On June 11, 2020 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) reported that data related to TAVALISSE (fostamatinib disodium hexahydrate) tablets will be highlighted in a presentation at the Virtual Edition of the 25th EHA (Free EHA Whitepaper) Annual Congress taking place June 11-21, 2020 (Press release, Rigel, JUN 11, 2020, View Source [SID1234561019]). The presentation will be made available on the event’s website at www.ehaweb.org/congress/ on Friday, June 12 at 8:30 am CEST.

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In this previously presented post-hoc analysis, 32 patients received TAVALISSE as a second-line therapy, and 78% (25/32) achieved ≥1 platelet count of ≥50,000/µL (without rescue therapy). Adverse events were manageable and consistent with those previously reported with fostamatinib.

Fostamatinib disodium hexahydrate is an oral drug designed to inhibit spleen tyrosine kinase (SYK), a key signaling component of the body’s immune process that leads to platelet destruction in immune thrombocytopenia (ITP) and proposed red blood cell destruction in warm autoimmune hemolytic anemia (wAIHA). Fostamatinib is commercially available in the U.S. under the brand name TAVALISSE (fostamatinib disodium hexahydrate) tablets and is the first and only SYK inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic ITP who have had an insufficient response to a previous treatment. TAVALISSE is currently being investigated in a Phase 3 trial for the treatment of wAIHA, a rare, serious blood disorder for which there are no approved therapies.

Poster Presentation
Abstract #EP1625
Second-line Therapy for Immune Thrombocytopenia with the Spleen Tyrosine Kinase Inhibitor Fostamatinib
Presenter: Dr. Nichola Cooper
Session Topic: 32. Platelets Disorders

About ITP
In patients with ITP, the immune system attacks and destroys the body’s own blood platelets, which play an active role in blood clotting and healing. Common symptoms of ITP are excessive bruising and bleeding. People suffering with this disease may live with an increased risk of severe bleeding events that can result in serious medical complications or even death. Current therapies for ITP include steroids, blood platelet production boosters (TPO-RAs) and splenectomy. However, not all patients respond to existing therapies. As a result, there remains a significant medical need for additional treatment options for patients with ITP.

About AIHA
Autoimmune hemolytic anemia (AIHA) is a rare, serious blood disorder in which the immune system produces antibodies that result in the destruction of the body’s own red blood cells. AIHA affects approximately 45,000 adult patients in the U.S. and can be a severe, debilitating disease. To date, there are no disease-targeted therapies approved for AIHA, despite the unmet medical need that exists for these patients. Warm AIHA (wAIHA), the most common form of AIHA, is characterized by the presence of antibodies that react with the red blood cell surface at body temperature.

About TAVALISSE
Indication
TAVALISSE (fostamatinib disodium hexahydrate) tablets is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Important Safety Information
Warnings and Precautions

Hypertension can occur with TAVALISSE treatment. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects. Monitor blood pressure every 2 weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for blood pressure control maintenance during therapy. If increased blood pressure persists, TAVALISSE interruption, reduction, or discontinuation may be required.
Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE. Monitor LFTs monthly during treatment. If ALT or AST increase to >3 x upper limit of normal, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation.
Diarrhea occurred in 31% of patients and severe diarrhea occurred in 1% of patients treated with TAVALISSE. Monitor patients for the development of diarrhea and manage using supportive care measures early after the onset of symptoms. If diarrhea becomes severe (≥Grade 3), interrupt, reduce dose or discontinue TAVALISSE.
Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients. Monitor the ANC monthly and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction, or discontinuation.
TAVALISSE can cause fetal harm when administered to pregnant women. Advise pregnant women the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Verify pregnancy status prior to initiating TAVALISSE. It is unknown if TAVALISSE or its metabolite is present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during TAVALISSE treatment and for at least 1 month after the last dose.
Drug Interactions

Concomitant use of TAVALISSE with strong CYP3A4 inhibitors increases exposure to the major active metabolite of TAVALISSE (R406), which may increase the risk of adverse reactions. Monitor for toxicities that may require a reduction in TAVALISSE dose.
It is not recommended to use TAVALISSE with strong CYP3A4 inducers, as concomitant use reduces exposure to R406.
Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs and may require a dose reduction of the CYP3A4 substrate drug.
Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (eg, rosuvastatin) and P-Glycoprotein (P-gp) substrate drugs (eg, digoxin), which may require a dose reduction of the BCRP and P-gp substrate drug.
Adverse Reactions

Serious adverse drug reactions in the ITP double-blind studies were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which occurred in 1% of TAVALISSE patients. In addition, severe adverse reactions occurred including dyspnea and hypertension (both 2%), neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%).
Common adverse reactions (≥5% and more common than placebo) from FIT-1 and FIT-2 included: diarrhea, hypertension, nausea, dizziness, ALT and AST increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia.

On June 11, 2020 ImmuPharma PLC (LSE AIM: IMM – Euronext Growth: ALIMM), the specialist drug discovery and development company, reported that it has entered into agreements with two specialist US healthcare investors for a total investment of up to $6.30 million (£4.94 million) comprising an issue of unsecured convertible securities ("Securities") and associated options ("Options") (Press release, ImmuPharma, JUN 11, 2020, View Source [SID1234560987]).

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Highlights

ImmuPharma is to issue $3 million (£2.35 million) in face value of Securities to two US specialist healthcare investors, L1 Capital Global Opportunities Master Fund and Lind Global Macro Fund LP, managed by The Lind Partners, LLC ("the Investors") with a maturity period of 18 months.
At any time, during the maturity period, the Investors may convert their Securities (in whole or in part) to 13,086,619 ordinary shares in the Company, in aggregate, at a price of 17.96p ("Conversion Price") which is equivalent to 120% of the Volume Weighted Average Price ("VWAP") of the ordinary shares for 09 June 2020.
During the maturity period, the Company may require the investors to convert their securities to ordinary shares, if the VWAP on each of at least 20 consecutive trading days shall be equal to or have exceeded 35.92p (200% of the Conversion Price).
Should any securities remain unconverted on 10 December 2021 the Company will repurchase, from the Investors, the outstanding face value of the unconverted Securities.
In addition, the Investors have been granted 15,703,942 Options in the Company, which may be exercised at any time up to 3 years, with an exercise price the same as the Conversion Price, which, if all exercised, would amount to $3.60 million (£2.82 million).
The initial net proceeds of the Securities (after subscription and expenses) received by the Company of $2.39 million (£1.87 million) and any additional funds received of up to $3.60 million (£2.82 million), following exercise of the Options, will be used primarily to fund:
– Continued expansion of the Company’s R&D programmes; and
– General working capital

Commenting, ImmuPharma’s Chairman, Tim McCarthy, said:

"We are delighted to welcome L1 Capital Global Opportunities Master Fund and Lind Global Macro Fund LP as new investors into ImmuPharma. This is the first significant investment from specialist US healthcare funds and illustrates the attention we are now receiving from knowledgeable global investors. It particularly exemplifies the strengthened investment thesis of ImmuPharma, as we continue to strengthen and progress our recently expanded development pipeline to value inflexion points, including Lupuzor and the partnership with Avion Pharmaceuticals, as we prepare for the start of a new international optimised Phase III trial, in lupus patients".

On June 11, 2020 Avidity Biosciences, Inc. (Nasdaq:RNA), a biopharmaceutical company pioneering a new class of oligonucleotide-based therapies called Antibody Oligonucleotide Conjugates (AOCs), reported the pricing of its initial public offering of 14,400,000 shares of common stock at a public offering price of $18.00 per share (Press release, Avidity Biosciences, JUN 11, 2020, View Source [SID1234561004]). The shares are expected to begin trading on the Nasdaq Global Market on June 12, 2020 under the ticker symbol "RNA". All of the shares are being offered by Avidity. The gross proceeds from the offering, before deducting underwriting discounts and commissions and other offering expenses payable by Avidity, are expected to be $259.2 million. The offering is expected to close on June 16, 2020, subject to satisfaction of customary closing conditions. In addition, Avidity has granted the underwriters a 30-day option to purchase up to an additional 2,160,000 shares of common stock at the initial public offering price, less underwriting discounts and commissions.

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Cowen, SVB Leerink, Credit Suisse and Wells Fargo Securities are acting as joint book-running managers for the offering.

Registration statements relating to the offering have been filed with the Securities and Exchange Commission and became effective on June 11, 2020. The offering will be made only by means of a prospectus. Copies of the prospectus may be obtained from Cowen and Company LLC, c/o Broadridge Financial Solutions, Attention: Prospectus Department, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone at (833) 297-2926, or by email at [email protected]; or from SVB Leerink LLC, Attention: Syndicate Department, One Federal Street, 37th Floor, Boston, MA 02110, or by telephone at (800) 808-7525, ext. 6218, or by email at [email protected]; or from Credit Suisse Securities (USA) LLC, Attention: Prospectus Department, Eleven Madison Avenue, 3rd Floor, New York, NY 10010, or by telephone at (800) 221-1037, or by email at [email protected]; or from Wells Fargo Securities, LLC, Attention: Equity Syndicate Department, 500 West 33rd Street, New York, NY 10001, or by telephone at (800) 326-5897, or by email at [email protected].

On June 11, 2020 Kymera Therapeutics, Inc., a biotechnology company pioneering targeted protein degradation to invent breakthrough protein degrader medicines for patients, reported that it will present preclinical data on its potent and highly selective STAT3 degraders as well as the first data from its novel IRAKIMiD degraders combining IRAK4 and IMiD substrate degradation (Press release, Kymera Therapeutics, JUN 11, 2020, View Source [SID1234561020]). Data will be shared in two separate presentations (Abstracts #10165 and #4349, respectively) during the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II on Monday, June 22 at 9:00 AM EDT.

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STAT3 is an attractive but elusive target known to regulate genes implicated in oncogenesis, tumor immune evasion, inflammation and fibrosis. In cancer, STAT3 has been shown to drive tumor growth and promote an immunosuppressive tumor microenvironment (TME). Kymera has previously reported the ability of its highly selective STAT3 degraders to achieve tumor regression in mouse xenograft models of STAT3-dependent hematologic malignancies. The company will present preclinical data demonstrating that its STAT3 degraders downregulated immune checkpoint signals on tumor cells and positively modulated composition and activity of immune cells in the TME, leading to in vivo antitumor activity in a solid tumor model refractory compared to standard anti-PD-1/L1 immunotherapy. These findings demonstrate the potential for STAT3 degraders to drive antitumor responses through both tumor cell-intrinsic and -extrinsic immunomodulation as well as direct antitumor effects.

Kymera will also present the first data from its potent IRAKIMiD degraders in development for the treatment of MYD88-mutant lymphomas, which constitute approximately one quarter of all diffuse large B-cell lymphomas (DLBCL). IRAKIMiDs are novel heterobifunctional degraders that target degradation of both IRAK4 and IMiD substrates with a single small molecule. While IRAK4 degradation alone offers a viable therapeutic approach that we believe is superior to IRAK4 kinase inhibition, targeting two complementary pathways in lymphoma biology addresses potential tumor escape mechanisms and shows synergistic activity in MYD88-mutant lymphomas compared to IRAK4 degraders or IMiDs alone. In fact, IRAKIMiDs demonstrated improved cell death and breadth of activity relative to IMiDs or IRAK4-selective degraders, and drove strong in vivo tumor regressions in multiple models of MYD88-mutant B cell lymphoma that Kymera believes are superior to what has been observed in preclinical studies with other agents such as BTK inhibitors and IMiDs.

"Our STAT3 and IRAKIMiD programs exemplify the tremendous potential of targeted protein degradation in oncology, allowing us to inhibit well-validated, high impact disease pathways through targets like STAT3 previously considered undruggable, and through selective multi-targeting of IRAK4 and IMiD substrates with a single degrader," said Jared Gollob, MD, Chief Medical Officer. "The dual effects of STAT3 degraders on both tumor cells and the tumor microenvironment, as well as the dual effects of IRAKIMiDs on multiple pathways involved in tumor cell growth and survival in MYD88-mutant lymphomas, drive robust antitumor responses in preclinical models that support progression of both programs into the clinic in 2021."

AACR Study Highlights

ABSTRACT #10165 / POSTER #LB-088, "A STAT3 selective targeted protein degrader decreases the immune-suppressive tumor microenvironment and drives antitumor activity in preclinical models," presented by Fred Csibi, PhD, Associate Director, Oncology Biology at Kymera Therapeutics.

KTX-201 (formerly known as KYM-003) is a potent and highly selective STAT3 degrader with activity in immune and tumor cells.
Degradation of STAT3 with KTX-201 in both immune and tumor cells reversed expression of genes that contribute to immune suppression.
KTX-201 treatment resulted in reversal of immunosuppression in an in vitro non-small cell lung cancer model as well as antitumor activity in a mouse colorectal cancer model resistant to immune checkpoint inhibitors.
ABSTRACT #4349 / POSTER #5222, "Degraders targeting both IRAK4 and IMiD substrates show combinatorial effects leading to broader activity with durable and complete regressions in MYD88 mutant lymphoma xenografts in vivo," presented by Duncan H. Walker, PhD, VP of Oncology at Kymera Therapeutics.

IRAK4 degradation, but not IRAK4 kinase inhibition, showed additive and synergistic activity with IMiDs in vitro; IRAKIMiDs, which combine these activities in a single molecule, showed potent in vitro and in vivo activity.
Degradation of both IRAK4 and IMiD substrates correlated with in vitro cell growth inhibition, consistent with a requirement for both activities for cell death.
Regressions observed in xenograft models of MYD88-mutant lymphoma were associated with degradation of both IRAK4 and IMiD substrates, consistent with the dual-targeting activities of these molecules.

On June 11, 2020 University of Helsinki reported that 1,5 million euros funding supports a new investigator-initiated breast cancer clinical trial in Finland that takes on MYC (Press release, University of Helsinki, JUN 11, 2020, View Source [SID1234561087]).

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A Finnish Jane and Aatos Erkko Foundation awarded 1,5 million euros to support a VeMA clinical breast cancer study scheduled to start in HUS Comprehensive Cancer Center already this year. The clinical trial is among the first in the world having a biologic rationale rooted to MYC oncoprotein’s apoptosis promoting function.

The award is for a long-term translational collaboration project between breast cancer researchers at the University of Helsinki and clinicians in Helsinki University Hospital.

VeMA is an early phase investigator-initiated clinical trial in metastatic breast cancer setting, which tests the safety of a new combination treatment regimen that includes two targeted therapy agents combined with an immunotherapy agent anti-PD-L1. The study is expected to find the right dosage for further studies and biomarkers to guide patient selection with improved precision and to monitor treatment responses.

"We are truly excited to start VeMA in HUS, since the biologic rationale for the study comes from a research laboratory working next door. VeMA study is a beautiful example of translational research, that is a process where scientific discoveries made with cancer cells and animal models in a research laboratory serve as grounds for a clinical concept that will be tested in patients in the hospital," says the Principal clinical Investigator, Director and Chief Oncologist Johanna Mattson from HUS Comprehensive Cancer Center.

The study Co-Investigator, Research Director Juha Klefström from the University of Helsinki says that VeMA has been totally handcrafted as a local collaboration between the Medical Faculty and HUS Comprehensive Cancer Center.

"MYC oncoprotein drives abnormal pattern of cell proliferation in about half of the breast cancer cases. However, at the same time, MYC renders cells vulnerable to apoptotic cell death. The key question that has for a long time inspired our work is: can we somehow exploit this inherent apoptotic vulnerability of MYC expressing cancer cells in design of new therapies that would selectively kill cancer cell but leave normal cell unharmed? Now we are about to test this concept for the first time to help women suffering from breast cancer," he says.

Most clinical cancer trials are designed and funded by pharmaceutical industry. In the investigator-initiated trials, the researchers are allowed to design the trial by themselves but the main challenge is to find funding from public sources to support the study.

Thanks to the support of the Jane and Aatos Erkko Foundation, the VeMA study can now be launched as planned. Pharma has contributed to the study by donating the three drugs needed for the study for free.