open-label study of lasofoxifene in combination with Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib, evaluated 29 heavily pre-treated women with ER+/HER2- locally advanced or metastatic breast cancer and an ESR1 mutation. Results were initially shared at a poster discussion session during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and updated in June at ASCO (Free ASCO Whitepaper) 2023.

The primary endpoint for ELAINE-2 was safety/tolerability, with secondary endpoints including PFS and ORR. With patient follow-up through Jan. 31, 2023, the combination of lasofoxifene and abemaciclib continued to be well-tolerated, with clinically meaningful efficacy in women with ER+/HER2- metastatic breast cancer and an ESR1 mutation. The PFS, a median of 13 months, and ORR of 56% were promising.

"Lasofoxifene has demonstrated compelling anti-tumor activity against tumors with increasingly prevalent ESR1 mutations, and potential benefit on quality of life with respect to vaginal and sexual health," said Paul Plourde, M.D., vice president of oncology clinical development for Sermonix. "We look forward to the results of ELAINE-3, and a greater understanding of lasofoxifene’s potential."

An accompanying invited (closed-access) editorial by Dr. Seth Wander of Massachusetts General Hospital addresses the context of these two seminal trials in the current and future treatment landscape of ER+/HER2- advanced breast cancer.

Annals of Oncology provides rapid and efficient peer-review publications on innovative cancer treatments or translational work related to oncology and precision medicine.

To learn more about Sermonix Pharmaceuticals and lasofoxifene, visit SermonixPharma.com. To learn more about the ELAINE studies, visit elainestudy.com.

About Lasofoxifene
Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with a CDK4/6 inhibitor in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies, with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue selective oral endocrine therapy could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

On December 11, 2023 Electra Therapeutics, Inc., a clinical stage biotechnology company developing antibody therapies against novel targets for immunological diseases and cancer, reported the presentation of the first clinical data for ELA026, the company’s lead candidate in development for the treatment of secondary hemophagocytic lymphohistiocytosis (sHLH), a life-threatening inflammatory disease (Press release, Electra Therapeutics, DEC 11, 2023, View Source [SID1234638415]). The results were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting being held in San Diego, California, December 9-12, 2023.

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Data from ten sHLH patients in the ongoing Phase 1b clinical study showed favorable safety results and overall response rate (ORR) of 70% in all patients dosed with ELA026. An ORR of 88% was observed in the eight patients with evaluable data. The majority of enrolled patients were difficult-to-treat, malignancy-associated HLH and displayed poor prognostic clinical and biomarker features at baseline.

ELA026 is a monoclonal antibody that targets signal regulatory protein (SIRP)-α/β1/γ on the cell surface of myeloid and T cells, the pathological immune cells that induce the hyperinflammatory response in sHLH. The Phase 1b study is an ongoing open-label, multi-dose, single-arm, multicenter study designed to evaluate the safety and efficacy of ELA026, assess biomarkers and identify a dose for Phase 2/3 testing (ClinicalTrials.gov identifier: NCT05416307).

"sHLH is a life threatening and challenging disease that is devastating for patients and has no approved treatment options," said Swaminathan P. Iyer, MD, Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. "The patients enrolled in the study thus far are among the sHLH patient subtypes with the worst prognosis, and we are encouraged by this data showing that ELA026 is well tolerated and leads to promising responses."

Study Results Presented at ASH (Free ASH Whitepaper) Annual Meeting
The poster presentation at ASH (Free ASH Whitepaper), titled "A Phase 1b Study of ELA026, a Monoclonal Antibody Targeting Signal Regulatory Protein-α/β1/γ, in Patients with Newly Diagnosed and Previously Treated Secondary Hemophagocytic Lymphohistiocytosis," was presented by the lead author, Abhishek Maiti, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. The data describe an analysis of ten patients in the first two cohorts of the ongoing clinical study, including the following highlights:

Of the ten enrolled patients, eight were associated with a malignancy trigger and two had an unknown trigger. Five patients had relapsed/refractory sHLH.
Overall, ELA026 was well tolerated with a favorable safety profile in the study.
ELA026 achieved ORR of 70% in ten patients dosed and ORR of 88% in eight patients with evaluable data, despite poor baseline prognostic and clinical indicators related to sHLH.
Three patients with ≥ 90% reduction of ferritin and sCD25 from baseline or peak values also had tumor complete responses, including a patient with peripheral T-cell lymphoma refractory to chemotherapy.
ELA026 reduced peripheral monocyte and lymphocyte counts and resulted in early and rapid decrease in c-reactive protein (CRP) and sHLH-associated cytokines and biomarkers.
"We are pleased to present these promising first clinical results for ELA026 in the treatment of sHLH patients," Kim-Hien Dao, DO, PhD, Vice President, Head of Clinical Development at Electra. "We are extremely encouraged by the data from the first two cohorts, and we look forward to continuing enrollment for this study as we advance the ELA026 clinical program."

About Secondary Hemophagocytic Lymphohistiocytosis (sHLH)
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory condition for which there is no approved treatment. It can be triggered by cancer (malignancy-associated HLH, or mHLH), infections, or autoimmune disease. sHLH is associated with a systemic inflammatory response for which patients require immediate and aggressive treatment with intensive care. Without treatment, patients may experience multiple organ failure and death. sHLH has a high mortality rate during the first months of diagnosis, with mHLH patients having the poorest outcomes.

On December 11, 2023 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs, for hard-to-treat tumors and viruses, reported the presentation of preliminary efficacy findings from the Company’s ongoing European Phase 1B/2 clinical trial evaluating Annamycin for the treatment of acute myeloid leukemia or AML (MB-106) to key opinion leaders and current investigators at a meeting held in conjunction with the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition (ASH) (Free ASH Whitepaper) in San Diego on December 10, 2023 (Press release, Moleculin, DEC 11, 2023, View Source [SID1234638431]). Additionally, the Company will have a paper published on its MB-106 clinical trial as part of ASH (Free ASH Whitepaper). A link will be provided on the Company’s website once this publication is available online.

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The KOL presentation included an update to the positive preliminary efficacy findings previously reported on MB-106. To date, among patients who had an evaluable post treatment bone marrow biopsy, or who dropped out due to an adverse event (AE), there have been 4 complete responses (CR’s) or 36% of the intent to treat (ITT) subjects (n=11) and 44% of the subjects treated (dosed with Annamycin) (n=9). Two subjects experienced adverse events and were not dosed with one being an allergic reaction to Annamycin, the first the Company has seen in over 70 subjects dosed in the Company’s multiple Annamycin clinical trials; the second dropout was due to an allergic reaction to cytarabine. There continues to be no evidence of cardiotoxicity as measured by ejection fraction, strain analyses, ECGs, and cardiac biomarkers including Troponin-I and T in MB-106.

"We believe that our growing body of preliminary clinical data demonstrated by Annamycin in the treatment of patients with AML continues to be highly encouraging and bolsters our confidence in its potential to be a meaningful option for patients," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin. "While still preliminary, the complete response rate we are seeing continues to reflect what we believe is an efficacy level greater than we need for eventual approval of Annamycin. Our recruitment rate continues to exceed expectations and we are optimistic that we will be fully recruited within the next few months."

Currently, the median age of subjects in MB-106 is 69 years with a median number of prior therapies for AML of one. While two of the Company’s complete responders are too recent to measure durability, the Company is seeing durability as high as 8 months and climbing, and the Company has yet to see any relapses of CR’s experienced to date in the trial. The Company has recruited 16 subjects to date with 2 subjects withdrawing from the trial due to adverse events and 3 other subjects having received treatment and not having the bone marrow aspirate fully evaluated.

Additionally, one of the subjects treated but not evaluated experienced a grade 4 serious adverse event (SAE) with septic shock caused by Escherichia coli (E. coli) and was reported on a Suspect Adverse Reaction Report to the appropriate regulatory bodies and ethics committees. The subject was treated for the infection, the SAE is still reported as "ongoing," and the subject is recovering. This subject will be evaluated until resolution of the SAE and will be assessed for efficacy per protocol.

The presentation to the KOL’s mentioned above will be posted on the Company’s website and filed on Form 8-K with the Securities and Exchange Commission.

Annamycin currently has Fast Track Status and Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of relapsed or refractory acute myeloid leukemia, in addition to Orphan Drug Designation for the treatment of soft tissue sarcoma. For more information about the MB-106 Phase 1B/2 trial, visit clinicaltrialsregister.eu and reference EudraCT 2020-005493-10 or clinicaltrials.gov and reference NCT05319587.

About Annamycin

Annamycin is the Company’s next-generation anthracycline that has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin. Importantly, Annamycin has also demonstrated a lack of cardiotoxicity in multiple early-stage human clinical trials, including ongoing trials for the treatment of AML and STS lung metastases. For that reason, although additional data will be necessary, the Company believes Annamycin may not face the same usage limitations imposed on doxorubicin, one of the most common currently approved anthracyclines. Annamycin is currently in development for the treatment of AML and STS lung metastases and the Company believes the drug may have the potential to treat additional indications.

About "Complete Remission"

Per the American Cancer Society, the goal of treatment for acute myeloid leukemia is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way. Source: View Source

On December 11, 2023 Laekna (2105.HK), a clinical-stage biotechnology company, reported the results of a phase Ib study to evaluate the efficacy and safety of afuresertib plus fulvestrant in patients with locally advanced or metastatic HR+/HER2- breast cancer who failed standard of care therapies at the 2023 San Antonio Breast Cancer Symposium (SABCS) on December 8 (Press release, Laekna Therapeutics, DEC 11, 2023, View Source;laekna-reports-afuresertib-phase-ib-breast-cancer-study-results-302011286.html [SID1234638464]).

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From May 2022 to April 2023, 20 patients (19 female and 1 male) with locally advanced or metastatic HR+/HER2- breast cancer who had failed 1-2 lines of endocrine therapy were enrolled in the Phase Ib study. The median duration of follow-up was 11 months.

As of October 16, 2023, the main study results are as follows:

– 70% of the patients were previously treated with CDK4/6 inhibitors.

– Among the total patient population, the confirmed ORR was 30% (95% CI, 11.9, 54.3), the median PFS was 7.3 months (95% CI, 3.7, NE). The disease control rate (DCR) was 80%.

– Among the 11 patients with specific biomarker alterations (PIK3CA/AKT1/PTEN), the confirmed objective response rate was 45.4% (95% CI, 16.7, 76.6), the disease control rate was 82%, and the median PFS was 7.3 months (95% CI, 3.6, 8.2).

– Among the 17 Chinese patients, the confirmed ORR was 29.4% (95% CI, 10.3, 60.0), the disease control rate was 82.4%, and the median PFS was 7.3 months (95% CI, 3.6, 8.2).

– The results demonstrated a well-tolerated safety profile of afuresertib plus fulvestrant. No dose modification was required during the safety run-in period. No patient discontinued treatment due to TEAE. No serious adverse event (SAE) was reported.

Investigators concluded that the combination therapy of afuresertib and fulvestrant has shown promising efficacy with a well-tolerated safety profile, supporting further evaluation in the upcoming Phase III part of the study.

Academician Binghe Xu, the lead investigator of the study, said: "While therapies for breast cancer are increasing, the treatment of drug resistance remains one of the clinical challenges. With the approval of the world’s first AKT inhibitor last month, patients with locally advanced or metastatic HR+/HER2- breast cancer now have new hope. The Phase Ib data of the combination therapy of afuresertib and fulvestrant are promising. I look forward to the next Phase III study of afuresertib in breast cancer."

"Biomarkers of response and/or resistance to endocrine-based therapies has become a prominent topic in the field of breast cancer treatment. It is also the central theme of the ‘Poster Spotlight Session’ in which our study was presented," said Dr. Yong Yue, Chief Medical Officer of Laekna. "Compared with the PFS data of 3-4 months for fulvestrant monotherapy[1], the median PFS of afuresertib plus fulvestrant is significantly increased to 7.3 months, with a favorable safety profile."

Lakena has initiated the Phase III pivotal trial of afuresertib plus fulvestrant in the treatment of HR+/HER2- breast cancer. The company strives to bring new hope to patients.

Notes

Breast cancer

The latest data released by the International Agency for Research on Cancer (IARC) of the World Health Organization show that the number of new cases of breast cancer in 2020 reached 2.26 million worldwide, surpassing lung cancer for the first time and becoming the world’s most prevalent cancer with 685,000 deaths. The latest epidemic data of malignant tumors in China also show that breast cancer has ranked first among women, with about 420,000 new cases each year[2].

Approximately 69% of breast cancer patients in the United States are considered HR+/HER2[3], and the proportion of this subtype among Chinese patients is 62%[4]. Although most patients with this type of breast cancer initially benefit from first/second-line endocrine ± CDK4/6 inhibitors and/or chemotherapy, most may develop drug resistance after a period, leading to treatment failure.

With further research on AKT, it has been demonstrated that factors such as PTEN loss and AKT/PIK3CA mutation can lead to excessive activation of the AKT signaling pathway, resulting in the occurrence, development, and drug resistance of tumors, especially prevalent in HR+ breast cancer. AKT has consequently emerged as a popular target for treating tumors.

Afuresertib

Afuresertib (LAE002) is an AKT inhibitor developed by Laekna. Laekna has initiated multiple clinical studies of combination therapies with Afuresertib in patients with PROC, HR+/HER2− breast cancer, mCRPC, TNBC, PD-1-resistant cervical cancer, and endometrial cancer.