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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"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.

On August 26, 2022 InDex Pharmaceuticals Holding AB (publ) reported that interim report January – June 2022 (Press release, InDex Pharmaceuticals, AUG 26, 2022, View Source [SID1234618701])

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Period April – June 2022
Net sales amounted to SEK 0.0 (0.0) million
Operating loss amounted to SEK –21.7 (–42.6) million
Result after tax amounted to SEK –21.7 (–42.6) million, corresponding to SEK –0.04 per share (–0.08) before and after dilution
Cash flow from operating activities amounted to SEK –53.0 (–45.1) million
Period January – June 2022
Net sales amounted to SEK 0.0 (0.0) million
Operating loss amounted to SEK –40.6 (–51.9) million
Result after tax amounted to SEK –40.6 (–52.0) million, corresponding to SEK –0.08 per share (–0.11) before and after dilution
Cash flow from operating activities amounted to SEK –71.4 (–53.6) million
Cash and cash equivalents at the end of the period amounted to SEK 395.6 (478.8) million
Number of employees at the end of the period was 7 (7)
Number of shares at the end of the period was 532,687,650
All comparative amounts in brackets refer to the outcome during the corresponding period 2021.

Significant events during the quarter
Peter Zerhouni stepped down as CEO of InDex. The company’s CFO Johan Giléus has been appointed acting CEO while a new CEO is being recruited
InDex strengthened the organisation with Eva Arlander as Chief Development Officer and presented a new management team
Significant events after the reporting period
InDex got a new patent for cobitolimod granted in Europe
Other events
InDex participated with a booth at the Digestive Disease Week (DDW) in San Diego
The annual general meeting in InDex Pharmaceuticals Holding AB was held on June 1, 2022
CEO statement
We remain fully focused on the implementation of the phase III study CONCLUDE, which evaluates the drug candidate cobitolimod as a new and unique treatment for patients with moderate to severe left-sided ulcerative colitis. The study is progressing according to plan, i.e. we expect the results to be available during H2 2023. We see great interest in the study and cobitolimod when we, together with our experienced CRO, Parexel Biotech, visit the participating clinics. In the beginning of July, we invited all CRAs of the study, i.e. Parexel’s employees who have ongoing contact with the participating clinics, to a two-day meeting in Stockholm. The purpose of the meeting was to jointly discuss the CONCLUDE study and the benefits of cobitolimod.

At the end of June, the planned consultation meeting with the Japanese regulatory authority, PMDA, was held. It was very encouraging that the PMDA supports our proposed clinical development plan for cobitolimod and that they agree to include Japanese patients in our second induction study in the phase III program, without conducting any specific clinical studies in Japanese subjects. In addition, complementary pharmacokinetic data for cobitolimod in Japanese patients can be collected during the remaining phase III program. This is a unique decision by the PMDA, indicating great potential for cobitolimod and a need for new treatment options that can help more patients with moderate to severe ulcerative colitis. In addition, the positive feedback from PMDA is advantageous for discussions with potential candidates for strategic collaborations in Japan.

At the end of May, InDex participated with a booth at the premier medical congress in the world in gastroenterology, the Digestive Disease Week (DDW) in San Diego, USA. Our participation was very successful and resulted in many valuable contacts, and several new clinics expressed interest to join our phase III study with cobitolimod. We will take the experience with us when we now plan for our participation in the United European Gastroenterology Week (UEGW) in October.

In parallel with the global clinical phase III study CONCLUDE, InDex is conducting a smaller clinical pharmacokinetic study (PK study) with cobitolimod in Sweden. The patient recruitment in the PK study has gone faster than expected and the study is well underway. The aim of the study is to confirm that the systemic uptake of cobitolimod is limited, which has been shown in previous preclinical and clinical studies. The study will include at least 6 patients with moderate to severe ulcerative colitis treated with doses of 500 mg of cobitolimod administered rectally. A limited systemic uptake is a significant advantage compared to competing drugs for ulcerative colitis that act on the whole body and can cause severe side effects outside the inflamed colon.

In July, we announced that a new patent for cobitolimod has been granted in Europe. The patent provides additional protection for the use of cobitolimod in the treatment of inflammatory bowel disease. The patent provides an exclusivity period until August 2040, and further strengthens, broadens and extends our robust intellectual property position for cobitolimod in Europe. Corresponding patent applications have been filed in the strategically most important patent territories globally.

With great interest from the clinics for our phase III study and cobitolimod, our successful interactions with the Japanese regulatory authority, as well as with a strengthened patent portfolio, I look forward to an exciting and eventful fall where we will take important steps forward for InDex.

The full report is attached as a PDF and is available on the company’s website View Source

Publication
This information is information that InDex Pharmaceuticals Holding AB (publ) is obliged to make public pursuant to the EU Market Abuse Regulation (MAR). The information was submitted for publication through the agency of the contact person set out above at 8:00 CET on August 26, 2022.

On August 26, 2022 Patrys reported that the Olivia Newton-John Cancer Research Institute (ONJCRI) has been awarded a $100,000 Victorian State Government Victorian Medical Research Acceleration Fund (VMRAF) grant to support its research investigating the potential for PAT-DX1 and PAT-DX3 to be incorporated into new treatments for metastatic breast cancer (Press release, Patrys, AUG 26, 2022, View Source [SID1234618662]).

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The research program, led by Professor Robin Anderson, Head of ONJCRI’s Translational Breast Cancer Program and Metastasis Research Laboratory, will evaluate the ability of PAT-DX1 and PAT-DX3 to control tumour growth and metastasis in preclinical models of breast cancer. It will also evaluate in animal models the use of PAT-DX1 and PAT-DX3, in combination with DNA damaging agents such as radiation and chemotherapy, for treating triple negative breast cancer.

Patrys CEO and Managing Director, Dr James Campbell, was delighted to share this news today:

"We are delighted that this VMRAF grant will allow us to expand our ongoing research program with Professor Anderson at the internationally-recognised ONJCRI. We have recently discovered that PAT-DX1 inhibits the formation of NETs, molecules that are implicated in the progression and metastasis in some cancers, and this new grant focused on metastatic breast cancer is an exciting addition to our programs."