On August 27, 2019 Inhibitor Therapeutics, Inc. (formerly known as HedgePath Pharmaceuticals, Inc.) (the "Company") entered into that certain Amended and Restated Sublicense Agreement, dated December 17, 2018 (the "Previous Sublicense Agreement"), between Mayne Pharma International Pty Ltd ("Mayne Pharma International") and the Company (Filing, 8-K, HedgePath Pharmaceuticals, AUG 27, 2019, View Source [SID1234539012]). Pursuant to the Previous Sublicense Agreement, Mayne Pharma International sublicensed to the Company the exclusive U.S. rights to two certain third party patents relating to the use of itraconazole as a treatment for cancer and age-related macular degeneration (the "Patents"). On August 21, 2019, the Company received written notice of termination of the Previous Sublicense Agreement due to the fact that the third party from whom Mayne Pharma was itself sublicensing the Patents had terminated such sublicense agreement.

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On August 27, 2019, the Company and Mayne Pharma International entered into a new Sublicense Agreement, effective August 20, 2019 (the "New Sublicense Agreement"), under which the Company received from Mayne Pharma International a sublicense to the Patents on nearly identical terms as the Previous Sublicense Agreement (including with respect to licensed field, the licensed indications and the license fees, milestone payments and minimum annual and running royalties that may be owed by the Company to Mayne Pharma International, as well as the terms related to patent prosecution and infringement, reporting and indemnification). Mayne Pharma International was able to enter into the New Sublicense Agreement because, subsequent to the termination of the Previous Sublicense Agreement, Mayne Pharma International entered into a direct license agreement with respect to the Patents with The Johns Hopkins University, the owner of the Patents.

The Patents consist of: (i) US Provisional Application No 60/583,076 entitled "New Angiogenesis Inhibitors", subsequently filed as PCT/US05/23015 on June 27, 2005 and (ii) US patent No 8,653,083 entitled "Hedgehog Pathway Antagonists to Treat Disease", filed on August 22, 2005, and subsequently filed as PCT/US2006/32952 on August 22, 2006, together with the inventions disclosed and claimed therein, and all continuations, divisions and reissued based thereof, and any patents issuing, granted or registered therefrom.

The New Sublicense Agreement has a term commencing on August 20, 2019 and continuing until the earlier of: (a) the date of expiration of the last to expire Patent; or (b) notice by Mayne Pharma International with immediate effect promptly after termination or expiry of its rights to license the Patents. Mayne Pharma International and the Company have the right to terminate the New Sublicense Agreement upon the occurrence of certain events, including the bankruptcy of a party or breach of a party’s obligations under the New Sublicense Agreement (subject to a notice and cure period). Mayne Pharma International may also terminate the New Sublicense Agreement upon the expiration or termination of that certain Third Amended and Restated Supply and License Agreement, dated December 17, 2018, between the Company and Mayne Pharma Ventures Pty Ltd, an affiliate of Mayne Pharma International.

On August 27, 2019 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" or the "Company"), a biopharmaceutical company focused on the development of novel cancer therapies, reported that the Company anticipates that its current cash position, which includes the $6.7 million in net proceeds from the underwritten offering completed August 16, 2019, will be sufficient to complete enrollment in all three patient groups of its two ongoing Phase 2 clinical trials for its lead compound, VAL-083, which the Company believes will occur by the fourth quarter of calendar year 2020 (Press release, DelMar Pharmaceuticals, AUG 27, 2019, View Source [SID1234539011]).

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"To date, we have had steady enrollment in our two Phase 2 trials, and believe that with the additional capital from our recent financing, we will be in the position to complete enrollment of our Phase 2 clinical trial in China for first-line treatment with radiation for newly diagnosed MGMT-unmethylated GBM patients, as well as both arms of our Phase 2 trial with MD Anderson Cancer Center (MDACC) – one for patients with recurrent disease and one for newly diagnosed patients who have undergone chemoradiation with temozolomide, but will now receive VAL-083 as adjuvant therapy," commented Saiid Zarrabian, president and CEO of DelMar. "We believe the complete enrollment of both of these trials is an important inflection point for the Company and we are grateful to now have the capital to reach that milestone. In the meantime, we expect to provide updates on one or more of these open-label Phase 2 GBM trials at the Society of Neuro-Oncology meeting November 20-24, the American Academy of Cancer Research in April 2020 and the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in May 2020."

The Company’s Phase 2 trial in China is a single-arm, open-label study testing VAL-083 in combination with standard radiotherapy in GBM patients who have an unmethylated promoter of the methylguanine DNA-methyltransferase (MGMT) gene. The clinical trial in newly-diagnosed GBM patients is designed to determine if first-line treatment with VAL-083 plus radiotherapy can provide improvements over the historical efficacy of standard of care temozolomide (TMZ) plus radiotherapy. Efficacy will be measured based on tumor response to treatment, progression-free survival, progression-free survival at six months, and overall survival compared to historical results in the target population. To date, the Company has enrolled 20 of the 30 patients required for the trial, with positive early results previously reported.

The Company is also conducting a Phase 2 trial with MDACC with one arm treating patients with recurrent disease, administering VAL-083 in patients who have been heavily pre-treated with TMZ prior to disease recurrence. The recurrent arm will allow a total of 83 patients to be enrolled. The second trial arm will enroll up to 24 newly-diagnosed patients who have undergone surgery and chemoradiation with TMZ but will now receive VAL-083 in place of standard of care TMZ for adjuvant therapy. The Company will provide enrollment and treatment updates as appropriate.

About VAL-083

VAL-083 (dianhydrogalactitol) is a "first-in-class", bifunctional, DNA-targeting agent that introduces inter-strand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers, including GBM and ovarian cancer in historical clinical trials sponsored by the U.S. National Cancer Institute (NCI). DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by common mechanisms of chemoresistance, including MGMT, in cancer cell models and animal studies. Further details regarding these studies can be found at:

View Source

On August 27, 2019 Arvinas, Inc. (Nasdaq: ARVN), a biotechnology company creating a new class of drugs based on targeted protein degradation, reported the initiation of patient dosing in its second clinical program (Press release, Arvinas, AUG 27, 2019, View Source [SID1234539006]). The Phase 1 clinical trial of ARV-471, an oral estrogen receptor (ER)-targeting PROTAC protein degrader, will evaluate the safety, tolerability, and pharmacokinetics of ARV-471 in patients with locally advanced or metastatic ER positive / HER2 negative breast cancer. Arvinas anticipates preliminary data from the trial in 2020.

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"ARV-471 is a potent ER degrader that has demonstrated significant anti-tumor activity in preclinical models, and we are hopeful it will address an important need for patients with advanced ER positive breast cancer not adequately treated with current standards of care," said Ronald Peck, M.D., Chief Medical Officer of Arvinas. "ARV-471 is Arvinas’ second targeted protein degrader to enter the clinic, making this another exciting and significant development for our company and the field."

The Phase 1 clinical trial will assess the safety, tolerability, and pharmacokinetics of ARV-471 and will include measures of its pharmacodynamic and anti-tumor activity as secondary endpoints. In preclinical studies, orally administered ARV-471 demonstrated improved in vivo ER degradation potency and anti-tumor activity both as a monotherapy and in combination with a CDK4/6 inhibitor, as compared to current standard of care treatment regimens. In future trials, the company plans to investigate ARV-471 for use as both a single agent and in combination with other modalities, such as CDK 4/6 inhibitors. Additional information on this clinical trial can be found on www.clinicaltrials.gov.

About locally advanced or metastatic ER positive / HER2 negative breast cancer
In the United States, breast cancer is the second most common cancer and the second leading cause of cancer death in women. The American Cancer Society estimates that there will be approximately 268,000 women diagnosed with invasive breast cancer in the U.S. in 2019. Metastatic breast cancer accounts for approximately 6% of newly diagnosed cases. Approximately 80% of newly diagnosed breast cancers are ER+, with many patients developing resistance to current treatment options over time.

Women with locally advanced or metastatic breast cancer are treated with systemic therapies, including hormone therapy, chemotherapy, and targeted therapy, either as single agents or in combination. Women with metastatic or recurrent ER positive breast cancer are often treated with hormone therapy, such as tamoxifen, an aromatase inhibitor, or fulvestrant, alone or in combination with targeted drugs such as CDK 4/6 inhibitors. In patients with aggressive disease or whose disease continues to progress with hormonal treatment regimens, chemotherapy may be prescribed.

A current standard of care for women with ER positive locally advanced or metastatic breast cancer is fulvestrant, which is administered as a monthly intramuscular injection, either as a single-agent or in combination with another targeted therapy. While fulvestrant has validated the importance of ER degradation as a therapeutic intervention, up to 50% of ER can remain when compared to baseline levels after six months of treatment with fulvestrant.

About ARV-471
ARV-471 is a PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER). Arvinas’ Phase 1 trial of ARV-471 will assess its safety, tolerability, and pharmacokinetics, and will also include measures of anti-tumor activity and pharmacodynamic readouts as secondary endpoints.

In preclinical studies, ARV-471 demonstrated near-complete ER degradation in tumor cells, induced robust tumor shrinkage when dosed as a single agent in multiple ER-driven xenograft models, and showed superior anti-tumor activity as a single agent and in combination with a CDK4/6 inhibitor when compared to a standard of care agent, fulvestrant (as a single agent and in combination with a CDK4/6 inhibitor). Arvinas believes the differentiated pharmacology of ARV-471, including its iterative degradation activity, has the potential to translate into meaningful clinical benefit for patients.

On August 26, 2019 Oncoceutics, Inc. reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s Investigational New Drug (IND) application for ONC206, allowing the first-in-human trial of the compound (Press release, Oncoceutics, AUG 26, 2019, View Source [SID1234558333]). ONC206 is the first of the family of drug candidates, which we call "imipridones", that possess the same core chemical structure as ONC201.

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The first clinical trial for ONC206 in adults with primary central nervous system neoplasms will be conducted at the National Cancer Institute (NCI) under the leadership of Mark Gilbert, MD, Chief of the Neuro-Oncology Branch, Center for Cancer Research (CCR) and Brett Theeler, MD, Clinical Collaborator at the NCI Neuro-Oncology Branch, CCR.

Dr. Gilbert has previously demonstrated that ONC206 exerts therapeutic effects in preclinical models for neuro-oncology indications that are commonly recognized as refractory to standard of care. ONC206 has been studied extensively by several other research groups and showed antitumor activity in different tumor types. Preclinical studies suggest that the properties of ONC206 include penetrance of the blood brain barrier, feasibility of oral administration, demonstration of a well-tolerated safety profile, and selective antagonization of dopamine receptor D2 (DRD2). While DRD2 is targeted by both ONC206 and ONC201, the receptor pharmacology of ONC206 is unique and distinct, which may offer therapeutic options beyond those of ONC201. ONC206 was very well tolerated in GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses that did not reveal any dose-limiting toxicities.

ONC206 is protected by issued composition of matter patents in the USA and Europe.

"We are pleased by the FDA’s acceptance of our IND application for ONC206 that provides further validation of our overall development program," said Martin Stogniew, PhD, Chief Development Officer of Oncoceutics. "The introduction of another imipridone into clinical trials represents a major milestone for the company and demonstrates the therapeutic value of the new class of imipridone compounds.

"DRD2 has emerged as a viable novel target in neuro-oncology and controls diverse signaling pathways. However, druggable ligands to target DRD2 have remained elusive. We are encouraged to see the different biological effects exerted by ONC201 and ONC206 via dopamine receptor activated pathways, including their synergistic cooperation that clearly demonstrates the multi-functionality of this G protein-coupled receptor. The common features of both compounds that include high penetrance of the blood brain barrier, convenient oral administration and excellent tolerability is rewarding for our patients, in particular children," said Sabine Mueller, MD, PhD, Head of Clinical Programs, DIPG Center of Expertise Zurich and Adjunct Associate Professor, University of California, San Francisco.

"We plan to evaluate the safety and clinical activity of ONC206 in patients with central nervous system malignancies," said Dr. Gilbert. "This clinical trial will incorporate biomarker information derived from our molecular studies of ONC206 in an effort to enable future patient selection."

On August 26, 2019 (the "Effective Date"), Alpine Immune Sciences, Inc. (the "Company") and its wholly-owned subsidiary, AIS Operating Co., Inc. ("AIS" and together with the Company, the "Borrowers"), reported that it has entered into an Amended and Restated Loan and Security Agreement (the "Loan Agreement") with Silicon Valley Bank (the "Bank"), pursuant to which the Bank agreed to extend term loans to the Company with an aggregate principal amount of up to $15.0 million (the "Term Loans") (Filing, 8-K, Alpine Immune Sciences, AUG 26, 2019, View Source [SID1234551115]). The Company intends to use the proceeds to replace and refinance AIS’ existing loan facility pursuant to the Loan and Security Agreement by and between AIS and the Bank dated as of December 16, 2016 (the "Original Agreement"), as well as for potential working capital and other general corporate purposes, including the advancement of the Company’s development programs.

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Borrowings under the Loan Agreement will consist of up to three separate tranches. The initial tranche of $5.0 million was funded on August 26, 2019, $3.0 million of which will be used to repay amounts owing under the Original Agreement. The second tranche of up to $5.0 million is available in multiple advances at the Borrowers’ option at any time through April 30, 2020. The third and final tranche of up to $5.0 million is available in multiple advances at the Borrowers’ option at any time from the date on which Bank receives and approves evidence that the Borrowers have initiated a Phase 2a trial of ALPN-101 in psoriatic arthritis through July 31, 2020. Each term loan advance, other than the final term loan advance, must be in an amount of not less than $0.5 million and, after repayment, no term loan advance may be re-borrowed.

The Term Loans shall accrue interest at a floating per annum rate of 0.25% above the prime rate, subject to a floor of 5.75%, which interest is payable monthly commencing in September 2019. Upon the occurrence and during the continuance of an event of default, a default interest rate will apply that is 4.0% above the otherwise applicable interest rate. The Term Loans are interest only until September 30, 2020, after which the Term Loans will be payable in 34 equal monthly installments of principal plus interest, with the final installment due and payable on July 1, 2023. If Borrowers receive aggregate net new capital of at least $40 million on or prior to June 30, 2020, the Term Loans will be interest-only until June 30, 2021, after which the Term Loans will be payable in 25 equal monthly installments of principal plus interest, with the final installment due and payable on July 1, 2023.
The Borrowers may prepay all, but not less than all, of the Term Loans subject to a prepayment fee equal to $75,000, which represents the deferred portion of the final payment due under the Original Agreement, plus the outstanding principal balance under the Term Loans at the time of such prepayment multiplied by (i) 2.0%, if the prepayment occurs on or prior to the first anniversary of the Effective Date, (ii) 1.0%, if the prepayment occurs after the first anniversary of the Effective Date, but on or prior to the second anniversary of the Effective Date or (iii) 0%, if the prepayment occurs after the second anniversary of the Effective Date, but prior to the maturity date for the Term Loan. A fee in the amount of 5.5% of the Term Loans funded is payable to the Bank on the date on which the Term Loans are prepaid, paid or become due and payable in full.
The Loan Agreement contains customary representations and warranties, events of default (including an event of default upon a material adverse change of the Borrowers) and affirmative and negative covenants, including, among others, covenants that limit or restrict the Borrowers’ ability to, among other things, incur additional indebtedness, grant liens, merge or consolidate, make acquisitions, pay dividends or other distributions or repurchase equity, make investments, dispose of assets, engage in any new line of business, and enter into certain transactions with affiliates, in each case subject to certain exceptions. As security for its obligations under the Loan Agreement, the Borrowers granted the Bank a first priority security interest on substantially all of Borrowers’ assets, except intellectual property, and subject to certain other exceptions.
The foregoing description of the Loan Agreement is not complete and is qualified in its entirety by reference to the full text of the Loan Agreement, a copy of which is filed as Exhibit 10.1 to this Current Report on Form 8-K and is incorporated by reference herein.