On November 12, 2021 MingSight Pharmaceuticals reported the close of a pre-Series B round of $20M, led by Kaitai Capital (Press release, MingSight Pharmaceuticals, NOV 12, 2021, View Source [SID1234595475]). The proceeds will be used for the clinical development of MS-553, a new generation inhibitor of protein kinase C (PKC) beta for the treatment of Chronic lymphocytic Leukemia (CLL) and Diabetic Macular Edema (DME).

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"We greatly appreciate the trust and support of our investors," said Kai Zhang, MD, MBA, CEO and Co-founder of MingSight. "This investment will facilitate the rapid development of the MS-553 program. We are very excited to see MS-553 demonstrate strong efficacy and safety data in our CLL and DME trials. We will work hard to bring forward a truly differentiated product to market to improve upon the treatment options for these serious diseases."

Michael Niesman, Ph.D., CSO and Co-founder of MingSight, said: "We are very glad that our investors share our excitement about the promise of MS-553. Many companies have been convinced of the importance of Protein Kinase C (PKC) in serious diseases like CLL and diabetic eye disease. Because of the major innovations of MS-553 compared to previous pan-PKC inhibitors, we have been able to generate data demonstrating proof of mechanism and significant activity in CLL and DME where other PKC inhibitors have failed. We look forward to working with Kaitai and our other investors to accelerate the development of this unique compound."

Zehua Huang, Partner at Kaitai Capital, said: "We believe MingSight has a world class team and advisory group, and its program is well positioned for the future marketplace. With initial efficacy in CLL patients with C481S and PLCG2 mutations, MS-553 showed distinct promise of its market potential. MS-553 has the potential to improve upon the standard of care therapies for CLL as a single agent or in combination with BTK inhibitors, BCL-2 inhibitors, or other agents. As for its application in DME treatment, MS-553 has the potential to provide an alternative, non-invasive approach to ocular injections of anti-VEGF agents. A key characteristic of MS-553 is its preferential distribution to the retina following oral administration. The initial clinical data of MS-553 in DME patients such as BCVA and CRT readings are very impressive. We are confident that MingSight will succeed in rapidly developing MS-553 and bringing its benefits to patients worldwide."

About MS-553

MS-553 is an investigational drug candidate and a new generation PKC beta inhibitor. It differentiates from the previous generation of pan-PKC inhibitors with its novel chemotype and significant advantages in selectivity, safety, and PK properties.

MS-553 is a potentially the only B-cell receptor inhibitor in clinical development that can address the BTK resistant mutations in both BTK and PLCG2. Its mechanism of action is also synergistic or additive to other approaches that constitute the current standard of care of CLL.

MS-553 also has the potential, if approved, to become the first oral DME therapy with anti-VEGF like efficacy. MS-553 has the unique PK property of preferential distribution to the retina and its mechanism of action addresses both the aberrant VEGF signaling and the inflammation that are characteristics of DME.

In a phase 1/2 study, MS-553 demonstrated promising efficacy and safety in CLL patients who have failed BTK inhibitors including those with C481S and PLCG2 resistant mutations. MS-553 also demonstrated clinical activities including reduction of retinal thickness and improvement of visual acuity in a phase 1b trial of DME patients.

On November 12, 2021 Ankyra Therapeutics, a company developing cancer therapies based on tumor localized immune potentiating agents that boost anti-tumor immune responses, reported the closing of a $45 million Series B financing (Press release, Ankyra Therapeutics, NOV 12, 2021, View Source [SID1234595474]). Proceeds from the financing will be used to progress Ankyra’s lead molecule, ANK-101 through Investigational New Drug (IND) enabling studies and into Phase 1 clinical trials, as well as advance additional cytokine programs .

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Several new investors including Borealis Ventures, Fidelity Management & Research Company LLC, GV, Sands Capital Ventures, and Spring Mountain Capital joined existing investors Polaris Partners and Mithril Capital. In connection with the closing of the financing, Phil Ferneau of Borealis Ventures will join the Ankyra Therapeutics Board of Directors.

Ankyra Therapeutics has developed a highly differentiated technology platform that significantly expands the therapeutic window of immune-modulating oncology drugs by forming an extended drug depot following intratumoral administration. The company is rapidly progressing its lead molecule into clinical studies.

"We are fortunate to have the support of investors who share our vision of developing tumor-localized cytokines and other immune therapies to treat cancer with enhanced efficacy and safety," said Tillman Gerngross, Co-founder, and Executive Chairman of Ankyra Therapeutics. "This is an important moment for the company as we work to bring our first development program through IND and into Phase 1 clinical trials, and we are excited to bring Howard Kaufman, and his proven track record of successful clinical development, to the Ankyra team."

Dr. Kaufman has been a leading authority on tumor immunotherapy and oncolytic viruses for the treatment of melanoma. He led the first successful phase III trial of an intratumoral agent resulting in FDA approval for the treatment of melanoma. He served as president of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) from 2014-2016. Prior to joining Ankyra, Dr. Kaufman was Head of Research and Development at Immuneering Corporation. Dr. Kaufman also served as chief medical officer at Replimune Group, Inc., where he oversaw the strategic development of the company’s pipeline.

"Systemic treatment with cytokines and other immune agonists has been limited by broad immune activation and systemic toxicity. Intratumoral administration can improve the therapeutic window of immune activating drugs, but the approach has been limited by rapid clearance from the tumor microenvironment. There is a significant need for approaches that improve the therapeutic window and reduce the frequency of dosing. Ankyra’s approach is a true platform that can extend drug bioavailabity and enhance anti-tumor immune responses, while avoiding systemic adverse events. We look forward to extending our preclinical observations into cancer patients in our upcoming Phase 1 clinical trial," stated Howard Kaufman, Chief Medical Officer of Ankyra.

On November 12, 2021 Epizyme, Inc. (Nasdaq: EPZM), a fully integrated, commercial-stage biopharmaceutical company developing and delivering novel epigenetic therapies, reported that Grant Bogle, President and Chief Executive Officer of Epizyme, will present at the Jefferies London Healthcare Conference (Press release, Epizyme, NOV 12, 2021, View Source [SID1234595473]). A pre-recorded fireside chat will be available to play on demand starting at 3:00am EST (8:00am GMT) on November 18, 2021.

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A live webcast of the fireside chat will be available in the investor section of the Company’s website at www.epizyme.com and will be archived for 60 days following the presentation.

On November 12, 2021 Scholar Rock (NASDAQ: SRRK), a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, reported that initial clinical data from Part A of its DRAGON Phase 1 proof-of-concept trial (NCT04291079) at the ongoing 36th Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (November 10-14, 2021), which supported dose selection and advancement into Part B (Press release, Scholar Rock, NOV 12, 2021, View Source;L-1-for-the-Treatment-of-Solid-Tumors—-Announces-Advancement-into-Part-B [SID1234595472]). The DRAGON trial is investigating SRK-181, a selective inhibitor of TGFβ1 activation, in patients with locally advanced or metastatic solid tumors that have shown primary resistance to checkpoint inhibitor therapies.

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The main objectives of DRAGON Part A are to evaluate the safety and tolerability of SRK-181 alone (Part A1) or in combination with anti-PD-(L)1 checkpoint inhibitor therapy (Part A2) and to determine the recommended dose for the Part B dose expansion phase. Part A1 enrolled patients who have experienced treatment failure from available standard of care therapy, and Part A2 enrolled patients who did not respond to prior anti-PD-(L)1 therapy. Based on the safety and pharmacokinetic data from Part A, Scholar Rock has initiated Part B, which is evaluating SRK-181 dosed 1500 mg every three weeks (Q3W) in patients receiving an approved anti-PD-(L)1 therapy dosed Q3W and 1000 mg every two weeks (Q2W) in patients receiving an approved anti-PD-(L)1 therapy dosed Q2W.

"While checkpoint inhibitor therapy has definitely advanced the treatment of cancer, resistance to this type of therapy remains a very significant unmet medical need," said Nagesh Mahanthappa, Ph.D., Interim CEO. "We are excited that the DRAGON Part A results support moving forward in Part B with a dose of SRK-181 aimed at robustly suppressing TGFβ1 signaling, and look forward to advancing our program to test our hypothesis that SRK-181 can overcome resistance to checkpoint inhibitors thereby increasing the number of patients who may benefit from cancer immunotherapy."

Details for the virtual e-poster are as follows:

Title: First-in-Human Phase 1 Trial of SRK-181: A Latent TGFβ1 inhibitor, Alone or in Combination with Anti-PD-(L)1 Treatment in Patients with Advanced Solid Tumors (DRAGON trial) (#532). The full abstracts were made available on the SITC (Free SITC Whitepaper) website on November 9, 2021.
Time: Virtual e-posters will be on display on the SITC (Free SITC Whitepaper) 2021 virtual meeting platform starting November 12, 2021.
Highlights from the DRAGON Part A data presented at SITC (Free SITC Whitepaper) include:

As of September 7, 2021, 29 patients have been dosed in Part A of the trial. The median number of prior lines of therapy was 4 (range 1, 9) for Part A1 and 4 (range 2, 6) for Part A2.
As of October 12, 2021, no dose-limiting toxicities were observed with SRK-181 in Part A. Doses up to 3000 mg Q3W and 2000 mg Q2W as a monotherapy in Part A1 and 1600 mg Q3W in combination with anti-PD-(L)1 therapy in Part A2 have been evaluated.
The most common (>10%) treatment-emergent adverse events of any grade related to treatment were fatigue, decreased appetite, and nausea (Part A1) and rash maculo-papular (Part A2).
Preliminary data showed a pharmacokinetic (PK) profile of SRK-181 consistent with that which is generally observed for monoclonal antibodies.
Preliminary anti-tumor effects were assessed using RECIST1.1 and reported based upon local investigator reads:
Among 19 patients in Part A1 (monotherapy), eight patients had a best response of stable disease (SD). There were three patients with ovarian cancer in Part A1; each of these patients had stable disease, with tumor regression observed in two patients.
Among 10 patients in Part A2 (combination therapy), one patient with renal cell carcinoma (RCC) who had a lack of response to prior anti-PD-1 therapy had a partial response (PR) after treatment with SRK-181 dosed 800 mg Q3W in combination with the same anti-PD-1 therapy. In addition, four patients had a best response of SD.
The efficacy and safety of SRK-181 are being evaluated in DRAGON Part B. With early data anticipated to be available in 2022, Part B will enroll and dose patients in multiple proof of concept cohorts conducted in parallel, including urothelial carcinoma (UC), cutaneous melanoma (MEL), non-small cell lung cancer (NSCLC), as well as a miscellaneous cohort of other solid tumors. Another cohort focusing on patients with clear cell renal cell carcinoma (ccRCC) is being added based on emerging insights, including preliminary data from Part A. Each cohort will enroll up to 40 patients with locally advanced or metastatic solid tumors who have demonstrated primary resistance to anti-PD-(L)1 therapy. The ccRCC cohort will also explore the effects of SRK-181 in patients with relapsed response after anti-PD-(L)1 treatment. Patients in the UC, MEL, NSCLC and ccRCC cohorts will be treated with SRK-181 in combination with pembrolizumab, and patients in the miscellaneous solid tumor cohort will be treated with SRK-181 in combination with any approved anti-PD-(L)1 therapy.

The selection of the Part B dose was based upon safety and PK results from Part A. Patients receiving an approved anti-PD-(L)1 therapy dosed Q3W will be dosed with SRK-181 dosed 1500 mg Q3W, while patients receiving an approved anti-PD-(L)1 therapy dosed Q2W will be dosed with SRK-181 dosed 1000 mg Q2W. Drug exposures from these regimens are anticipated to exceed the levels hypothesized as needed for anti-tumor effects, as predicted from PK modeling and preclinical tumor model data.

"We are pleased by the Part A data, which have enabled the initiation of Part B with a dose regimen aimed at robustly testing the therapeutic hypothesis for SRK-181 in overcoming tumor resistance to anti-PD-(L)1 therapy," said Yung Chyung, M.D., CMO. "Part B has been specifically enriched with solid tumor types for which we believe there may be a higher potential for early efficacy signals on the basis of translational and preclinical insights."

About SRK-181
SRK-181 is a selective inhibitor of TGFβ1 activation and is an investigational product candidate being developed to overcome primary resistance to checkpoint inhibitor therapy, such as anti-PD-(L)1 antibodies. TGFβ1 is the predominant TGFβ isoform expressed in many human tumor types. Based on analyses of various human tumors that are resistant to anti-PD-(L)1 therapy, data suggest TGFβ1 is a key contributor to the immunosuppressive tumor microenvironment, excluding and preventing entry of cytotoxic T cells into the tumor, thereby inhibiting anti-tumor immunity (1). Scholar Rock believes SRK-181, which specifically targets the latent TGFβ1 isoform, has the potential to overcome this immune cell exclusion and induce tumor regression when administered in combination with anti-PD-(L)1 therapy while potentially avoiding toxicities associated with non-selective TGFβ inhibition. The DRAGON Phase 1 proof-of-concept clinical trial (NCT04291079) in patients with locally advanced or metastatic solid tumors is ongoing. The efficacy and safety of SRK-181 have not been established. SRK-181 has not been approved for any use by the FDA nor any other regulatory agency.

(1) Martin et al., Sci. Transl. Med. 12: 25 March 2020

On November 12, 2021 Aulos Bioscience, an immuno-oncology company working to revolutionize cancer care through the development of potentially best-in-class IL-2 therapeutics, reported that preclinical data for AU-007, a computationally evolved human antibody that leverages a highly differentiated approach to harnessing the power of IL-2 to eradicate solid tumors (Press release, Aulos Bioscience, NOV 12, 2021, View Source [SID1234595470]). Data were presented in a poster presentation at the 36th Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting.

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"These positive preclinical data demonstrate the ability of AU-007 to tip the balance toward immune activation and away from immune suppression by preventing IL-2 from binding to T regulatory cells," said Aron Knickerbocker, Aulos Bioscience’s chief executive officer. "While high-dose IL-2 has shown clinical benefit, associated toxicities have limited its therapeutic use. With AU-007, we are leveraging a mechanism of action unlike any other IL-2 therapeutic in development, with the potential for lower toxicity and a sustained anti-tumor response. Supported by these data, we are continuing to advance AU-007 into a Phase 1/2 clinical trial."

AU-007 mediates human immune activation by precisely blocking an epitope on IL-2 that binds to CD25. This action redirects IL-2 to promote T effector cell expansion through binding the IL-2 receptor CD122/132 dimer while uniquely breaking the IL-2 negative feedback loop and blocking T regulatory cell (Treg) expansion, which requires activation through the CD25-containing IL-2 receptor trimer (CD25/CD122/CD132). Aulos Bioscience presented data at SITC (Free SITC Whitepaper) establishing both the specificity and activity of AU-007. In preclinical studies, AU-007 was shown to bind human IL-2 with picomolar affinity and completely inhibit its binding to CD25 while preserving binding to CD122/CD132. When evaluated for activity in mouse models of cancer, administration of AU-007 complexed with human IL-2 resulted in expansion of CD8+ T effector cells, NK cells and NKT cells in a dose-dependent manner, but had no effect on the expansion of CD4+ Tregs. Additionally, AU-007 was shown to inhibit downstream signaling of IL-2 on human CD4+ Tregs, as measured by STAT phosphorylation, in a dose-dependent manner, but did not affect IL-2 signaling on human CD8+ T effector cells, NK cells and NKT cells.

Utilizing human peripheral blood mononuclear cells (PBMCs) activated only with anti-CD3/anti-CD28 co-stimulation, AU-007, but not an isotype control antibody, inhibited the proliferation of Tregs, indicating that AU-007 can capture endogenous IL-2 and prevent the Treg cell expansion negative feedback loop. By comparison, no inhibition of CD8+ T effector cell, CD4+ T effector cell, NK cell and NKT cell proliferation was observed under the same conditions. In murine models, AU-007 also demonstrated tumor growth inhibition in multiple cancers. AU-007 has been shown to be safe and well tolerated in primate toxicology studies (data not presented).

The poster presentation is available on the Aulos Bioscience website.

About AU-007
AU-007 is a computationally evolved, human IgG1 monoclonal antibody that is highly selective to the CD25-binding portion of IL-2. With a mechanism of action unlike any other IL-2 therapeutic in development, AU-007 leverages the body’s own IL-2 to reinforce anti-tumor immune effects. This is achieved by preventing IL-2 secreted by T effector cells from binding to trimeric receptors on T regulatory cells while still allowing IL-2 to bind and expand T effector cells. This prevents the negative feedback loop caused by other IL-2-based treatments and biases the immune system toward activation over suppression. AU-007 also prevents IL-2 from binding to trimeric receptors on vasculature and pulmonary endothelium, which may significantly reduce the vascular leak syndrome and pulmonary edema associated with high-dose IL-2 therapy.